Cognitive outcomes after C ritical Illness

1. Cognitive outcomes after Critical Illness Prof. GamalElewa, MD Faculty of Medicine, Ain Shams University 27 29th March, 2019 Egyptian Annual Conference

2. AGENDA • Prevalence of neurocognitive impairment in critically ill • Spectrum of neurocognitive impairment in critically ill patients • Risk factors of neurocognitive dysfunction • Delayed sequelae of neurocognitive impairment in critically ill • Prevention and treatment

3. INTRODUCTION • Intensivistsare alert to dysfunctions in pulmonary, cardiac, and renal parameters as a source of morbidity and mortality in ICU patients • Effect of this illness on brain function is for long ignored and under-appreciated. • Thus, despite improvements in short-term outcomes, (ICU) survivors suffer considerable long-term complications* • Society of Critical Care Medicine did a conference in which these long-term complications were named “Post-intensive care syndrome”# • *Oeyen, et al. Quality of life after intensive care: a systematic review of the literature. Crit Care Med 2010; 38:2386–400 • # Needham, et al. Improving long-term outcomes after discharge from intensive care unit: report from a stakeholders’ conference. Crit Care Med 2012; 40:502–9

4. INTRODUCTION • Survivors of critical illness often suffer from new or exacerbation of baseline neurological dysfunctions unrelated to their primary illness. • This Neurocognitive impairment is: • - prevalent, • - important, • - neglected (under reported and under studied) and • - potentially modifiable • Valsanet al, Medical Science, Vol. 7, Issue 2, Feb. 2017. ISSN – 2249 • IwashynaTJ. Survivorship will be the defining challenge of critical care in the 21stcentury. Ann Intern Med 2010;153:204–5 • Jackson JC, Ely EW. Cognitive impairment after critical illness: aetiologies, risk factors, and future directions. SeminRespirCrit Care Med 2013;34(2):216–22

5. DEFINITIONS • Post intensive care syndrome (PICS) includes psychiatric and physical dysfunction. • At least, half of patients discharged from ICUs have at least one manifestation of PICS • Current data suggest that neurocognitive impairment after an ICU stay is common and it persists 6 years or more after hospital discharge

6. D.D. • Mild cognitive impairment differs from cognitive impairment after an ICU stay • Mild cognitive impairment is: • - progressive and • - associated with aging, • Cognitive impairment in ICU survivors: • - develops rapidly after acute illness and • - usually related to numerous pathologic and neurochemical pathways

7. DEFINITION • Petersen et al (1999) proposed initial criteria for mild cognitive impairment: • • Memory impairment in relation to age and education • • Normal general cognitive functioning • • Normal activities of daily living • • No dementia. • Petersen et al. Mild cognitive impairment: clinical characterization and outcome. Arch Neurol 1999; 56:303–8

8. DEFINITION • Later, other areas of impairment besides memory were recognized, such as language, attention, perception, reasoning, and motor planning* • Therefore, mild cognitive impairment is currently classified into subtypes: • - amnestic (affecting single or multiple domains) and • - non amnestic (also affecting single or multiple domains)# • Wergin R and Modrykamien A. Cognitive impairment in ICU survivors: Assessment and therapy. Cleveland clinic J of Medicine, Oct 2012; vol 78: 10 • *Palmer et al. What is mild cognitive impairment? Variations in definitions and evolution of nondemented persons with cognitive impairment. ActaNeurolScandSuppl 2003; 179:14–20 • #Petersen RC. Mild cognitive impairment as a diagnostic entity. J Intern Med 2004; 256:183–94

9. DEFINITION • Impairment of specific cognitive domains may be challenging to detect, and neuropsychological testing is often needed. • Cognitive impairment is usually diagnosed using restrictive or comprehensive evaluation tools. • *Lonieet al. Screening for mild cognitive impairment: a systematic review. Int J Geriatr Psychiatry 2009; 24:902–15

