Lithuanian University of Health Sciences Faculty of Medicine Department of Intensive Care Hady Sayah

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Lithuanian University of Health Sciences

Faculty of Medicine

Department of Intensive Care

Hady Sayah

DELIRIUM IN THE ICU: LONG-TERM OUTCOMES

Medical Integrated Master’s Study Programme

Supervisor:

Vidas Pilvinis

MD, PhD

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1. SUMMARY

INTRODUCTION: delirium is a neuropsychiatric disorder the frequently complicates critical illness. It is a

state of altered consciousness and disrupted attention and cognition. The DSM-V defines delirium as an acute disturbance that represents a change from baseline in attention and awareness primarily, with an additional cognitive disturbance. The disturbance cannot be diagnosed in the presence of a pre-existing cognitive disorder or the context of a diminished level of arousal.

AIM: To determine the long-term impact of delirium on critically ill patients.

OBJECTIVES: (1) to estimate the incidence of delirium in the ICU, (2) to analyze the relationship

between delirium duration and cognitive impairment, and (3) to determine the effect of delirium on quality of life.

RESULTS: this review assessed 34 articles that studied the incidence of delirium, the relationship between

delirium duration and cognitive impairment, and the impact of delirium on quality of life. A positive association between duration of delirium and long-term cognitive impairment was found. An association between delirium and quality of life was inconclusive.

CONCLUSION: delirium is a serious and frequent complication in the ICU and has long-lasting

detrimental effects on cognitive and mental functions, and potentially the quality of life in survivors of critical illness. The conventional course of critical care largely influences the emergence of delirium and thus, the prevention of delirium should be a priority in the ICU to achieve better patient outcomes.

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2. ACKNOWLEDGMENTS

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3. CONFLICT OF INTERESTS

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4. PERMISSION ISSUED BY ETHICS COMMITTEE

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5. ABBREVIATIONS

ICU - intensive care unit

DSM-5 - diagnostic and statistical manual of mental disorders; fifth edition PICS – post-intensive care syndrome

ICU-AW - intensive care unit acquired weakness

LTCI-CI – long-term cognitive impairment after critical illness PTSD – post-traumatic stress disorder

QOL – quality of life

HRQOL – health-related quality of life ARDS – acute respiratory distress syndrome SICU – surgical intensive care unit

PF – physical functioning MH – mental health

CABG – coronary artery bypass grafting POD – postoperative delirium

P-ADL – personal activities of daily living SCCM – society of critical care medicine A2F - ABCDEF

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6. TERMS

EQ-5D – European quality of life version 5D

EQ-5D-3L – European quality of life version 5D three-level

EQ-5D-VAS – European quality of life version 5D visual analogue scale EQ-6D - Dutch European quality of life – six dimensions self-qualifier SF-36 - the medical outcomes study 36-item short-form health survey CAM-ICU – confusion assessment method for the intensive care unit ICDSC – intensive care delirium screening checklist

RBANS – repeatable battery for the assessment of neuropsychological status TMT – trail making test

CFQ – cognitive failure questionnaire

DTI-MRI – diffuse tensor imaging magnetic resonance imaging FA – fractional anisotrophy

MOT – motor screening task SRM – spatial recognition memory

VVLT – visual verbal learning performance PHQ-9 – patient health questionnaire- 9 GAD-7 generalized anxiety disorder-7

PTSS-10 – post-traumatic stress symptom scale-10 SF-12 - medical outcomes study 12-item short form NIHSS – national institute of health stroke scale

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7. INTRODUCTION

Delirium is an acute neuropsychiatric syndrome that symptomizes an underlying acute brain dysfunction. Delirium as a phenomenon experienced by the patient is a state of altered consciousness, reduced awareness, impaired cognitive functions, and a general inability to focus, command attention or formulate thoughts coherently. It is often accompanied by confusion, delusions, fear, paranoia, hallucinations, disorientation, and misperceptions.

