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LITHUANIAN UNIVERISTY OF HEALTH SCIENCES

FACULTY OF NURSING

Department of Geriatrics

Title of master thesis

The risk factors of delirium in older patients hospitalized in geriatric

units

Submitted in partial fulfillment of the requirements for the degree of Master

of Medicine

Author:

Firas Jaly

Supervisor:

Prof. dr. Jurate Macijauskiene

June 2019

Kaunas, Lithuania

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SUMMARY 3

ACKNOWLEDGEMENTS 4

CONFLICT OF INTEREST 4

ABBREVIATIONS 5

INTRODUCTION 6

AIM 8

OBJECTIVES 8

LITERATURE REVIEW 9

NON-MODIFIABLE RISK FACTORS 10

DEMENTIA AND COGNITIVE IMPAIRMENT 10

ADVANCING AGE 11

FRAILTY 12

MALE SEX 12

CHRONIC RENAL OR HEPATIC DISEASE 13

POTENTIALLY MODIFIABLE RISK FACTORS 14

SENSORY IMPAIRMENT 14

URINARY CATHETERIZATION 15

POLYPHARMACY 15

PHYSICAL RESTRAINT 19

ENVIRONMENT 19

INFECTION 20

SURGERY 21

OTHER ASSOCIATED RISK FACTORS 24

SOCIODEMOGRAPHIC AND EDUCATION 24

METHODOLOGY 26

DISCUSSION 28

FINDINGS AND THEIR SIGNIFICANCE: 28

STRENGTHS AND LIMITATIONS OF THIS REVIEW: 30

IMPLICATION FOR FUTURE RESEARCH: 31

IMPLICATION FOR CLINICAL PRACTICE: 31

CONCLUSIONS 33

REFERENCES 35

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SUMMARY

Author – Firas Jaly

Scientific Supervisor – prof. Jurate Macijauskiene

Research title – The risk factors of delirium in older patients hospitalized in geriatric units

Aim – To determine the most important risk factors for delirium in older patients hospitalized in

geriatric units.

Objecives: 1) To assess and evaluate the most common risk factors of delirium among elderly

hospitalized patients by systematically analyzing the literature. 2) To find correlations between patient

clinical and sociodemographic variables and the importance of these risk factors. 3) To find the rates

at which these risk factors precipitate delirium, and therefore determine their significance. 4) To

demonstrate that improved clinical practices can help to decrease the incidence of delirium in older

hospitalized patients.

Methodology. This was a Systematic Literature review where research was conducted using different

databases (PubMed, UpToDate, BMJ, ResearchGate etc.). Articles from the year 1995 onwards (with

well over 70 % of cited papers published in the last 10 years) were chosen with keywords such as

“delirium”, “acute confusional state”, “dementia”, “transitory neurological deficit” were first used.

These were then cross searched with terms such as “risk factors”, “common causes”, “in elderly”, “old

age”, “geriatric patients”, “geriatric department”, “prevalence “and finally “incidence”. Articles which

filled these criteria were chosen for this review.

Results. Delirium is a common and serious condition which affects a high proportion of the

hospitalized elderly population. Studies estimate that 11% to 25% of older patients will have delirium

upon admission, with a further 29% to 31% of those initially admitted without delirium developing it

during hospitalization. The most significant risk factor for delirium ion older patients was dementia,

followed by surgery. Other significant risk factors identified were polypharmacy, IUC, male sex,

sensory impairment, environment, along with education and socioeconomic factors, physical restraint

and infection.

Conclusions. Significant risk factors in this systematic literature review were age, male sex, dementia,

underlying renal and hepatic dysfunction, polypharmacy, urinary catheterization, infection, sensory

impairment, physical restraint, and surgery. Education and socioeconomic background were also found

to contribute to the development of delirium. Early recognition of the potentially modifiable risks and

multicomponent interventional pathways can undoubtedly decrease the incidence of delirium.

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ACKNOWLEDGEMENTS

I would like to express my deepest appreciation to Dr Jurate Macijauskiene for her

guidance who enabled me through my final year project

CONFLICT OF INTEREST

The author reports no conflicts of interest

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ABBREVIATIONS

ADL’s- Activities of daily living

ADR’s- Adverse drug reactions

ASA- American society of anesthesiologists

BBB- Blood brain barrier

DAP’s- Drugs with anticholinergic properties

ICU- Intensive care unit

IUC- Indwelling urinary catheter

OR- Operation room

RF’s- Risk factors

SES- Socioeconomic status

SIRS-Systematic Inflammatory response syndrome

UTI’s- Urinary tract infections

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INTRODUCTION

Delirium sometimes referred to as acute confusional state is a disorder characterized by acute changes

in mental status and alterations of consciousness with one of its defining features being its fluctuating

course [1]. Delirium is a common, serious and often-unrecognized complication of age related chronic

and acute conditions. The diagnosis of delirium is considered a medical emergency and is often

complicated by the lack of early recognition of its risk factors and presenting symptoms by clinicians.

As many as one third of older medical patients experience delirium at as some stage during

hospitalization. Studies have shown that among geriatric surgical patients, the risk for delirium varies

from 15% to 53%, whilst delirium was recorded in 50% to 80% of those requiring intensive care [2].

Most cases of delirium are diagnosed or develop during hospitalization, with higher incidences found

with increasing age. Prevalence of delirium in therapeutic wards is high. According to the literature,

11% to 25% of older patients will have delirium upon admission (prevalent delirium). A further 29%

to 31% of those initially admitted without delirium will develop it during their hospital stay (incident

delirium) [2]. Past studies have recorded the prevalence of delirium in the Intensive care unit (ICU) at

a rate of 11% and 87%, also demonstrating that the risk is particularly higher in elderly patients with

pre-existing cognitive impairments [3].

Patients who develop delirium are at an increased risk for adverse medical outcomes. Studies have

associated delirium with a 3 to 5 times increased risk of nosocomial infections and a tenfold increased

risk of in hospital mortality [4]. Delirium is a major cause of prolonged hospital stay and poor physical

recovery and patients who develop it are posed to a significantly increased risk of developing other

neurological diseases, such as dementia, further down the line [4]. After hip fracture surgery in patients

>60 years of age delirium was the most commonly seen complication (19%), this study further

concluded that delirium was one of only two independent risk factors for mortality [5]. The strong

association between delirium and morbidity, mortality and increased health care costs have of late led

to the its more formal classification as a target organ injury in critical care contexts [6].

As with most diseases seen in the geriatric department delirium is a multifactorial disorder. Risk

factors for delirium are numerous and varied and include underlying neurological diseases such as

dementia, stroke or Parkinson’ disease [7]. Other precipitating factors include infection,

overmedication (or polypharmacy), dehydration and the use of urinary catheters. Multivariate analysis

of variables affirmed that old age (>75), diabetes, and ASA classification (> 2 level) were independent

risk factors of post-operative delirium [8]. Despite its high incidence the heterogeneity in its

presentation and in part due to its multifactorial nature delirium is often under diagnosed or all together

misdiagnosed.

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Early identification of these risk factor is pivotal to the prevention and treatment of delirium. Studies

estimate that around 30%-40% of cases are preventable, with prevention shown to be the most

effective strategy in curtailing the incidence of delirium in hospitalized patients [4]. Many iatrogenic

causes have been attributed to the development of delirium and are therefore avoidable. One study

estimated that failure of delirium recognition by physicians occurred at a rate of up to 70% [9]. When

stringent protocols on delirium evaluation, prevention and treatment have been applied remarkably

better outcome have been seen. Multicomponent non-pharmacological interventions have been used to

“both prevent the development and mitigate the complications of inpatient delirium” [10]. Application

of this pathway on one neurology ward was not associated with a decrease in the number of patients

developing delirium, however it was associated with a reduction in length of stay among delirious

patients [10]. Knowledge of potential risk factors is important and can guide clinicians in the diagnosis

and assessment of those in danger of developing delirium and substantially improve their prognosis.

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AIM

To determine the most important risk factors for delirium in elderly patients hospitalized in

geriatric units.

OBJECTIVES

1. To assess and evaluate the most common risk factors of delirium among elderly hospitalized

patients by systematically analyzing the literature.

2. To find correlations between patient clinical and sociodemographic variables and the

importance of these risk factors.

3. To find the rates at which these risk factors precipitate delirium, and therefore determine their

significance

4. To demonstrate that improved clinical practices can help to decrease the incidence of delirium

in older hospitalized patients.