10. Neurocognitive Assessment and Diagnosis • Montreal Cognitive Assessment is probably the one most often used since it is readily available, simple, and reliable, with high sensitivity (90%) and specificity (87%) • It evaluates orientation, memory, language, attention, reasoning, and visual-constructional abilities. • Maximum score is 30; cognitive impairment is definedas a score of < 26 • *Informant Questionnaire On Cognitive Decline in Elderly (IQCODE) (for patients >50 years and patients <50 years with known memory problems): to assess any pre-existingneurocognitive impairment • Deliriumduring hospital stay is assessed using Confusion Assessment Method for ICU (CAM-ICU) and Richmond Agitation-Sedation Scale (RASS) • Delirium is diagnosedif RASS >3 awake and CAM-ICU positive • Wergin R and Modrykamien A. Cognitive impairment in ICU survivors: Assessment and therapy. Cleveland clinic J of Medicine, Oct 2012; vol 78 (10 • *Valsanet al, Cognitive impairment in critically ill. Indian Journal of Applied Research. Feb. 2017

11. Neurocognitive Assessment • Patients are assessed at time of discharge or at 30 days afterweaning from ventilator by the following tests : • a. Components of PGI-BBD (PGI brain dysfunction battery developed by Pershad et al., at PGIMER, in India): • i. PGI Memory Scale (PGIMS): • ii. Bender Gestalt test: visual motor maturation • iii. Nahor Benson test- • iv. Trail making test Part B: visuo-conceptual and visuo-motor functions

12. Neurocognitive Assessment • i. PGI Memory Scale (PGIMS)*: • It is to assess multiple domains of neuropsychological status of adults • It has 10 sub parts, one each for: • - remote memory - recent memory, • - mental balance - attention • - concentration - delayed recall, • - immediate recall - verbal retention for dissimilar pairs, • - visual retention, and - recognition • *PershadD, Wig NN. A battery of simple tests of memory for use in India. Neurol India. 1976; 24:86–93

13. Neurocognitive Assessment • A patient was considered to have neuro-cognitive dysfunction, if he/she is scored positive on any of the psychometric tests positive for dysfunction • Any score other than 0 was considered positive.

14. Neurocognitive Assessment and Diagnosis • Besides formal testing, an informalevaluation is recommended • Informal evaluation includes: word definition, reading and verbal fluency, reading comprehension, and performance of instrumental activities of daily living. • Observing patients daily tasks provides therapists with information, as these tasks require using multiple cognitive processes. • So, if functional breakdown occurs during this assessment, clinician needs to identify the domain or specific level of cognitive dysfunction involved in that deficit* • *VogenthalerDR. An overview of head injury: its consequences and rehabilitation. BrainInj 1987; 1:113–27

15. Neurocognitive Assessment and Diagnosis • Other tests of cognition assessindividualdomains. • Studies of long-term cognitive impairment after ICU admission used these Specific tests to define outcomes.(25) • • Digit Span and Trail making Test A (assess attention and orientation)* • • Rey Auditory Verbal Learning Test (evaluate verbal memory) • • Complex Figure Test (helpful in defining visual-spatial construction and delayed visual memory) • • TrailmakingTest B (also included in Montreal Cognitive Assessment; assess executive function). • *Girard et al. Delirium as a predictor of long-term cognitive impairment in survivors of critical illness. CritCare Med 2010; 38:1513–20

16. INCIDENCE • Moller and colleagues evaluated cognitive function in patients aged ≥ 60 yr after major abdominal and orthopedic surgery: • About 25% of patients had cognitive dysfunction a week after surgery and 10% had cognitive changes 3 months p.o. • But, in healthy control,in same age, and did not undergo anesthesia and surgery, incidence was only 3% • Although incidence of late p.o. cognitive dysfunction was 14% for patients >70 yr, it was only 7% for patients between ages of 60 to 70 yr. • Moller, et al. Long-term postoperative cognitive dysfunction in the elderly: ISPOCD1 study. The Lancet 1998;351:857-61