According to the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-V), delirium is an acute rapidly developing and volatile cognitive disturbance, representing a change from baseline in attention and awareness, with an additional disruption in memory, orientation, language, visuospatial ability, or perception. Delirium is caused by a concurrent medical condition, substance intoxication/withdrawal, or medication side effect. A diagnosis of delirium is excluded if the disturbance can be explained by another previously diagnosed neurocognitive disorder (namely dementia), or if the disturbance takes place is in the context of a severely reduced level of arousal, such as coma[1]. Delirium may additionally be accompanied by some psychomotor and emotional disturbances, like hyper/hypo-activity, sympathetic overstimulation, sleep-wake disturbances, fear, depression, euphoria, and perplexity. In recent decades, an intricate relationship between delirium in the intensive care unit (ICU) and mortality has been elucidated. But beyond survivability, further research is required to better understand the long-term outcomes of delirium in survivors of critical illness, especially in long-terms of cognition and quality of life. Our thesis aims to analyze the latest literature on the matter and summarize our findings in a manner that provides a comprehensive yet clear understanding for academics as well as health care professionals in an attempt to raise interest and awareness of this rather overlooked topic while setting a milestone and a template for future research.

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8. AIM AND OBJECTIVES

Aim of the thesis: to determine the long-term impact of delirium on critically ill patients. Objectives of the thesis:

1. Estimate the frequency of delirium in the ICU

2. Analyze the relationship between the duration of delirium and long-term cognitive impairment 3. Analyze the effect of delirium on the quality of life after discharge

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9. LITERATURE REVIEW (BACKGROUND?):

9.1 DELIRIUM IN THE ICU

Delirium is present in almost all hospital settings, but it is a major concern in the ICU. This is due to two main reasons. (1) The first is that ICU patients are originally at higher risk to develop delirium since an ICU population often consists of elderly patients, emergency surgery and trauma patients, and patients with high severity-of-disease, all high-risk groups for delirium[2–7]. (2) The second reason is that a stay in the ICU further precipitates the risk of delirium. The typical intensive care setting is a bad environment for rest. Around-the-clock, patients are exposed to light, monitor sounds, high activity, and they are often isolated or immobilized. Furthermore, sedation and mechanical ventilation are frequently required in the treatment of ICU patients. Some physicians might have the misconception that sedated patients are sleeping patients because deep sedation can give the impression of sleep or even a coma, but a sedated patient’s brain is active and unable to rest. Isolation, immobility, the absence of visits, benzodiazepines, and mechanical ventilation are all risk factors for delirium[3,4,8,9]. Sleep deprivation is also suggested to be a contributor to delirium[10]. Delirium is associated with various negative outcomes such as increased duration of mechanical ventilation, increased ICU length of stay, ICU readmission, admission to a nursing home, and mortality[11–13].

9.2 ICU-DELIRIUM AND MORTALITY

Before researchers focused their attention on the impact of delirium on survivors of critical illness, it was first necessary to determine the effect of delirium on survivability. Therefore, in the past two decades the relationship between delirium and mortality has been well analyzed and documented in the literature. In a 2004 study on mechanically ventilated patients, Ely EW et al. showed that delirious patients had more than double the risk of dying within 6 months after discharge[14].

Likewise, in 2010 Shehabi et al. found that delirium is an independent predictor of 30-day mortality in mechanically ventilated patients[11]. They also demonstrated an increase in 30-day mortality in

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correspondence with increasing duration of delirium. The relationship between the duration of delirium and survivability is depicted in Fig. 1.

Fig. 1 Kaplan-Meier graph showing the relationship between delirium and mortality (From Shehabi et al. Delirium duration and mortality in lightly sedated, mechanically ventilated intensive care patients)[11]

This relationship stimulates us to expect a similar relationship between increasing delirium duration and long-term cognitive impairment.

“With increasing life expectancy and with improved survival through the influence of surgery and antibiotics, we are now beginning to see an increasing incidence of so-called senile and arteriosclerotic dementias. Do we know how often such developments are initiated during delirious episodes experienced in the course of serious illness?” - Engel and Romano, 1959[15]

9.3 TERMINOLOGY SURROUNDING DELIRIUM AND THE OUTCOMES OF CRITICAL ILLNESS

One of the challenges of studying delirium is the heterogeneity of the terminology used to describe it. Popular terms include “ICU-psychosis”[16] (which was probably earlier used to describe hyperactive

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delirium), “acute confusional state” and “encephalopathy”[17,18]. Further, a bigger challenge is met when addressing the outcomes of critical illness. The relevant terms are briefly outlined below.