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LITERATURE REVIEW

Development of delirium in geriatric patients is attributed to a series of complex interactions

of numerous risk factors [7]. These risk factors are broadly grouped into modifiable (sometimes

referred to as potentially modifiable) and non-modifiable risk factors [7]. Modifiable risk factors are

behaviors or exposures that can increase a person’s probability of developing a disease, they are

modifiable as in principle they can be changed. In contrast non modifiable risk factors are those which

are non-adjustable and cannot be varied regardless of actions undertaken.

Table 1

[7] Modifiable and nonmodifiable risk factors of delirium

(Fong TG, Tulebaev SR, Inouye SK)

Risk factors are further divided into predisposing (vulnerability) and precipitating (acute insults) for

delirium in hospitalized older patients. [11]. While a single cause can cause delirium, more frequently

it is polyfactorial in origin. [12] The multifactorial model for the development of delirium has been

well-established and universally recognized [13]. The occurrence of delirium involves numerous inter-

relationships between “vulnerable patients with multiple predisposing factors and exposure to noxious

insults or precipitating factors. Thus, in patients who are highly vulnerable to delirium, such as those

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with underlying dementia and multimorbidity, a relatively benign insult--such as a single dose of

sleeping medication--may be enough to precipitate delirium” [12]. The opposite is equally true. Table 2

[12] Effect of predisposing and precipitating factors on vulnerability of the patients

(Inouye SK, Westendorp RGJ, Saczynski JS)

Table 3

[14] Precipitating and predisposing risk factors

(Davis D)

Non-Modifiable risk factors

Dementia and cognitive impairment

The links between underlying cognitive impairment and dementia as important risk for delirium are

well established. Older patients with dementia have the highest risk for delirium [15]. Some sources

state that they can increase the risk by up to five times and are also associated with worse outcomes.

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[16] Previous studies had determined dementia as the number one leading risk factor of delirium, with

delirium also being cited as an independent risk factor for subsequent dementia [17]. Dementia cause

for progressive neuronal loss. Late stage dementia even causes for a decrease in the size of the brain

(atrophy) and a progressive worsening in many cognitive functions. This means that the brain

“reserve” is diminished, leading to an increase in vulnerability for the development of delirium. In

Alzheimer’s disease there is a decrease in cholinergic activity, which contributes to cognitive decline

and may result in delirium down the line. However, the exact mechanisms of how dementia

predisposes for delirium have not been completely elucidated. There is a lack of studies here. More

researched has been the way in which delirium, through direct toxic effects on the brain, cerebral

ischemia, and chronic stress leads to neuronal dysfunction and damage. This of course can cause

dementia. Many of the same mechanisms may be implicated when it comes to dementia and cognitive

impair predisposing to delirium. This has yet to be fully determined. What is unquestionable however,

is the link between the presence of cognitive impairment/ dementia and the development of delirium.

The prevalence of both delirium and dementia in clinical settings and how they are intrinsically linked

has led to them often going unrecognised or being mistaken for each other [17]. One Dutch study

which assessed the risk factors of patients acutely admitted to their medical wards found that cognitive

impairment was the strongest indicator for the development of delirium, identifying a nine fold

increase in risk [18]. This is further supported by previous studies which found cognitive impairment

to be a strong predictive marker for delirium (relative risk 2.8; CI, 1.2 to 6.7) [19]. Another study

undertaken at the Royal Orthopaedic hospital in Birmingham corroborated this when they found that

older patients undergoing femoral fracture surgeries were much more likely to become delirious post-

operatively if they had a prior diagnosis of dementia on admission (51% vs 37%, p=0.02) [20].

Advancing Age

Clinical experience and recent research has suggested that delirium is a key component in the decline

of functionality, independence and health in elderly patients admitted into clinical wards. Studies have

shown that delirium affects 14-56% of hospitalized geriatric patients [7]. Another study stated that a

minimum of 20% of the 12.5 million patients over 65 years of age admitted each year into the hospital

in the United States suffer from complications of delirium [21]. This clearly underlines the link

between increasing age and the development of delirium. A meta-analysis published in 2014 reported

increasing age as “statistically significantly associated with increased delirium risk in pooled analysis;

mean difference 2.74 (95% CI 0.11, 5.38, P = 0.04)” [22]. Another study which assessed patients older

than 60 years of age admitted to the hospital found that there was a clear increase in the number of

cases of delirium in patients over the age of 75 [23]. Another 2016 study attempted to outline the

association between delirium and frailty in patients discharged from the hospital. There are multiple

reasons for why advancing age may lead to higher incidences of delirium. One theorized cause of

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delirium is oxidative metabolism. An inadequate supply of oxygen to the brain results in an inadequate

oxidative metabolism. This in turn leads to cerebral dysfunction. The normal aging process causes a

decrease in organ function which may interfere with oxygen supply. This places older patients at a

higher risk of delirium than their younger counterparts, particularly in settings of increased stress, such

as postoperatively. Physiologic changes in aging many increase the development of drug induced

delirium. This is particularly significant as polypharmacy and anticholinergic toxicity are common

place among older patients. Certain geriatric diseases such as Alzheimer’s disease and other forms of

dementia are also linked to delirium. Age related decreases in cognitive reserve and brain size also

predispose to the onset of an acute confusional state. This may explain increasing rates of delirium in

older populations and why advancing age is such an important risk factor of delirium.

Frailty

Frailty, a geriatric syndrome defined “as a clinically recognizable state of increased vulnerability

resulting from aging-associated decline in reserve and function across multiple physiologic systems

such that the ability to cope with every day or acute stressors is comprised” [24], was found to be

intrinsically linked to the development of delirium. Of the 114 patients analyzed 20% developed

delirium. Of those 20% almost 90% presented with frailty. On the other hand, the mean frailty score

for non-delirious patients was significantly lower than for delirious participants [25]. It has long been

established that frailty steadily increases with age, with rates quoted as: 65-69 years: 4%; 70-74 years:

7%; 75-79 years: 9% 80-84 years: 16%; >85 years [26]. With an increase of age leading to an increase

in the prevalence of frailty, and a subsequent increase in frailty associated with a greater incidence of

delirium, it becomes very clear than age is one of the major risk factor for the development of delirium

being both a non-modifiable and predisposing factor. The reasoning behind this is that frailty leads to

an increased state of vulnerability in elderly patients for the development of delirium as subjects suffer

from a multitude of diseases. They are also usually less mobile, more dependent, and less socially

active. These factors when combined lead to a decrease in cognitive reserve and a subsequent increase

in the likelihood of the development of delirium when certain precipitating factors are present.

Male Sex

Another predisposing, non-modifiable risk factor of delirium was gender. Older males are widely

reported to have an apparent increased risk for delirium [27]. This is attributed to the fact that males,

especially those with cognitive impairment such as dementia have a higher burden of comorbidities

than woman. Some of these comorbidities (such as renal and hepatic impairment, which are discussed

further in this review) are well established causes of delirium in older patients. This fact seems to be

supported by the literature. However, the exact pathogenesis of this is still unclear. When compared to

women, men were found to be at a higher risk of post-operative delirium after hip fracture repair [28].

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Although there were differences between male and female participants with regards to preoperative

risk factors associated with delirium, the relationship between male sex and postoperative delirium

remained robust even after adjusting for other risk factors [28]. One clinical study, which analyzed

both surgical and medical patients who developed delirium found that more males were recorded in the

delirious participants when compared to the control group. There were also more males patients in the

medical subgroup (70.4%) and the surgical subgroup (69.5%) than in the control group (46%) [29].

One study carried out in a Lithuanian cardiac intensive care unit demonstrated that on average male

patients were 7 years younger than their female counterparts. Furthermore, it showed that patients

younger than 65 years of age who experienced delirium were more likely to be male (also had a more

severe form of the disease), whilst the majority of patients older than 85 years were female [30]. One

study, which evaluated people with dementia who later on suffered from delirium, reported that

delirium severity scores were higher for males than for females [15]. Males also had a higher risk of

developing delirium in the ICU (63% vs 36%) compared to females [31]. Although much of the

evidence points to a general risk increase in men, this is not always the case. In a pooled analysis male

sex was not significantly linked with delirium risk [22]. However, it is clear than when taking a wider

view and considering factors such as environment (ICU, surgery), age, and various other factors, the

male sex was consistently cited as a risk factor in vulnerable patients.

