Delirium, The Geriatrics Ward Challenge

Delirium or acute confusion state is a medical emergency, characterized by altered mental status with fluctuating deficits in attention and cognition. It’s an important cause of morbidity and mortality. Even though most of the causes are secondary to medical conditions and after they are solved, the delirium disappear, there are cases that it can persist for weeks and months. Many risk factors are known, such as polypharmacy, restraint use, multiple illness, frailty, advanced age. Instruments like CAM (Confusion Assessment Method) can be useful to diagnose and nonpharmacological measures with low-dose antipsychotic drugs can be helpful in its resolution.


INTRODUCTION
Diagnosing delirium is a herculean task. Delirium is a non-benign clinical condition 1 with acute brain dysfunction 1-3 that is characterized by acute changes, in hours or weeks, in both attention and cognition. Diagnosis is made with clinical data, regarding to 4 criteriaacute onset and fluctuating course, inattention and change in the level of consciousness or disorganized thinking [1][2][3][4][5][6][7][8][9][10][11][12][13] . These criteria are included in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition  and in the International Statistical Classification of Diseases and Related Health Problems, 10 th Revision (ICD 10). From its first description in 1980, the importance of attention has risen, being the most important criteria 7,10,11,13 . Many terms have emerged to describe delirium -"acute confusional state", "acute brain syndrome", "acute cerebral insufficiency" and "toxic-metabolic encephalopathy" 11 . In 2004, it costed 2500 dollars per patient per hospitalization, increasing the indirect costs due to home health care, rehabilitation services and informal caregiving 11,13 Already in 2011, it costed over 164 billion of dollars in the USA and over 182 billion dollars in 18 European countries 10 . Due to ethics, delirium may affect people's ability to consent, communicate or complete interviews 12,13 .

Forms
Despite first being described over 2500 years ago, delirium remains frequently unrecognized and poorly understood 10,13 .
It's described two major psychomotor forms of deliriumhyperactive and hypoactive, that can be intermittent and be both present in the same patient in different evaluation times. Each one has different characteristics and consequently different prognoses 4,10,11,12 . The hyperactive is more frequently found in acute alcohol withdrawal and the hypoactive in older patients and generally associated with a worse prognosis 10,12 . Restlessness, irritability, agitation, combat is common in hyperactive delirium, and one the other side symptoms like lethargy, decreased learning, reduced mobility and social activity and increased sleep are present mainly in hypoactive delirium 6 . The earlier the prevention and the treatment are activated, the better are the prognosis 9 .

Screening and Diagnosis
Screening

Risk Groups
Delirium can affect both young and elder, being high risk groups. The first one because the brain networks are underdeveloped and the last because of the cumulate damage in the same network 10 .

Pathogenesis
The real pathogenic mechanisms are not well understood, but several of them were proposed, such as neurotransmitter imbalance with acetylcholine deficiency and dopamine excess, reduced cerebral blood flow and metabolism, dysregulation of stress response and the sleep-wake cycle and finally inflammation (due to infectious and non-infectious stimulus) 1,5,9,10,11 .
Histologically are found changes like apoptosis, activation of microglia and astrocytes 1,8,9,10 . The development of delirium involves the complex interrelationship between a vulnerable patient with multiple predisposing factors (including its genetics) and exposure to noxious insults or precipitating factors. In patients, very vulnerable with underlying dementia and multimorbid, the tiniest and benign insult can precipitate delirium 10,11 .
Even though there are many theories, the final common pathway is still unknown 10 .

Mediators
Mediators like cytokines (IL1, Il6 and TNFα) 1,3 and prostaglandins are pointed. Creactive protein (CRP) was also studied but it is not consensual. Some studies showed the elevation of IL6 and IL8 in older patients that developed delirium and with patients with schizophrenia 1,9 . Other markers were also pointed such as s100B (calcium-binding protein B), IL1β 3,9 , and TNF receptors serum levels, the last two independent of on course sepsis 3 . Insulin-like growth factor (IGF)-1, IL1β and IL1 receptor antagonist (RA), interferon (IFN) γ have been also associated with delirium. Literature point that low levels of IGF1 were associated with the delirium severity 9 .

Etiology
The etiology is commonly multifactorial 8,9,10,11,13 organic and most of them modifiable 5,6,8,9 . On the other hand, there are no modifiable risk factors like dementia and cognitive impairment, advanced age, history of previous delirium, stroke, neurological disease, falls or gait disorder, multiple comorbidities, male sex, chronic or hepatic disease 11 .
The are some risk factors and conditions such advanced age (≥ 60 years old) alcohol dependence/abuse 10,11 and depression 10 .
Infection is the common cause of infection in the elderly, especially the ones located on the urinary tract 4 . Most of the causes of delirium need medical hospitalization and that's the main reason that it's more frequent in hospitals and medical facilities 12,13 .