9.3.1 Post‐intensive care syndrome (PICS): a disorder that encompasses physical, cognitive, and mental

impairments that occur in the aftermath of critical care.

9.3.2 Intensive care unit‐acquired weakness (ICU‐AW): acute functional and neuromuscular

impairment which is acquired during critical care. It is a part of the physical component of PICS[19].

9.3.3 Long-term cognitive impairment after critical illness (LTCI-CI): the term is self-explanatory.

LTCI-CI can be viewed as a part of the cognitive component of PICS and should be differentiated from Alzheimer’s disease (AD), mild cognitive impairment (MCI), and postoperative cognitive decline (POCD).[20]

9.3.4 Post-traumatic stress disorder (PTSD): PTSD is a common sequela of critical illness[21], and is a

factor in the mental component of PICS.

9.4 ASSESSMENT OF QUALITY OF LIFE AFTER CRITICAL ILLNESS

When evaluating the quality of life (QOL) after critical illness, there is a trend to use two instruments: the EuroQol version 5D (EQ-5D) and the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36), both of which are measures of health-related quality of life (HRQOL) [22,23]. While this is beneficial for the systematization and comparison of results, such HRQOL instruments are potentially inaccurate measures of QOL, as they exclude general QOL domains[24].

9.5 INSTRUMENTS OF ASSESSMENT OF COGNITIVE FUNCTION AND QOL

1) Repeatable Battery for the Assessment of Neuropsychological Status (RBANS): a comprehensive test of global cognition by attention, language, visuospatial abilities, and immediate and delayed memory. The score of RBANS is on a scale of 40 to 160 with higher scores indicating better results.

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2) Trail Making Test (TMT): a neuropsychological test of memory (part A) and executive functioning (part B). It is scored on a scale of 0 to 100 with higher scores indicating better results. 3) Cognitive Failure Questionaire (CFQ): a 25-item questionnaire that measures failures of

perception, memory, and action in everyday life. The total score of CFQ is on a scale of 0 to 100 with higher scores indicating worse results.

4) Motor Screening Task (MOT): a test of the speed of motor skill

5) Spatial Recognition Memory (SRM): a test of visuospatial recognition memory

6) Visual Verbal Learning Test (VVLT): a test of memory and learning ability in the visual-verbal domain

7) Patient Health Questionnaire- 9 (PHQ-9): a self-test for depression. The score is on a scale of 0 to 27 with higher scores indicating worse results.

8) Generalized Anxiety Disorder-7 (GAD-7): a self-test of the severity of generalized anxiety. The score is on a scale of 0 – 21 with higher scores indicating worse results.

9) Post-Traumatic Stress Symptom Scale-10 (PTSS-10): an assessment of PTSD symptoms. The score is on a scale of 10 to 70 with higher scores indicating worse results.

10) European Quality of Life version 5D (EQ-5D): is an instrument for the measurement of HRQOL and contains 5 dimensions; mobility, self-care, usual activities, pain/discomfort, and anxiety/depression.

11) European Quality of Life version 6D (EQ-6D): is EQ-5D with a sixth dimension; cognition.

12) Medical Outcomes Study 36-item Short-Form Health Survey (SF-36): an instrument for the measurement of HRQOL by eight domains: physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, and mental health.

13) Medical Outcomes Study 12-item Short Survey (SF-12): a 12-item instrument for the measurement of HRQOL, based on SF-36.

14) Intensive Care Unit Memory Tool (ICUM): an instrument for the assessment of the recall of factual and delusional memories from the ICU.

15) Telephone Interview for Cognitive Status (TICS-m): is an instrument of assessment of global cognition especially designed to be performed by telephone.