Chronic renal or hepatic disease

Chronic kidney disease (CKD), or renal disease in general has long been regarded as a risk factor of

delirium. Epidemiological data also clearly suggest that CKD (at all stages) conveys a higher risk of

developing cognitive disorders, especially dementia. [32]. For example, hemodialysis patients were

found to be three times more likely to have a severe cognitive impairment or dementia [33].

Dementia/severe cognitive impairment is in turn associated with an increase in the development of

delirium (as stated previously in this review) as it represents a state of low brain reserves [34].

Furthermore the cerebral edema induced by electrolyte shifts during hemodialysis led to what is known

as “disequilibrium syndrome” [33] which symptoms are consistent with delirium [35]. A study

undertaken in the ICU reported that both stage 2 and stage 3 acute kidney injury was associated with

an increase in the incidence of delirium, with AKI being present 37% of the time when patients had

normal mental status as compared to 50% of the time on delirious days [36]. Uremia has also been

commonly described as a cause of delirium [37]. However, other factors, which are associated with

kidney disease, can also be attributed to the increase in the incidence of delirium among these patients.

Drug regimes, such as steroids and cyclosporine for instance, used in the treatment of a variety of

CKD’s have also been attributed as risk factors of delirium [37]. This should also be taken into

consideration. Regardless it has been proven beyond doubt that a strong correlation between renal

disease (both acute and chronic) and the development of delirium exist.

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Delirium can also be in part attributed to liver disease. One study found that 55% of cirrhotic patients

suffer from various psychiatric diseases such as hepatic encephalopathy, anxiety, and also delirium. A

vitamin B12 deficiency (caused by liver disease) has also been showed to cause delirium [38] [39].

Hepatic encephalopathy occurs in 60-80% of patients suffering from cirrhotic liver disease. Hepatic

encephalopathy is cause by the toxic effects of nitrogenous wastes on the brain. This toxic waste

disturbs brain function by altering neurotransmission, which control consciousness and behavior. Most

patients with hepatic encephalopathy and liver failure also have a certain degree of cerebral edema,

which also adversely effects cognitive function. An increase in ammonia (main nitrogenous waste)

leads to more glutamate being present in the brain. This causes astrocytes to swell and precipitates an

upregulation in GABA (a neurotransmitter involved in the development of delirium). This complex of

reactions means that older patients with hepatic failure, and more specifically hepatic encephalopathy

develop a variety of neuropsychiatric disorders, including delirium. Another explanation to why

hepatic disease leads to an increase in the incidence of delirium is that patients are usually taking

multiple drugs for treatment (polypharmacy) and also present with many comorbidities such as renal

disease, infections, and malnutrition (all predisposing and precipitating factors of delirium).

Potentially Modifiable risk factors

Sensory Impairment

Sensory impairment is consistently listed as one of many patient characteristics, which when treated

can decrease the development of delirium. In the presence of sensory impairment, particularly poor

vision, patients have an increased occurrence of delirium due to a number of factors. Those who suffer

from these impairments are less inclined to move and be active and are therefore immobilized for

longer periods of times. This immobilization often leads to the placement of urinary catheters, which

has been found to be a major cause of delirium. Those with deafness are usually less responsive and

interact less with their environment, predisposing them to the development of delirium [40]. Studies

show that sensory impairment leads to delirium, which adversely impacts hospital outcomes and

subsequent patient recovery [41]. This fact is very important, as it points to a modifiable risk factor

that may affect a large portion of patients [41]. Furthermore, the association between sensory

impairment and delirium is well established and can be significantly influenced through interventions

[42]. A study into nursing practices found that simple interventions targeted at dementia, vision loss,

hearing loss and immobility, when implemented by nurses, can prevent delirium in those with these

risk factors.[43]. One example offered by the study was an 8-intervention vision protocol, which was

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implemented, in their renal unit. 42.5% of the sample of patients studied suffered from visual

impairment (in large part due to diabetic retinopathy). Providing aids for visual perception was found

to improve orientation to the environment and ability to perform ADL’s. Marking a pitcher with red

tape enabled patients to have easier access to fluids and prevented dehydration. All of these were found

to positively influence patient recovery and hindered the development of delirium [43]. Another study,

which implemented similar intervention, found that delirium developed in 9% of the intervention

group as compared with 15% in the control group, a 34% decrease in incidence [44]. This shows that

although hearing and vision loss are major risk factors for delirium, they can be minimized by

improved medical and nursing practices.

Urinary catheterization

The presence of an indwelling urinary catheter poses a considerable risk of delirium in geriatric

patients. In 1996, the insertion of a urinary catheter was found to be one of 5 major hospital related

insults that could help precipitate new onset delirium [13]. In 1999, minimizing the use of indwelling

urinary catheters was shown to reduce the risk of delirium in hospitalized geriatric patients [45]. A

study of older patients undergoing surgery for osteoporotic hip fractures confirmed that patients with

an indwelling urinary catheter preoperatively had 4.9 times higher risk for delirium perioperatively

[46]. Urinary catheters have also been associated with an increased occurrence of delirium in elderly

patients hospitalized with cardiac disease [47]. Another Italian study which aimed to evaluate the

association of urinary catheterization and delirium in patients >65 yrs. either hospitalized or in nursing

homes further strengthened these claims when they found that IUC’s had a significant increase in the

incidence of cognitive impairment and delirium (with the latter being significant also in the subset of

patients without underlying dementia) [48]. Many mechanisms for why catherization has an affect

delirium have been proposed. Indwelling urinary catheters cause a sensation of urination, which can be

stressful to patients. This stress may contribute to the development of delirium [49]. It must also be

noted that patients who require urinary catherization may have a poorer physical state and suffer from

many more comorbidities, which can also conduce to delirium. More importantly, deconditioning-

related disability and IUC-related UTIs are what are most attributed to delirium in elderly patients

[50]. Therefore, responsible and appropriate use of urinary catheters can go a long way in the

prevention of UTI’s, stress, disability, and ultimately delirium particularly in older hospitalized

patients.

Polypharmacy

Drug related harm in elderly patients is one of the most pertinent and challenging problems facing

geriatricians today. Older patients are much more vulnerable to morbidity and mortality associated

with drug consumption because of age related changes in both pharmacokinetics and

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pharmacodynamics along with frequent comorbidities (such as cardiovascular and cognitive disorders)

attributed to old age. This means that geriatric patients are more susceptible to ADR’s [51].

Table 4

Pharmacokinetic changes in elderly [52]

(Lee H-C, Tl Huang K, Shen W-K)

Polypharmacy is described as “Simultaneous and long term use of different drugs by the same

individual” [53], or in other words the use of multiple medications concurrently. One observational

cohort study performed in a geriatric unit demonstrated a clear association between polypharmacy and

the occurrence of delirium. Their results showed that symptoms of an acute confusional state were

positive in 69% of patients receiving polypharmacy as compared to 30% of those who were not [54].

Another study identified drugs as the most common reversible cause of delirium [55] .It is estimated

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that polypharmacy alone may account 12-39% of all cases of delirium [56]. A wide variety of

pharmaceuticals have been affiliated with the appearance of delirium, but certain classes of drugs are

move commonly identified as causative agents of delirium.

Table 5

[55] Common drugs associated with delirium [

(Alagiakrishnan K, Wiens CA)

Anticholinergics, high dose narcotics, and benzodiazepines. A number of studies have concluded that

anticholinergic usage is one of the most typical precipitating factors [57]. Studies theorize, that

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characteristic symptoms of delirium are mediated by a lack of acetylcholine and a relative excess of

dopamine [58] [59]. Results of one study which assessed use of drugs with anticholinergic properties

(DAP’s) and delirium recorded that 27% of patients using multiple DAP’s (≥2) developed delirium,

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whilst only 17% of those not using multiple DAP’s were recorded as having delirium (however in a

logistic regression analysis with age, gender and Charlson comorbidity index as covariates, DAP’S did

not predict delirium) [60]. Nevertheless, there is a clear association between anticholinergic use and

delirium and these drugs, whilst at times difficult to avoid in elderly patients, must be avoided in those

at high risk of delirium. Concurrent medical issues also greatly contribute to the appearance of drug

induced delirium. For example in those with heart failure, hepatic congestion means a reduction in

metabolism, and renal insufficiency means a decline in drug elimination [55]. Another example is the

reduced blood brain barrier in those suffering from dementia or stroke, which may allow for

potentially harmful drugs to gain access to the brain, therefore making dis-integrity of BBB strongly

associated with delirium susceptibility [61]. Pharmacokinetic age related changes, which generally

lead to an increased half-life (due to increase in fat mass), decreased renal and hepatic function, along

with a minimization in volume of distribution also play a vital role in the event of drug-related

delirium. Pharmacodynamic changes such as an increase in cholinergic receptor sensitivity in the older

population has also been previously proven [62]. In general, age related receptor changes occur in all

organs, with the final outcome being “a heightened sensitivity of the brain to adverse drug reactions

(ADR’s) [55]. In short, multiple medications, co-morbidities, and of course physiological changes in

the elderly all mean that polypharmacy is one of the major players in the development of delirium in

geriatric patients, being at the same time one of the most avoidable.