History and Physical Examination
A good clinical history may be essential. Obtaining it from an informed observer (e.g. family member, caregiver or staff member) and performing a brief cognitive assessment may simply the diagnosis work-up. This is fundamental because it allows to establish the patient's baseline 9,10 . The physical examination of the delirious patient should be a comprehensive effort to find clues as to the cause of delirium. Commitment to a systematic and through examination may provide a key piece of data to aid rapid diagnosis. Examination begins with the vital signs, which can be critical for determine the underlying cause 12 .

Non-Analytical
Neuroimaging: Some neuroimage studies have been made and changes like brain atrophy 9 impaired total and regional perfusion 10 and ventricular dilatation and white matter lesions 11 were found. Magnetic Resonance Imaging (MRI) or computed tomography (CT) scans are recommended for acute neurological findings, history of or signs of recent fall or head trauma, fever with suspicion of encephalitis or decreased level of consciousness with no identified etiology. Patients with delirium can have normal CT scan in almost 98%. Lumbar puncture can be also useful when the delirium is persistent or no etiology has been pointed 10 MRI may be used to study the integrity of blood-brain barrier and its role in the development of delirium. New studies with PET and SPECT imaging have been made to study cholinergic receptors and dopaminergic activity 11 . Even so more studies need to be made, because the ones available are limited for small samples sizes, inadequate control groups and lack of baseline scans prior to delirium 9,10 .

Electroencephalogram (EEG)
EEG has limited sensivity and specificity in the diagnosis of delirium, however it is the result of a characteristic pattern of diffuse slowing with increased theta and delta activity and poor organization of background rhythm that correlates with its severity. It can be useful to differentiate organic etiologies from functional or psychiatric disorders in difficult-to-assess patients, to evaluate deteriorating mental status in patients with dementia and to identify occult seizures. Quantitative and spectral EEG can be useful but need further investigation 10 .

Delirium and Dementia
Delirium serves multiple roles: it is a marker of vulnerability, unmasks unrecognized dementia, mediates the effects of noxious insults and itself leads to permanent neuronal damage and dementia 9 .
Dementia is a chronic and progressive neurodegenerative condition, that evolves in months or years leading to deficits in the domains of cognition, decline in the functionality and with neuropsychiatric symptoms. It can be a delirium cause and its evolution may be enhanced by it 1,8,9 . In the clinical practice, sometimes it's difficult to distinguish between delirium and dementia 1,4,[7][8][9][10][11] and they may be shows that the presence of delirium in patients with dementia leads to bad prognosis and accelerate the trajectory of cognitive decline with patients not returning to their premorbid baseline once the acute delirium resolves 8,[9][10][11] leading to persistent and cognitive losses 10,11 . It is an independent risk factor for dementia 9 .
Dementia rises the risk of delirium in 2-5fold 10 .

Prevention and Treatment
The treatment of delirium requires a multicomponent strategy aimed at both optimizing preventative measures in addition to pharmacologic management 6,10-12 . It is preventable in about 30-40% of the cases 9-11 . It is undetected in 33-66% 13 . The principal aims in the prevention and treatment of delirium is to identify the causes optimizing the environment to lessen confusion and associated distress 8,10 . The patient safety is important, but also the active search for causes and symptom control 10 . There are better results when the family and the patient are involved in care, particularly for reorientation and prevention of self-harm 10,12 . The major outcomes in the management of delirium is to focus on treatments that enhance recovery, maximize functional status and improve clinical outcomes 10 .

Non-Pharmacological Measures
Due to delirium prevention, nonpharmacological strategies are the mainstay 4 11,12,16 . Most of these multicomponent interventions have good evidence in the hospital population but lack of evidence in the patients with dementia and delirium in the community 8 .