16) Modified Rankin Scale (mRS): a scale for measuring the degree of dependence in daily activities in survivors of stroke. The scale ranges from 0 to 6 with higher scores indicating worse results 17) Quality of Life in Neurological Disorders (NeuroQol): an instrument that measures QOL in

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10. METHODOLOGY

10.1 INCLUSION CRITERIA

The inclusion criteria were the following: (1) observational studies and randomized controlled trials, (2) studies done on adult humans, (3) studies concerning ICU population that included delirium as a variable, (4) studies analyzing ICU-delirium and ICU-delirium outcomes, (5) studies published in the past 10 years (2010-2020), (7) full-text format accessible through the Lithuanian University of Health Sciences’

Databases’ function and (8) text is in English.

10.2 EXCLUSION CRITERIA

The exclusion criteria were the following: (1) other study designs, (2) studies published earlier than 2010, (3) studies analyzing delirium outside the context of the ICU or vice-versa, (4) full-text format inaccessible and (5) text is not in English.

10.3 IDENTIFICATION OF STUDIES

This systematic review was performed on the literature of ICU-delirium and its outcomes. The search for literature was conducted through the PubMed engine. The search terminology was divided according to the objectives of our thesis. The following are the search terms used in the Advanced Search Builder of PubMed:

1. Delirium incidence ICU

2. ((delirium) and (ICU OR intensive care OR critically ill)) and (cognition OR cognitive impairment OR cognitive dysfunction)

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3. ((delirium) and (intensive care OR ICU OR critically ill)) and (quality of life OR life quality OR health related quality of life OR hrqol)

The article selection process is presented in Fig. 2.

Fig. 2 Flow chart for selecting eligible articles

10.4 DATA EXTRACTION

For subsection 11.1, we extracted the following information from the articles: (1) the date and name of the author, (2) the method for delirium screening, (3) the total number of patients screened, and (4) the number of positive delirium patients. For subsections 11.2 and 11.3, we extracted, analyzed, and summarized information on methodology (assessment instruments, time-line, and study design) and results that are of value to our objectives, and narratively presented them.

1829 results yielded in PubMed

110 articles reviewed in PubMed

1719 excluded (title and date)

52 excluded (abstract review)

58 articles distilled for full-text review

24 articles excluded (full-text review)

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11. RESULTS

A total of 34 articles were included in our thesis, of which 22 (with a total of 13,092 patients) pertained to the incidence of delirium in the ICU, 6 pertained to the duration of delirium and long-term cognitive impairment and 8 pertained to delirium and quality of life (2 studies were used in 2 different subsections).

11.1 INCIDENCE

The results are summarised in Table 1.

Table 1. The incidence of delirium in 22 intensive care units

Name of the first author

Study design Population characteristics Delirium screening method Total patients screened (n) Total positive delirium patients (n/%) Rasheed et al. [9] Prospective cohort study Mixed CAM-ICU 342 59 (17,3) Tsuruta et al. [25] Prospective cohort study Mixed CAM-ICU 103 21 (20) Woien et al. [26] Prospective cohort study Mixed CAM-ICU 139 32 (23,4) Van Den Boogaard et al. [27] Prospective cohort study Mixed CAM-ICU 1613 411 (26) Kanova et al. [5] Prospective cohort study Mixed CAM-ICU 284 74 (26.1) Pan et al. [28] case-control

study Mixed CAM-ICU 452 163 (36.1) Wolters et al. [29] Prospective cohort study Mixed CAM-ICU 1101 412 (37) Limpawattana et al. [30] Prospective cohort study Mixed (≥ 65 years) CAM-ICU 99 44 (44,4) Mori et al. [2] Prospective

cohort study

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18 Yamamoto et al. [31] Randomized control trial Mixed (sepsis + mechanically ventilated) CAM-ICU 178 89 (48) Klein Klouwenberg et al. [32] Prospective cohort study Mixed CAM-ICU 1112 552 (50,2) Kwizera et al. [33] Prospective cohort study Mixed CAM-ICU 160 81 (50,94) Mehta et al. [34] Randomized control trial Mixed (mechanically ventilated) ICDSC 420 226 (53,8)