Physical restraint

Physical restrain has longed been established as a precipitating factor for delirium. Restraint causes an

increase in stress in older patients, which may help in precipitating delirium. These patients are also

immobilized and often need urinary catheters making infections a more common occurrence. Both

these factors are modifiable and precipitating risk factors of delirium in older patients. Patients who

require physical restraint often have cognitive impairments, which necessitate forced immobilization.

And according to the literature cognitive impairment is one of the most significant risk factors of

delirium. This goes a long way in explaining why physical restraint is linked to delirium. The high

incidence of delirium in those previously restrained demonstrates a strong association between the two

[63]. A common practice in the ICU, almost 40% of one cohort study who were restrained in the

intensive care unit developed delirium. Also very importantly, duration and number of restraints were

positively related to delirium. Patients who were restrained for more than 6 days had more than a 26x

higher risk of delirium than those who were retrained for less than 6 days [64]. There is also an even

higher relative risk of delirium for restrained patients outside the ICU according to Inouye [13].

Unnecessary restraints must be banned to mitigate this complication, and necessary restraining must be

minimized, or altogether abandoned if alternatives can be found.

Environment

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On a similar note, environment also plays a key role in the onset of delirium. The abrupt transfer of a

patient from one ward to another was found to seemingly increase incidence [63]. Likewise, a

reduction in daylight and visitors also left patients at a greater risk for delirium [63]. Recent research

indicates apparent beneficial effects that visitors may have on patients admitted to the ICU (as is the

case for many geriatric patients) in this sense [65]. These data points to the fact that, simple practice

such as increasing visible daylight, and allowing for more visitation times for ill elderly patients may a

go a long way in curtailing the prevalence of delirium in this population. The effect which

environment has on the onset of delirium stems from either a sensory overload or sensory deprivation.

An increase in stressful events such as frequent room transfers, visits to the emergency department

(particularly night-time visits) and hectic hospital environments can all contribute to an increased

incidence of delirium. Likewise, a low amount of mental stimulation such as in isolation of patients, a

lack of visitors, and a reduction of general activity also precipitate delirium. In both cases patients are

unable to orientate themselves in their environment and become more detached from reality,

predisposing them to cognitive impair. The association between environmental factors and delirium

are evidenced by studies demonstrating that non-pharmacological interventions, principally

environmental intervention programs are useful in countering the appearance of delirium.

Infection

Infection is one of the most decisive factors in the development of delirium [66]. One study showed

that delirium was closely related to SIRS criteria [67]. As stated previously UTI’s have well been

established as precipitating factors for delirium in patients. One systematic review found that UTI rates

ranged from 25.9% to 32% in those with delirium, in stark contrast to the 13% quoted for those

without delirium. It also disclosed that in subjects with UTI’s, delirium was present in 30% to 35% of

cases, whilst in those without UTI’s it ranged from 7.7% to 8% [68]. Another geriatric study which

focused on women 85 years or older almost identified UTI as a common cause of delirium (OR = 1.9).

UTI’s however, are not the only infections, which have been linked to the development of delirium.

Pneumonia and sepsis have also been shown to cause similar degrees of delirium. Research undertaken

to evaluate the severity of delirium and its relation to its triggers found no significant association

between the type of infection and the subsequent severity of delirium observed in their patients [66].

The mechanism by which sepsis contributes to delirium has been widely researched. Investigations

show that systematic inflammation and endothelial activation, which takes places during critical

infections, may lead to an increase in the movement of cytokines across the BBB [69]. They have also

been theorized to cause a disruption in the blood brain barrier [70]. The sum of which results in

cerebral ischemia and neuron apoptosis, which can display itself as delirium [71]. Studies in one

Swedish ICU concluded that patients with severe sepsis/shock had a higher incidence of delirium with

an OR OF 3.7 (95% CI) [72] clearly reinforcing previous studies undertaken on the matter.

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Surgery

Delirium is estimated to complicate between 15%-50% of major surgeries in elderly patients and is

associated with adverse outcomes such as prolonged hospitalization, dementia, increased rates of

institutionalization, poor functional recovery, and increased mortality [73]. However, studies belief

that medical professionals fail to recognize and adequately address up to 80% of postoperative

delirium [73]. The prevalence of post-surgery delirium is highly depends of patient’s age, preoperative

status, the urgency of the surgery (elective vs emergency) and of course the invasiveness of the surgery

[74].

22

Table 6

[75] Incidence of delirium according to the surgery performed

(Rudolph JL, Marcantonio ER)

Hip fracture surgery was associated with the highest incidence of delirium (this could be attribute to

the urgent nature of the surgery) [75]. Other studies seem to corroborate this finding. One inquest

performed in a surgery-traumatology centre in Groningen found that delirium was the most frequently

seen complication post-hip fracture surgery at 19% [5]. Almost identical results were produced in a

different study, which assessed 19.29% of their geriatric sample as delirious post-hip fracture surgery [8] . Incidence was also high in elderly patients who underwent cardiac and vascular related surgeries. Of the 1797 patients ≥ 65 years, including 230 patients ≥ 80 years, delirium was diagnosed post cardiac surgery in 21.4% and 33.5% respectively [76]. The

more extreme the procedure performed the higher the incidence of postoperative delirium.

Approximately 40% of patients with critical limb ischemia undergoing major leg amputation suffered

from delirium post-operatively [77].

23

Table 7

[78] Rates of delirium after different surgeries

(Pol R, van leeuwen B, Visser L, J Izaks G, Dungen J, Tielliu I, et al)

Delirium is closely linked with poor surgical outcomes [73]. Postoperative delirium was found to

contribute to at times a 5-fold increase in mortality [79]. Patients who develop delirium also tend to

have prolonged hospital stay when compared to those who do not. Furthermore, in hospital delirium is

related to a doubling in one-year health care expenses (as average costs per day among patients with

delirium were more than 2 times of that of non-delirious patients) [80]. Another intraoperative risk

factor, which is commonly associated with delirium, is the use of anesthesia. Delirium is routinely

linked to the use of medications pertaining to anesthetics i.e. benzodiazepams and meperidine [81]

(both of which were previously mentioned as risk factors in this review). The relationship of delirium

and the employment of general vs local anesthesia has not yet been fully elucidated. However,

research seems to suggest that general anesthesia poses a greater risk for the development of

postoperative delirium. In a recent study, a lighter depth of sedation was related to a 50% reduction in

postoperative delirium in comparison to deep sedation [82]. This same study found great success in

curtailing the incidence of postoperative delirium, by replacing general anesthesia with local (spinal

anesthesia) in a variety orthopedic procedures (including hip replacement surgery) [82]. It is also

important to point out that other intraoperative risk factors, which could be attributed to the high rates

of delirium seen post-surgery, such as urinary catheterization (refer to pg. 13 of this review) and

infections (pg. 17), are invariably linked with almost every possible form of surgery (and even more so

in the elderly). Therefore, caution should be used in deciding the type of anesthetic, surgery, and

medication employed in the management of geriatric patients undergoing surgery. Clinicians should

recognize the risks that surgery poses for the development of delirium and act accordingly. It is of the

utmost importance that surgeons, anesthesiologists, and geriatricians alike aim to lessen, as much as

possible, the medical, physical, and economic burdens which the development of delirium poses.