Pharmacological Approach
The pharmacological approach is reserved to patients with severe agitation 10,12 . Targeted pharmacological approaches are usually aimed at symptom reduction in the most severe cases but some studies point that they may have little impact altering the course of delirium and in some cases, may also aggravate the confusion 8 . The current on pharmacological agents are much more controversial and debatable 5 . Antipsychotic medication, in low dose, is commonly used to treat patients with delirium. A review showed that all atypical antipsychotic medications demonstrate similar rates of efficacy, but haloperidol has lower rates of extrapyramidal adverse rates and no higher mortality 4,5,6,11,12 . Another secondary effect is prolonged QT interval on the electrocardiogram 6,11 . Dealing with that secondary effects, they may be reduced by lowering the dose or discontinuing the medication. The most acceptable initial dose for haloperidol is 2 mg orally, intramuscular or intravenous. It is possible to repeat every 15-20 minutes. The dose may be doubled if the agitation is very severe in the ICU.
Regarding to the ward the dose is lower with 1 to 2 mg, with increasing of 0.25-0.5 mg every 4 hours according to the patient tolerance 6 Other drugs may be used such as olanzapine 2,5 to 5 mg once per day, risperidone 0.5 mg orally twice per day, ziprasidone 2 mg to 5 mg intramuscular. They must be closely monitored and their use should be temporary and therefore must be reduced when symptoms are solved. The is no clear benefit for managing presumed delirium with these drugs unless severe behavioral or psychiatric symptoms are present. Terminal delirium is considered irreversible and its management involve palliative care and the use of drugs like benzodiazepines, also useful in delirium due to alcohol and benzodiazepines withdrawal 4,6,11,12 In the hypoactive delirium drugs like benzodiazepines are not recommended 4 .
Quetiapine is an alternative to haloperidol and is one of the drugs of election used for treating delirium in the ICU, acting in many receptors such as 5HTA1, 5HT2, D1, D2, α1, α2 and histamine H1 receptors 2 .
Cholinesterase inhibitors have shown no benefit in preventing the postoperative delirium. Other drugs like gabapentin, trazodone and dexmedetomidine are being investigated 11 .
Because there is no certified scale to evaluate hypoactive delirium, the installation of antipsychotic drugs must careful, because hyperactive delirium can turn into hypoactive, with poor outcomes 10 .

Delirium in Different Scenarios
Delirium in the post-operative: Dealing with the post-operative scenario its incidence ranges from 9% to 87% depending on the population and the degree of operative stress 6 , it can be present in the first two days after surgery 11 and it can be present until 1 year after the surgery 10 . In the hospital scenario, it's overall prevalence is 15% to 50%, although may be higher specially in patients undergoing major surgical procedures 8,9,11 .
Delirium outside the hospital: When talking in post-acute care (PAC) and longterm care (LTC), delirium is very frequent in the elder (18%) 4,11 . Its development is more insidious and subtle in presentation, despite systemic screening tools. LTC patients are 10 times more likely to have delirium than the ones that are not in LTC settings. Attention that the presence of residual subsyndromal delirium at the time of hospital discharge also predicts adverse outcomes 4,12 . The symptoms may persist weeks of months after its initial recognition 4,5 .
Delirium in the ICU: Patients who develop delirium in the ICU are 2-4-fold increased risk of death both in and out of the hospital, those who develop delirium on general medical or geriatric wards are at 1,5-fold increased risk for death in the year following hospitalization and patients with delirium in the emergency department have approximately 70% increased risk of death during the first six months after the visit 10,11 .

Emergency Department
On the presentation to the emergency department, delirium is present in 8-17% of all seniors and 40% of nursing home residents 10 . Community: Delirium in the community is just 1% to 2% 11 .

Prognosis
Delirium is consistently associated with an increased mortality rate across all nonsurgical patient populations, including general medical, geriatric, intensive care unit (ICU), stroke, dementia, nursing home and emergency department 10 . Patients with delirium have longer hospital stays and longer 6-month survival than do patients without delirium 2,7,8,10 .
If the treatment is successful in the ICU scenario, it may decrease morbidity, the number of sedative agents used, length of ventilator days and associated complications 2 Studies show a mortality of 40% with 1-2 days of delirium, which rose to 70% if delirium persisted for more than 5 days, in the ICU. The longer the delirium, higher is the mortality rate 3,5,10,11 . When the delirium resolves, the prognosis improves 3 .

Complications Related to Delirium
At least 20% of the 12,5 million patients over 65 years of age hospitalized each year in the US experience complications during hospitalization because of delirium 11 .
Delirium makes the hospital stay longer, increases immobility leading to delayed admission to rehabilitation programs, leads to autonomy persistent cognitive deficits, enhances health cost 5-9,12 promotes harmful behaviors like falls, pulled lines or tubes, aspiration pneumonia and respiratory compromise 6,9 decreases oral intake with dehydration and malnutrition and also increases the incidence of pressure ulcers, urinary tract infections, deep venous thrombosis and pulmonary emboli 9,11 .

CONCLUSION
Nowadays it remains difficult the diagnosis of delirium because its many presentations. Consequently, it remains underdiagnosed and sub treated in the most different patient scenariosward, ICU, PLC, community.