Mesa et al. [35] Prospective cohort study Mixed CAM-ICU 230 184 (80) Falsini et al. [36] Prospective cohort study Medical (cardiac) CAM-ICU 726 111 (15,3) Tilouche et al. [3] Prospective cohort study Medical CAM-ICU 206 39 (19) Sanchez-Hurtado et al. [37] Prospective cohort study Medical (cancer) CAM-ICU 109 25 (22.9) Jayaswal et al. [38] Prospective cohort study Medical CAM-ICU 280 88 (31.4) Shehabi et al. [11] Prospective cohort study Medical (mechanically ventilated) CAM-ICU 354 228 (64,4) Pipanmekaporn et al. [6] Prospective cohort study Surgical ICDSC 4450 162 (3,6) Habeeb-Allah et al. [39] Prospective cohort study Surgical (cardiac) CAM-ICU 245 22 (9) Chaiwat et al. [40] Prospective cohort study Surgical CAM-ICU 250 61 (24.4) 13,092 3153 (24) Table 1. Results are filled in order of population and ascending incidence order. Mixed = medical, surgical, and trauma patients, CAM-ICU = confusion assessment method for the intensive care unit, ICDSC = intensive care delirium screening checklist

The main screening method was the CAM-ICU, and only two cohorts used the ICDSC. The lowest reported rate of delirium was 3.6% and the highest was 80%. In 17 of the 22 studies, the rate of delirium in the ICU was ≥ 20%. All three cohorts of mechanically ventilated patients had high rates of delirium

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(48%, 53.8%, and 64.4%). The average rate of delirium in the total number of mixed ICU patients would be 37.4% (2426/6472).

11.2 DURATION OF DELIRIUM AND LONG-TERM COGNITIVE IMPAIRMENT

An early study by Girard et al. was the first to identify deliruim as an independent predictor of long-term cognitive impairment. They uncovered a positive association between the duration of delirium and long-term cognitive impairment when using a specially designed comprehensive battery for cognitive assessment. This association was statistically significant (independent of all covariates) at 3 months (p = 0.02) and up to 12 months post-discharge (p = 0.03)[41].

Pandharipande et al. further elaborated this relationship in the Bringing to Light the Risk Factors and Incidence of Neuropsychological Dysfunction in ICU Survivors (BRAIN-ICU) study, a landmark study that employed the RBANS and TMT_B to asses cognition. Their first finding was that the duration of delirium is independently associated with worse global cognition and executive functioning at 3 months (p = 0.001 and p = 0.004 respectively) and 12 months (p = 0.04 and p = 0.007 respectively) post-discharge. A second finding was that survivors of critical illness often suffer cognitive impairment that is equivalent score-wise to mild traumatic brain injury(34% at 12-months) and mild Alzheimer’s disease(24% at 12 months)[42].

Wolters et al. demonstrated a similar relationship when examining the duration of delirium and self-reported cognitive impairment assessed by CFQ 1 year post-discharge. Patients with multiple days of delirium scored significantly higher (worse) on CFQ than patients without delirium after adjusting for covariates, while patients with only one day of delirium scored similarly to patients without delirium (p = 0.02)[43].

Furthermore, Girard et al. investigated cognitive impairment linked to different clinical phenotypes of delirium; hypoxic, sedative-associated, septic, and metabolic delirium. A fifth type, unclassified delirium, was designated positive delirium diagnosis that did not fit any of the aforementioned phenotypes. The RBANS was used to assess global cognition. The results are shown in Table. 2. Longer durations of hypoxic, sedative-associated, and unclassified delirium predicted worse cognitive impairment scores at both 3 and 12 months, while longer durations of septic delirium only had an association with cognitive

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impairment at 12 months. Only metabolic delirium had no association with global cognition at either time[44].