24

Other associated risk factors

Sociodemographic and education

Although the link between socioeconomic background and education has not been comprehensively

resolved, some studies claim that both poorer levels of education and social class may have a negative

impact on the development of delirium. One study, which attempted to assess the association of

education with the occurrence of delirium found that, on average, those who developed delirium had a

lower mean number of educational years (4.92 years in delirium patients vs 6.96 in non-delirium

patients) [83]. The level of educational attainment has been cited frequently as a marker for cognitive

reserve. In fact, higher levels of formal education are associated with an increase in cognitive reserve,

with lower levels coinciding with a reduction [84]. Another paper, which analyzed 2 separate studies

(on patients aged 65+), found that, in both cases, the risk of delirium was augmented among persons

with fewer years of education [85]. Furthermore, each year of completed education was associated

with a 0.91 lower odds of delirium (95% confidence interval: 0.87, 0.95). When compared to those

who had undergone 12 years of formal schooling, those who only completed 7 years had a 1.6 fold

increased risk of developing delirium [85]. Another aspect, which must be accounted for, is the

influence which education plays on the development of dementia. The relationship between dementia

and delirium has already been clarified in this review, with dementia leading to an increased

vulnerability of patients for the development of delirium. Studies show, that low education (<6 years)

is associated with an increased risk for Alzheimer’s disease [86]. Conversely, higher levels of

education convey certain protective factors against dementia [87]. In fact, the strong inverse

association of educational attainment with risk for dementia has led some researchers to claim that

education may be the most important protective factor for dementia [88]. This fact lends further

evidence to the claim that low education increases the incidence of delirium in the elderly, as higher

levels of dementia would invariably lead to more cases of delirium.

Socioeconomic status (SES) is defined by education, occupation, activity, and income both

individually and/or in combination [89]. The type of occupation one has may be used to gauge a

person’s underlying intelligence and mental capacity. One paper determined that “high occupational

status” was associated with a 50% decrease in the risk of dementia, whilst also having a positive effect

on cognitive reserve [90]. Activity, both cognitive and physical, diminishes the risk of cognitive

decline. Older persons, who had a greater participation in complex mental activities, demonstrated a

diminished cognitive decline [91]. Physical activity on the other hand promoted better cardiovascular

health, which reduces the incidence of cerebrovascular disease [92]. Social support may also play a

contributing role. Inouye identified a lack of social support as a risk factor of delirium in hospitalized

geriatric patients [42]. Similarly, social disengagement in Community-dwelling elderly persons was

associated with an increase in cognitive decline [93], predisposing them to future development of in-

hospital delirium. It is necessary to point out that not all of the studies are in accordance with one

another. One significant Australian study, which assessed 6609 hospital admissions for delirium, 1,059

25

readmissions during a three-year period, found absolutely no correlation between socioeconomic status

and the incidence of delirium, with lower socioeconomic groups not having particularly higher rates of

delirium [94]. All in all however, educational attainment, occupation, and activity signify important

predictors of delirium and their presence should be accounted for when assessing for the risk of

delirium in older hospitalized patients.

26

Peer reviewed papers

identified through

electronic search PubMed, NCBI= (432 )

Papers screened on basis

of title and abstract=

(123)

Full text assessed for

eligibility=(67)

METHODOLOGY

Peer reviewed papers Peer reviewed papers identified through identified through electronic search electronic search

UpToDate, medical ResearchGate, web

Journals= (60 ) search= (40)

Papers screened on basis Papers screened on basis

of title and abstract= (25) of title and abstract= (22)

Full text assessed for Full text assessed for

eligibility=(15) eligibility=(12)

Total number of studies included= (94)

27

To carry out the objectives outlined in this Systematic Literature review databases such as PubMed,

UpToDate, and the American Heart Journal (AHJ), ResearchGate were searched. Relevant papers

were selected in a rigorous and organized manner. Search terms such as “delirium”, “acute confusional

state”, “dementia”, “transitory neurological deficit” were first used. These were then cross-searched

with terms such as “risk factors”, “common causes”, “in elderly”, “old age”, “geriatric patients”,

“geriatric department”, “prevalence “and finally “incidence”.

Irrelevant papers were then excluded on the basis of title and abstract. The next step involved assessing

paper for eligibility based on their full text. Inclusion criteria were employed to further eliminate non-

relevant papers from our search. These consisted on the date of publication (papers could be no older

than 25 years (although well over 70% of cited papers were published in the last 10 years) and had to

be published in English), relevance to the topic, paper had to be peer reviewed and all types of studies

were included (both qualitative and quantitative).

The remaining batch of papers was meticulously analyzed and relevant information was extracted.

28

DISCUSSION

Findings and their significance:

This review identified 94 studies, which, in varying degrees, studied the risk factors, which both

precipitate and predispose to the development of delirium in elderly hospitalized patients. The studies

included, by and large, consisted of systematic reviews, meta-analysis, cohort studies, case control

studies, and some case-report studies. All of the papers researched which focused primarily on

delirium and its risk factors, included the risk factors discussed in the literature review section, alone

or in combination (with all of them being referenced to in most cases).

The studies demonstrated that dementia was by far the most significant predisposing, non-modifiable

risk factor which elderly patients could possess for the development of delirium. In fact, some studies

even claimed that dementia was the number one leading risk factor for delirium. The findings of this

study seem to suggest that also, with the strong relationship between prior cognitive impairment and

delirium being constantly affirmed in paper after paper. The presence of dementia therefore, should be

a red flag for geriatricians, and clinicians alike dealing with older person admitted to their wards.

With regards to predisposing factors, the findings suggest that surgery, and more specifically major

and particularly invasive surgery, is the one of the most prominent (if not THE most prominent)

determinant conditions for the appearance of delirium. Cardiological and non-elective orthopedic

surgeries (primarily hip fracture) were the most highly associated with incident delirium post-op. It

must be remembered however that surgery consist of a cocktail of interconnected and associated risk

factors which can precipitate a “perfect storm” for the development of an “acute confusional state” in

older patients. For example, routinely accompanying condition such as urinary catheterization,

infection, and arguably most importantly narcotics used in pain management and sedatives employed

in anesthesia, are some of the most consistently referenced risk factors for delirium. This shows that

surgery entails a multitude of precipitating (and therefore potentially modifiable) intra- and post-

operative risk factors, which coalesce with the end result of delirium. Additionally, most cases of

delirium occur 48hrs post-operatively. The research has proven that by attempting to minimize these

risk factors, positive results can be observed in relation to reducing the incidence of delirium in older

patients who are operated on, i.e. replacing general anesthesia with local whenever possible in patients

undergoing hip fracture surgery. Particular attention should also be payed to elderly patients who have

endured the very stressful experience of surgery in the previous 48 hours. More stringent monitoring

protocols in this group may generate a decrease in the prevalence of delirium postoperatively.

29

IUC is, according to the literature, one of the major in-hospital determinants of delirium in both

surgical and non-surgical geriatric patients. The longer a urinary catheter is present the more serious

the risk. IUC’s should be employed with care. The presence of a urinary catheter preoperatively was

associated with an almost fivefold increase in the risk of delirium post-operatively. Even in

institutionalized patients (e.g. those in nursing homes) and those on clinical wards, long-term

catheterization represented an important risk, regardless of surgery. Indeed, urinary catheterization was

among the most frequently mentioned risk factors of delirium during the course of this research.

As in previous studies, male sex and advancing age were found to be statistically significantly risks for

delirium. Perhaps not surprisingly increased age was associated with an increased vulnerability (e.g.

frailty syndrome) for acute and transient cognitive impairment. The evidence for the male sex

predisposing delirium was more varied. Some studies found no significant association between

delirium in male and female groups. Other studies claimed that males were more likely to develop

delirium in some age groups, and females more likely in others. Nonetheless, the majority of the data

encountered during this study pointed to an increase occurrence of delirium in males admitted to the

hospital.

Similarly, this study demonstrated clear and unequivocal confirmation that underlying renal and

hepatic disease along with the presence of infection predisposed to and precipitated delirium,

respectively. CKD necessitating hemodialysis and the presence of liver cirrhosis were the major

players. AKI, especially in the context of ICU, was also consistently linked to those who developed

delirium. Infection, regardless of its origin, was identified as a trigger of delirium. The presence or

absence of any of these conditions should be clarified in all elderly patients admitted to the hospital.

This will help to stratify patients according to their risk, and perhaps encourage medical practitioners

to take appropriate steps to avert the occurrence of delirium.

Whilst performing this review the importance of environment and its contribution to delirium was very

evident. The findings suggest that patients are more likely to develop delirium when they are suddenly

transferred from one ward to another. Moreover, physical restraint and sensory impairment (which also

form part of the environment of the patient) were consistently found to precipitate delirium to some

degree. Geriatricians should always be highly aware of this fact. When these conditions were improved

a significant reduction in the number of cases was seen, and this was demonstrated by many of the

papers studied.

Polypharmacy, an already well-established risk factor for delirium, was further elucidated in this study.