Table 2. Point estimates of the associations between delirium phenotypes and long-term cognition Comparison RBANS global cognition at 3

months

RBANS global cognition at 12 months Hypoxic 3 vs 0 days −3·85 (−7·07 to −0·64) −3·76 (−7·16 to −0·37) Septic 3 vs 0 days −2·65 (−6·05 to 0·75) −3·67 (−7·13 to −0·22) Sedative-associated 3 vs 0 days −6·52 (−9·66 to −3·37) −4·03 (−7·80 to −0·26) Metabolic 3 vs 0 days 0·15 (−1·52 to 1·81) 1·44 (−0·12 to 3·01) Unclassified 3 vs 0 days −4·72 (−6·93 to −2·51) −4·70 (−7·16 to −2·25)

(From Girard et al. Clinical phenotypes of delirium during critical illness and severity of subsequent long-term cognitive impairment: a prospective cohort study)[44]

A pilot study by Morandi et al. hypothesized a relationship between the duration of delirium, brain integrity, and consequent long-term cognitive impairment. To investigate their hypothesis they used Diffuse Tensor Imaging-Magnetic Resonance Imaging (DTI-MRI) to calculate Fractional Anisotrophy (FA) (a measure of white matter integrity). Firstly, they found a significant association between longer duration of delirium and white matter disruption (lower FA scores) in the genum and the splenium of the

corpus callosum (at discharge and after 3 months), the anterior limb of the internal capsule (at discharge),

and in the body of the corpus callosum (at 3 months). Secondly, they found that lower FA scores are associated with worse long-term cognitive impairment, as shown in Fig. 3[45].

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Lower FA in the anterior limb of the internal capsule (ALIC) (indicative of white matter disruption) at discharge was associated with worse attention scores at 3-month follow-up, after adjusting for age and presence of sepsis. Figure 3B) Lower FA (indicative of white matter disruption) in the genu of the corpus callosum (GCC) at 3-month was associated with better attention scores at 12-month follow-up, after adjusting for age and presence of sepsis. The solid black line shows the point estimate of the association between FA and cognitive outcomes, and the dash line indicates the 95% confidence interval.

(From Morandi et al. The relationship between delirium duration, white matter integrity, and cognitive impairment in intensive care unit survivors as determined by diffusion tensor imaging: the VISIONS prospective cohort magnetic resonance imaging study)[45]

Lastly, Denke et al. examined Acute Respiratory Distress Syndrome ARDS survivors50 ± 6 months post-discharge and performed cognitive assessments. A significant association was found between longer durations of delirium and cognitive impairment in the following domains; the speed of motor skills (p = 0.012) as measured by MOT, visual memory performance (p = 0.001) as measured by SRM, and learning efficiency and episodic declarative memory (p = 0.016) as measured by VVLT (p = 0.016)[46].

11.3 DELIRIUM AND QUALITY OF LIFE

A retrospective study by Wang et al. investigated 3-month psychiatric comorbidity in participants in the Pharmacologic Management of Delirium (PMD) clinical trial. Psychiatric assessment was performed using three instruments; PHQ-9, GAD-7 and PTSS-10, and QOL assessment using the EQ-5D-3L Index and the EQ-5D-VAS. 18/58 patients exhibited significant symptoms of depression, anxiety, and PTSD and were considered to have high psychiatric comorbidity. Furthermore, high psychiatric comorbidity was significantly associated with worse QOL in comparison with low to moderate comorbidity as measured by

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the EQ-5D-3L and the EQ-5D-VAS (p = 0.017 and p = 0.039 respectively). A direct relationship between delirium and QOL was not examined[47].

A prospective cross-sectional study by Chen et al. recruited patients who underwent coronary artery bypass grafting (CABG), and assessed by telephone interview for cognitive function (TICS-m), and QOL (SF-36) at 1 to 18 months post-discharge. Overall, 59.1% of the postoperative delirium (POD) group and only 17.4% of the non-POD group developed cognitive impairment (p < 0.05). The incidence of cognitive impairment in the POD group was relatively consistent throughout the whole interval (1 – 18 months) (p = 0.986), and POD was proven an independent risk factor for cognitive impairment after ICU-stay (p < 0.001). Cognitive impairment was in turn found to be significantly associated with worse QOL after discharge (p = 0.001), but no association was found between POD and QOL (p = 0.871)[48].

A similar observation was reported in a large prospective study by Wolters et al. that used EQ-6D to test cognitive functioning and QOL in a cohort of 1,101 subjects 1 year post-discharge. While there was a significant association between delirium and self-reported mild (p < 0.001) and severe cognitive impairment (p = 0.03), no statistically significant association was found between delirium and lower QOL after adjustment for confounders (p = 0.09)[29].