This topic has been well researched, and the most common culprits identified. Polypharmacy,

30

especially in patients who are hospitalized, is manageable. Physicians must attempt to cut down on the

number of drugs that older persons are taking or find alternatives to these drugs, which increase patient

vulnerability (e.g. diazepam’s, anticholinergics etc.).

Strengths and limitations of this review:

One of the main strengths of this review is that it is composed of a wide variety of published papers,

stemming from various different countries, consisting of multiple different populations and therefore

distinctly different sample groups. The difference in location also offered a wide range of different risk

factors studied, with studies performed in a number of different departments, including the ICU,

orthopedics, cardiac surgery, medical department and many others. Some of the studies included

offered a wide range of perspectives, with some studies focusing primarily on nursing practices, and

others on patient conditions and medical interventions. This helped to give a broader scope of the

subject. The risk factor which most often appeared (and that were studied in greater detail in this

review) were present consistently and repeatedly across a wide spectrum of hospital settings. My

review was, regrettably, limited to those papers, which were published in English. This may have

meant the exclusion of a range of relevant and applicable investigations produced in non-English

speaking countries. Although, some of the studies examined in this review were published bilingually

(in their native language and also in English).

As in all systematic literature reviews, the possibility of bias is increased when compared to other

methods of studies. There is no set method to ensure that all of the relevant literature is considered, and

this may increase the likelihood of a somewhat biased result. This review is no different. Although I

attempted, as much as possible to study as wide a range of papers as possible, keyword searches mean

that, in general, the papers, which were found and analyzed, supported the initial aim of the study.

However, a wide range of studies considered, and an inclusion of contrasting papers and results has

assisted in lessening this potential bias.

Another likely weakness of this study is that it does not focus on the risk factors on a department-to-

department level. Risk factors were studied generally, regardless of where they occurred and in what

specific setting. This most common and the most significant risk factors were then analyzed. The risk

factors and the effects which they played on the development of delirium were gathered from an array

of different texts, which often only studied risk factors of delirium in the context of a certain

department or condition. The positive aspect of this on the other hand, is that it highlights cross-

disciplinary aspects of delirium and its causes. This may help to aid in the understanding of delirium

(in hospitalized older patients) in a more holistic form, and therefore encourages interdisciplinary

31

management of this condition. This is a plus, as the importance of interdisciplinary work in the

management of geriatric patients is a well-acknowledged fact.

Implication for future research:

The risk factors for delirium are varied and often times intricate. The way in which they interact with

one another and provoke delirium in those older persons admitted to the hospital needs to be further

investigated. Although some risk factors have been definitively associated with the occurrence

delirium, the mechanism in which they bring about this disorder have not been fully elucidated e.g.

dementia. The relationship between frailty syndrome and dementia for instance, has been extensively studied.

The same cannot be said however for delirium. There is unfortunately a relative scarcity of research on

the topic. The occurrence of delirium is particularly challenging to document. It is by definition “an acute and

transitory condition”. This makes the recording of its appearance very difficult, as it requires periodical

monitoring by medical professionals who are able to recognize the condition. This means that the true

extent of its prevalence may be overlooked, and therefore its risk factors inadequately analyzed. Another significant gap in the literature is the study of the pervasiveness of already established risk

factors in wards, which harbor aging patients. There is a need for research in this area. Geriatric wards

must assess the prevalence of previously identified risk factors among their patient populations. The

same can be said for surgical and medical units. Nursing homes also house many elderly patients who

at some point develop delirium, both prior and post hospitalization. The rates of delirium risk factors in

these institutions must be determined. Finally, studies, which examined the effects of substituting general anesthesia with local anesthesia in

elderly patients at risk of acute cognitive impairment, were few and far between. This is a very

promising area, which could produce great benefits in the management of geriatric pts. who visit the

OR.

Implication for clinical practice:

The incidence of delirium is high. This review has demonstrated that certain risk factors are

consistently associated with its development. Moreover, many of the risk factors studied in this review

are potentially modifiable. The first step in the treatment of delirium is, of course, its recognition.

Nurses are the most likely to identify it presence due to their increased contact with patients. The

literature has shown that employment of nursing protocols to combat delirium results in a significant

decline in its appearance. One example of a potentially modifiable risk factor, which can be

successfully targeted by improved nursing practices, is sensory impairment. Findings indicate that

32

tackling deteriorated hearing and vision in older patients improves orientation in their environment,

thus hindering the potential appearance of delirium in these patients. Urinary catheters must be used with care, particularly long-standing catheters. The same can be said

for physical restraints. Avoiding this practice, especially in those at high risk, will prevent may cases

of in-hospital delirium. Geriatric patients must be evaluated for possible predisposing factors such as male sex, renal and

hepatic impairment, and polypharmacy. Greater attention must be paid to those who carry such risk

factors and appropriate measures taken wherever possible. Those with dementia who are hospitalized

with acute illnesses (such as infection) or are who are operated must be closely monitored as they pose

a high risk of developing an acute confusional state. Management of these potentially modifiable risk

factors is central to the success of multicomponent interventions aimed at eliminating delirium in older

hospitalized patients.

33

CONCLUSIONS

Delirium is a common and serious condition, which affects a high proportion of the hospitalized

elderly population. Studies estimate that 11% to 25% of older patients will have delirium upon

admission, with a further 29% to 31% of those initially admitted without delirium developing it during

hospitalization.

1. Significant risk factors in this systematic literature review were age, male sex, dementia,

underlying renal and hepatic dysfunction, polypharmacy, urinary catheterization, infection,

sensory impairment, physical restraint, and surgery.

2. Education and socioeconomic background were also found to contribute to the development of

delirium.

3. Dementia and surgery were by far the risk factors, which precipitated delirium at the highest

rate. Infection and urinary catheters also caused delirium in a high proportion of patients

4. Early recognition of the potentially modifiable risks and multicomponent interventional

pathways can undoubtedly decrease the incidence of delirium.

34

35

REFERENCES

1. Meyer O, Meyer S, Kressig RW. [Diagnosis of delirium]. Therapeutische Umschau Revue

therapeutique. 2010;67(2):69-73. 2. Joseph Francis J, MD, MPHG Bryan Young, MD, FRCPC. Diagnosis of delirium and confusional states. In: Janet L Wilterdink M, editor. UpToDate. UpToDate (Accessed on March 9, 2019: UpToDate; 2014. 3. Tilouche N, Hassen MF, Ali HBS, Jaoued O, Gharbi R, El Atrous SS. Delirium in the Intensive

Care Unit: Incidence, Risk Factors, and Impact on Outcome. Indian journal of critical care medicine : peer-

reviewed, official publication of Indian Society of Critical Care Medicine. 2018;22(3):144-9.

4. Joseph Francis J, MD, MPHG Bryan Young, MD, FRCPC. Delirium and acute confusional states: Prevention, treatment, and prognosis. In: Janet L Wilterdink M, editor. Uptodate. Uptodate (Accessed March 9, 2019)2019. 5. Flikweert ER, Wendt KW, Diercks RL, Izaks GJ, Landsheer D, Stevens M, et al.

Complications after hip fracture surgery: are they preventable? European journal of trauma and

emergency surgery : official publication of the European Trauma Society. 2018;44(4):573-80.

6. Pauley E, Lishmanov A, Schumann S, Gala GJ, van Diepen S, Katz JN. Delirium is a robust predictor of morbidity and mortality among critically ill patients treated in the cardiac intensive care unit. American heart journal. 2015;170(1):79-86, .e1. 7. Fong TG, Tulebaev SR, Inouye SK. Delirium in elderly adults: diagnosis, prevention and treatment. Nature reviews Neurology. 2009;5(4):210-20. 8. Wang C-G, Qin Y-F, Wan X, Song L-C, Li Z-J, Li H. Incidence and risk factors of postoperative delirium in the elderly patients with hip fracture. Journal of orthopaedic surgery and research. 2018;13(1):186-. 9. Pereira FB, Lopes MA. Delirium in elderly inpatients admitted to clinical wards Prevalence and investigation of clinical conditions in a Brazilian sample. Dementia & neuropsychologia. 2018;12(2):152-6. 10. Brown EG, Josephson SA, Anderson N, Reid M, Lee M, Douglas VC. Evaluation of a multicomponent pathway to address inpatient delirium on a neurosciences ward. BMC health services research. 2018;18(1):106. 11. Inouye SK. Predisposing and precipitating factors for delirium in hospitalized older patients. Dementia and geriatric cognitive disorders. 1999;10(5):393-400. 12. Inouye SK, Westendorp RGJ, Saczynski JS. Delirium in elderly people. Lancet (London, England). 2014;383(9920):911-22. 13. Inouye SK, Charpentier PA. Precipitating factors for delirium in hospitalized elderly persons.