Likewise, in the ARDS survivors study by Denke et al., 16% of patients were diagnosed with PTSD, and longer duration of delirium was significantly associated with subsequent PTSD diagnosis (median,7 days is PTSD patients vs median, 2 days in non-PTSD patients) (p < 0.027). Moreover, PTSD was significantly associated with worse results in the mental dimension of the SF-12 compared to patients without PTSD (p ≤ 0.021). A relation between delirium and SF-12 scores was not examined[46].

In a prospective study of 562 Surgical ICU (SICU) patients, Abelha et al. found evidence that at 6 months post-discharge, POD is an independent risk factor for dependence in personal activities of daily living (P-ADL) (p < 0.001), and an independent predictor of worse HRQOL as measured by three domains of the SF-36, physical functioning (B = 17.402, p = 0.007), vitality (B = 8.221, p =0.015) and social functioning (B = 16.805, p 0.005) (B represents the change in each SF-36 domain by the linear regression model, where the variable is delirium)[49].

A recent retrospective study by Niittvuopio et al. enrolled 332 patients who attended a post-intensive care follow up clinic 3 months post-discharge and measured HRQOL using the 36. Two domains of the

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36; physical functioning (PF) and mental health (MH) were used to classify patients as impaired or normal as compared with SF-36 measurements from healthy controls. Delirium was found to be the only ICU risk factor for impaired MH in this study, as 72% of patients with impaired MH experienced delirium during the ICU stay as compared to 50% of patients with normal MH (p = 0.037). In their interview at the follow-up clinic, patients with an impaired MH expressed fewer memories of visits by relatives (8% versus 26%, p = 0.028) and fewer memories of nurses (4% versus 21%, p = 0.041)[50].

A prospective study by Naidech et al. aimed to determine the prognostic significance of ICU-delirium in terms of functional outcomes and quality of life in survivors of intracerebral hemorrhage. They enrolled 114 patients and performed mRS and Neuro-QOL measurements at 28 days, 3 months, and 12 months post-discharge. After correction for age, national institute of health stroke scale (NIHSS) on admit, and any benzodiazepine use, delirium was independently associated with worse QOL in the domains of applied cognition–executive function, and fatigue at all intervals as compared with the general population (p = 0.045 and p = 0.01 respectively). Delirium was also associated with functional disability at 1 month (p = 0.018)[51].

An observational multicentre study by Svenningsen et al. focused on the qualitative analysis of the relationship between delirium, memories, and HRQOL. 360 ICU patients were recruited and interviewed by telephone using the ICUM tool one week after discharge, then re-interviewed after two and six months and supplemented with SF-36. Delirious patients had significantly less factual memories and more memories of delusions concerning their ICU stay compared to non-delirious patients, and significantly more delirious patients had no memories of the ICU at all (p < 0.001). Memories of delusions comprised most of the delirious patients’ memories, and such memories were fragmented and incoherent. No significant association was seen between delirium and any of the eight domains of the SF-36 at any time point[52].

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12. DISCUSSION

Although a conservative estimate (considering the lack of interest and training in the detection of delirium), we can state with confidence that at least 1 in 5 patients admitted to the ICU will develop delirium. Beyond that, our findings show that approximately half of all mechanically ventilated patients develop delirium, and the rate of delirium can reach an alarming 80% in some populations. This has huge implications when taking into account that among other complications, delirious patients are at an increasingly higher risk of dying anytime between their ICU stay and the consecutive 6 months. Furthermore, the discrepancies in the rates of delirium between different cohorts could be attributed to the type of cohort (mixed, medical, surgical, cancer and cardiac), the baseline characteristics, comorbidities, and severity of illness of the patients, as well as the competence of the evaluators of delirium.