Predictive model and interrelationship with baseline vulnerability. Jama. 1996;275(11):852-7. 14. Davis D. The impact of delirium on cognitive outcomes in population-based studies 2013. 15. Kolanowski AM, Hill NL, Kurum E, Fick DM, Yevchak AM, Mulhall P, et al. Gender differences in factors associated with delirium severity in older adults with dementia. Archives of psychiatric nursing. 2014;28(3):187-92. 16. ScienceDirect. Review of association between delirium and dementia in elderly people 2017, April [Available from: https://www.sciencedirect.com/science/article/pii/S0924933817311227.

17. Fong TG, Davis D, Growdon ME, Albuquerque A, Inouye SK. The interface between delirium and dementia in elderly adults. The Lancet Neurology. 2015;14(8):823-32. 18. Korevaar JC, van Munster BC, de Rooij SE. Risk factors for delirium in acutely admitted elderly patients: a prospective cohort study. BMC Geriatrics. 2005;5(1):6. 19. Inouye SK, Viscoli CM, Horwitz RI, Hurst LD, Tinetti ME. A Predictive Model for Delirium in Hospitalized Elderly Medical Patients Based on Admission Characteristics. Annals of Internal Medicine. 1993;119(6):474-81. 20. Tahir M, Malik SS, Ahmed U, Kozdryk J, Naqvi SH, Malik A. Risk factors for onset of

delirium after neck of femur fracture surgery: a prospective observational study. Sicot-j. 2018;4:27. 21. Inouye SK. Delirium in hospitalized older patients: recognition and risk factors. Journal

of geriatric psychiatry and neurology. 1998;11(3):118-25; discussion 57-8.

36

22. Ahmed S, Leurent B, Sampson EL. Risk factors for incident delirium among older people in

acute hospital medical units: a systematic review and meta-analysis. Age and ageing. 2014;43(3):326- 33. 23. Villalpando-Berumen JM, Pineda-Colorado AM, Palacios P, Reyes-Guerrero J, Villa AR, Gutierrez-Robledo LM. Incidence of delirium, risk factors, and long-term survival of elderly patients hospitalized in a medical specialty teaching hospital in Mexico City. International psychogeriatrics. 2003;15(4):325-36. 24. Xue Q-L. The frailty syndrome: definition and natural history. Clinics in geriatric medicine. 2011;27(1):1-15. 25. Verloo H, Goulet C, Morin D, von Gunten A. Association between frailty and delirium in older adult patients discharged from hospital. Clinical interventions in aging. 2016;11:55-63. 26. Clegg A, Young J, Iliffe S, Rikkert MO, Rockwood K. Frailty in elderly people. Lancet (London, England). 2013;381(9868):752-62. 27. Noimark D. Predicting the onset of delirium in the post-operative patient. Age and Ageing. 2009;38(4):368-73. 28. Oh ES, Sieber FE, Leoutsakos J-M, Inouye SK, Lee HB. Sex Differences in Hip Fracture Surgery: Preoperative Risk Factors for Delirium and Postoperative Outcomes. Journal of the American Geriatrics Society. 2016;64(8):1616-21. 29. Kim H, Chung S, Joo YH, Lee JS. The major risk factors for delirium in a clinical setting. Neuropsychiatric disease and treatment. 2016;12:1787-93. 30. Serpytis P, Navickas P, Navickas A, Serpytis R, Navickas G, Glaveckaite S. Age- and gender-related peculiarities of patients with delirium in the cardiac intensive care unit. Kardiologia polska. 2017;75(10):1041-50. 31. Karamchandani K, Schoaps RS, Printz J, Kowaleski JM, Carr ZJ. Gender differences in the use of atypical antipsychotic medications for ICU delirium. Critical Care. 2018;22(1):220. 32. Bugnicourt J-M, Godefroy O, Chillon J-M, Choukroun G, Massy ZA. Cognitive Disorders and Dementia in CKD: The Neglected Kidney-Brain Axis. 2013;24(3):353-63. 33. Murray AM. Cognitive impairment in the aging dialysis and chronic kidney disease populations: an occult burden. Advances in chronic kidney disease. 2008;15(2):123-32. 34. Schor JD, Levkoff SE, Lipsitz LA, Reilly CH, Cleary PD, Rowe JW, et al. Risk factors for delirium in hospitalized elderly. Jama. 1992;267(6):827-31. 35. Arieff AI. Dialysis disequilibrium syndrome: current concepts on pathogenesis and prevention. Kidney international. 1994;45(3):629-35. 36. Siew ED, Fissell WH, Tripp CM, Blume JD, Wilson MD, Clark AJ, et al. Acute Kidney Injury as a Risk Factor for Delirium and Coma during Critical Illness. American journal of respiratory and critical care medicine. 2017;195(12):1597-607. 37. Moreira JM, Matta SMd, Kummer AMe, Barbosa IG, Teixeira AL, Silva ACSe. Transtornos neuropsiquiátricos e doenças renais: uma atualização %J Brazilian Journal of Nephrology. 2014;36:396-400. 38. Hector M, Burton JR. What are the psychiatric manifestations of vitamin B12 deficiency? J Am Geriatr Soc. 1988;36(12):1105-12. 39. Lerner V, Kanevsky M. Acute dementia with delirium due to vitamin B12 deficiency: a case report. International journal of psychiatry in medicine. 2002;32(2):215-20. 40. Kalish VB, Gillham JE, Unwin BK. Delirium in older persons: evaluation and management. American family physician. 2014;90(3):150-8. 41. LaHue SC, Liu VX. Loud and Clear: Sensory Impairment, Delirium, and Functional Recovery in Critical Illness. American journal of respiratory and critical care medicine. 2016;194(3):252-3. 42. Inouye SK, Viscoli CM, Horwitz RI, Hurst LD, Tinetti ME. A predictive model for delirium in hospitalized elderly medical patients based on admission characteristics. Ann Intern Med. 1993;119(6):474-81. 43. Robinson S, Rich C, Weitzel T, Vollmer C, Eden B. Delirium Prevention for Cognitive, Sensory, and Mobility Impairments2008. 103-13 p. 44. Anderson D. Preventing delirium in older people. British Medical Bulletin. 2005;73-74(1):25-

34.

37

45. Inouye SK, Bogardus ST, Jr., Charpentier PA, Leo-Summers L, Acampora D, Holford TR, et

al. A multicomponent intervention to prevent delirium in hospitalized older patients. The New

England journal of medicine. 1999;340(9):669-76. 46. Kim JY, Yoo JH, Kim E, Kwon KB, Han B-R, Cho Y, et al. Risk factors and clinical outcomes of delirium in osteoporotic hip fractures. Journal of Orthopaedic Surgery. 2017;25(3):2309499017739485. 47. Eide LSP, Ranhoff AH, Lauck S, Fridlund B, Haaverstad R, Hufthammer KO, et al. Indwelling urinary catheters, aortic valve treatment and delirium: a prospective cohort study. BMJ Open. 2018;8(11):e021708. 48. Bo M, Porrino P, Di Santo S, Mazzone A, Cherubini A, Mossello E, et al. The association of indwelling urinary catheter with delirium in hospitalized patients and nursing home residents: an explorative analysis from the “Delirium Day 2015”2018. 49. Lepouse C, Lautner CA, Liu L, Gomis P, Leon A. Emergence delirium in adults in the post-anaesthesia care unit. British journal of anaesthesia. 2006;96(6):747-53. 50. Lee EA, Malatt C. Making the hospital safer for older adult patients: a focus on the indwelling urinary catheter. The Permanente journal. 2011;15(1):49-52. 51. Mortazavi SS, Shati M, Keshtkar A, Malakouti SK, Bazargan M, Assari S. Defining