There is a clear positive association between the duration of delirium and cognitive impairment in the long term, specifically in the domains of attention/concentration, immediate and delayed memory, executive functioning, visuospatial abilities, and learning. These impairments are consistently reported by objective testing and subjective self-evaluation of cognitive function, and seem to be persistent at 3 months, 12 months, 18 months, and as long as 4 years post-discharge. A 2015 study found newly developed cognitive impairment in about a fifth of ICU patients at the time of discharge and indicated a positive association between the severity of ICU-delirium and cognitive impairment at discharge[53]. Based on this finding and the association of delirium with the corruption of white matter integrity of the brain, we hypothesize that the cognitive impairment experienced in the long-term by ICU survivors could partly be a direct effect of the organic process of delirium, as an acute brain failure that potentially inflicts permanent damage to the brain, and leaves the patient with what resembles dementia.

We could not discuss LTCI-CI outside the scope of PICS. That is because LTCI-CI is itself the cognitive component of the PICS triad (physical, mental, and cognitive). According to the Society of Critical Care Medicine (SCCM), PICS is defined as an impairment in at least one of its three components, ie. a patient with LTCI-CI is by definition a patient with PICS. To avoid confusion over terminology, it is advised that intensive care specialists and academics in the field adopt a unified pool of terminology for usage in academia as well as in the course of health care. We suggest LTCI-CI be studied as a branch of PICS rather than a separate entity, to enable systematization of data and avoid dispersion and duplication of information.

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We believed it is intuitive to expect that as delirium has deleterious effects on cognition, it would harbor similar effects on QOL. However, our results were inconclusive. Out of 8 studies included, only 2 studies indicated an association between delirium and QOL, and out of 4 studies using the SF-36/SF-12, only 1. There was no clear effect of delirium on quality of life as per the remaining studies. This might be due to two reasons. First, the concept of quality of life is not readily defined and cannot be easily measured. Second, most of the studies on delirium and quality of life use the EuroQol-5d and the SF-36, which might not be ideal for the testing of overall quality of life, and additionally, these tools might be inadequate in detecting the effects of such variables as delirium on HRQOL[52]. Nonetheless, even the articles that found no association between delirium and QOL still imply that delirium does, in fact, affect QOL, but this effect is indirectly presented with the aid of an intermediary; Since delirium is associated with depression, anxiety, PTSD, and cognitive impairment, and since each of these factors is associated with worse QOL, we interpret that delirium may have a covert effect on QOL through its effect on psychiatric and cognitive health. Our findings also point to an intricate and complex relationship between delirium and memory. Delirium is often accompanied by memories of delusion which might be a key component in the development of PTSD.

Ultimately, delirium is a major issue in critical care and has huge implications for patient outcomes. A stay in the ICU can be a critical point in the lives of patients, as they are likely to be discharged to a life of lesser quality than their life before the ICU, with newly acquired cognitive and mental health problems. It is essential to understand that the course of critical care plays a key role in the development and perpetuation of delirium and that it is in the hands of intensivists to limit this role. Reducing the incidence and duration of delirium will improve the results of critically ill patients. We urge intensivists to prioritize the prevention of delirium in their daily practice and adopt different methods and initiatives to reduce the risk factors involved. Such initiatives are already taking place, like the one by the Society of Critical Care Medicine known as the ICU Liberation Bundle or the ABCDEF bundle (A2F bundle). The A2F bundle is a comprehensive management guide based on modern literature. It is comprised of six components that promote ideal care of critically ill patients, with emphasis on reducing delirium and improving long-term outcomes[54]. The A2F bundle focuses on (1) optimizing the management of pain, (2) refining the choice, dose, and mode of administration of sedative and analgesic agents, (3) interrupting sedation and mechanical ventilation to allow spontaneous breathing, (4) preventing and managing delirium, (5) reducing the time of immobility and bed-rest and encouraging patients to move, as well as (6) involving the patient’s family in the course of treatment. The A2F Bundle has shown great promise in improving the outcomes of critical illness[55].

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13. CONCLUSION

Delirium is a serious and frequent complication in the ICU and has long-lasting detrimental effects on cognitive and mental functions, and potentially the quality of life in survivors of critical illness. The conventional course of critical care largely influences the emergence of delirium and thus, the prevention of delirium should be a priority in the ICU to achieve better patient outcomes.

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Lithuanian University of Health Sciences Faculty of Medicine Department of Intensive Care Hady Sayah