polypharmacy in the elderly: a systematic review protocol. BMJ Open. 2016;6(3):e010989. 52. Lee H-C, Tl Huang K, Shen W-K. Use of antiarrhythmic drugs in elderly patients. Journal of geriatric cardiology : JGC. 2011;8(3):184-94. 53. Masnoon N, Shakib S, Kalisch-Ellett L, Caughey GE. What is polypharmacy? A systematic review of definitions. BMC geriatrics. 2017;17(1):230-. 54. Hein C, Forgues A, Piau A, Sommet A, Vellas B, Nourhashemi F. Impact of polypharmacy on occurrence of delirium in elderly emergency patients. Journal of the American Medical Directors Association. 2014;15(11):850.e11-5. 55. Alagiakrishnan K, Wiens CA. An approach to drug induced delirium in the elderly. Postgraduate Medical Journal. 2004;80(945):388. 56. Moore AR, O'Keeffe ST. Drug-induced cognitive impairment in the elderly. Drugs & aging. 1999;15(1):15-28. 57. Elie M, Cole MG, Primeau FJ, Bellavance F. Delirium risk factors in elderly hospitalized patients. Journal of general internal medicine. 1998;13(3):204-12. 58. Flacker JM, Lipsitz LA. Neural mechanisms of delirium: current hypotheses and evolving concepts. The journals of gerontology Series A, Biological sciences and medical sciences. 1999;54(6):B239-46. 59. Trzepacz PT. Is there a final common neural pathway in delirium? Focus on acetylcholine and dopamine. Seminars in clinical neuropsychiatry. 2000;5(2):132-48. 60. Luukkanen MJ, Uusvaara J, Laurila JV, Strandberg TE, Raivio MM, Tilvis RS, et al. Anticholinergic drugs and their effects on delirium and mortality in the elderly. Dementia and geriatric cognitive disorders extra. 2011;1(1):43-50. 61. Skoog I, Wallin A, Fredman P, Hesse C, Aevarsson O, Karlsson I, et al. A population study on blood-brain barrier function in 85-year-olds. Neurology. 1998;50(4):966. 62. Feinberg M. The problems of anticholinergic adverse effects in older patients. Drugs & aging. 1993;3(4):335-48. 63. Van Rompaey B, Elseviers MM, Schuurmans MJ, Shortridge-Baggett LM, Truijen S, Bossaert L. Risk factors for delirium in intensive care patients: a prospective cohort study. Critical care (London, England). 2009;13(3):R77-R. 64. Pan Y, Jiang Z, Yuan C, Wang L, Zhang J, Zhou J, et al. Influence of physical restraint on delirium of adult patients in ICU: A nested case-control study. Journal of clinical nursing. 2018;27(9-10):1950-7. 65. Gonzalez CE, Carroll DL, Elliott JS, Fitzgerald PA, Vallent HJ. Visiting preferences of patients in the intensive care unit and in a complex care medical unit. American journal of critical care : an official publication, American Association of Critical-Care Nurses. 2004;13(3):194-8. 66. Kuswardhani RAT, Sugi YS. Factors Related to the Severity of Delirium in the Elderly

Patients With Infection. Gerontology & geriatric medicine. 2017;3:2333721417739188-.

38

67. Mariz J, Santos NC, Afonso H, Rodrigues P, Faria A, Sousa N, et al. Risk and clinical-outcome

indicators of delirium in an emergency department intermediate care unit (EDIMCU): an observational

prospective study. BMC emergency medicine. 2013;13:2. 68. Balogun SA, Philbrick JT. Delirium, a Symptom of UTI in the Elderly: Fact or Fable? A Systematic Review. Canadian geriatrics journal : CGJ. 2013;17(1):22-6. 69. Qin L, Wu X, Block ML, Liu Y, Breese GR, Hong JS, et al. Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia. 2007;55(5):453-62. 70. Descamps L, Coisne C, Dehouck B, Cecchelli R, Torpier G. Protective effect of glial cells against lipopolysaccharide-mediated blood-brain barrier injury. Glia. 2003;42(1):46-58. 71. Hughes CG, Patel MB, Pandharipande PP. Pathophysiology of acute brain dysfunction: what's the cause of all this confusion? Current opinion in critical care. 2012;18(5):518-26. 72. Brück E, Schandl A, Bottai M, Sackey P. The impact of sepsis, delirium, and psychological distress on self-rated cognitive function in ICU survivors-a prospective cohort study. Journal of intensive care. 2018;6:2-. 73. Marcantonio ER. Postoperative delirium: a 76-year-old woman with delirium following surgery. Jama. 2012;308(1):73-81. 74. Rudolph JL, Marcantonio ER. Review articles: postoperative delirium: acute change with long-term implications. Anesthesia and analgesia. 2011;112(5):1202-11. 75. Rudolph JL, Marcantonio ER. Review articles: postoperative delirium: acute change with long-term implications. Anesthesia and analgesia. 2011;112(5):1202-11. 76. Kotfis K, Szylinska A, Listewnik M, Strzelbicka M, Brykczynski M, Rotter I, et al. Early delirium after cardiac surgery: an analysis of incidence and risk factors in elderly (>/=65 years) and very elderly (>/=80 years) patients. Clin Interv Aging. 2018;13:1061-70. 77. Shin YH, Yoon JS, Jeon HJ, Kim YB, Kim YS, Park JY. Postoperative delirium in elderly patients with critical limb ischemia undergoing major leg amputation: a retrospective study. Korean journal of anesthesiology. 2018;71(4):311-6. 78. Pol R, van leeuwen B, Visser L, J Izaks G, Dungen J, Tielliu I, et al. Standardised Frailty Indicator as Predictor for Postoperative Delirium after Vascular Surgery: A Prospective Cohort Study2011. 824-30 p. 79. Ganai S, Lee KF, Merrill A, Lee MH, Bellantonio S, Brennan M, et al. Adverse outcomes of geriatric patients undergoing abdominal surgery who are at high risk for delirium. Archives of surgery (Chicago, Ill : 1960). 2007;142(11):1072-8. 80. Leslie DL, Marcantonio ER, Zhang Y, Leo-Summers L, Inouye SK. One-year health care costs

associated with delirium in the elderly population. Archives of internal medicine. 2008;168(1):27-32. 81. Whitlock EL, Vannucci A, Avidan MS. Postoperative delirium. Minerva anestesiologica. 2011;77(4):448-56. 82. Sieber FE, Zakriya KJ, Gottschalk A, Blute MR, Lee HB, Rosenberg PB, et al. Sedation depth during spinal anesthesia and the development of postoperative delirium in elderly patients undergoing hip fracture repair. Mayo Clinic proceedings. 2010;85(1):18-26. 83. Mota SSd, Delgado VB, Schumacher-Schuh AF, Chaves MLF. Association of education with occurrence of delirium in patients from an emergency department %J Dementia & Neuropsychologia. 2016;10:198-203. 84. Farfel JM, Nitrini R, Suemoto CK, Grinberg LT, Ferretti REL, Leite REP, et al. Very low

levels of education and cognitive reserve: a clinicopathologic study. Neurology. 2013;81(7):650-7. 85. Jones RN, Yang FM, Zhang Y, Kiely DK, Marcantonio ER, Inouye SK. Does Educational Attainment Contribute to Risk for Delirium? A Potential Role for Cognitive Reserve. The Journals of Gerontology: Series A. 2006;61(12):1307-11. 86. Johansson B, Mortimer JA, Gatz M, Pedersen NL, Svedberg P, Berg S. Education and the Risk of Alzheimer's Disease: Findings From the Study of Dementia in Swedish Twins. The Journals of Gerontology: Series B. 2001;56(5):P292-P300. 87. Meng X, D'Arcy C. Education and dementia in the context of the cognitive reserve hypothesis: a

systematic review with meta-analyses and qualitative analyses. PloS one. 2012;7(6):e38268-e.

39

88. Jones RN, Fong TG, Metzger E, Tulebaev S, Yang FM, Alsop DC, et al. Aging, brain disease,

and reserve: implications for delirium. The American journal of geriatric psychiatry : official journal

of the American Association for Geriatric Psychiatry. 2010;18(2):117-27. 89. Oakes JM, Rossi PH. The measurement of SES in health research: current practice and steps toward a new approach. Social science & medicine (1982). 2003;56(4):769-84. 90. Valenzuela MJ, Sachdev P. Brain reserve and dementia: a systematic review. Psychological medicine. 2006;36(4):441-54. 91. Wilson RS, Bennett DA, Bienias JL, Mendes de Leon CF, Morris MC, Evans DA. Cognitive

activity and cognitive decline in a biracial community population. Neurology. 2003;61(6):812-6. 92. Shinton R, Sagar G. Lifelong exercise and stroke. BMJ (Clinical research ed). 1993;307(6898):231-4. 93. Bassuk SS, Glass TA, Berkman LF. Social disengagement and incident cognitive decline in community-dwelling elderly persons. Ann Intern Med. 1999;131(3):165-73. 94. Ore T, Ireland P. Is delirium sensitive to socioeconomic inequality?2014.