17. PREVALENCE • Hopkins et al analyzed 10 cohort studies of long-term cognitive impairment after an ICU stay: • Prevalencewas high: • - 78% at hospital discharge, • - 46% at 1 year, and • - 25% 6 years after discharge • Of the cognitive domains compromised, • - memory was the most often affected, • - followed by executive function and attention* • Hopkins RO, Jackson JC. Long-term neurocognitive function after critical illness. Chest 2006; 130:869–78 • *Sukantaratet al. Prolonged cognitive dysfunction in survivors of critical illness. Anaesthesia 2005; 60:847–53

18. PREVALENCE • Prevalence of neuro-cognitive dysfunction: • At time of icu discharge:24.5% • At 3 months of discharge:almost 50% of patients • Cognitive impairment occurs in up to 1/3 of ICU patients and may affect one or more cognitive domains* • *WerginR and Modrykamien A. Cognitive impairment in ICU survivors: Assessment and therapy. Cleveland clinic J of Medicine, Oct 2012; vol 78 (10)

19. Spectrum of neuro-cognitive dysfunction • 1. At time of discharge: Delayed recall, recent memory, retention for dissimilar pairs • At 3 months:visuomotor and executive functions were primarily impaired. • 2. Attention, immediate recall, mental balance, recent memory, retentionfor similar pairs, visual retention were less affected both at time of discharge and 3 months follow up. • Valsanet al, Cognitive impairment in critically ill. Indian Journal of Applied Research. Feb. 2017

20. CAUSES and RISK FACTORS • Potential causes: • - hypoxemia • - hypotension • - hyperglycemia: - > 153 mg/dL, and - higher glucose variability • - sedation and delirium • Hopkins RO, Jackson JC. Long-term neurocognitive function after critical illness. Chest 2006; 130:869–78 • Hopkins et al. Quality of life, emotional, and cognitive function following ARDS. J Int Neuropsychol Soc 2004; 10:1005–17 • Hopkins et al. Blood glucose dysregulation and cognitive outcome in ARDS survivors. Brain Inj 2010; 24:1478–1484

21. CAUSES and RISK FACTORS • Patients on mechanical ventilation are commonly given sedatives and analgesics. These medications are strongly associated with delirium • Benzodiazepineshave an independent, dose-related, temporal association with delirium, with 20% increase in delirium/ milligram of benzodiazepine • In another study, morphinewas the strongest predictor of delirium, with 6 fold increase • Arroligaet al. Use of sedatives opioids, and neuromuscular blocking agents in patients with acute lung injury and acute respiratory distress syndrome. Crit Care Med 2008; 36:1083–8 • Miller et al. Delirium and cognitive dysfunction in the intensive care unit. SeminRespirCrit Care Med 2006; 27:210–20 • Pandharipandeet al. Lorazepam is an independent risk factor for transitioning to delirium in intensive care unit patients. Anesthesiology 2006; 104:21–6 • Dubois et al. Delirium in an intensive care unit: a study of risk factors. Intensive Care Med 2001; 27:1297–304

22. CAUSES and RISK FACTORS • At time of discharge: • - mean ventilation days • - delirium days • - presence of respiratory failure • - sepsis • - alcohol consumption • Age, sex, use of physical restraints, smoking or type of ICU admission did not have significant association • Valsanet al, Cognitive impairment in critically ill. Indian Journal of Applied Research. Feb. 2017

23. CAUSES and RISK FACTORS • Risk factors for early (1 week) p.o. cognitive dysfunction: • -increasing age • - duration of anesthesia • - low education level • - a need for a second operation • - p.o.infection • - respiratory complications. • Moller, et al. Long-term postoperative cognitive dysfunction in the elderly: ISPOCD1 study. Lancet 1998;351:857-61

24. CAUSES and RISK FACTORS • At 3 months after discharge: • - the strongest predictor for development of neurocognitive decline was its presence at time of discharge (all patients who had decline at discharge continued to have it at 3 months) • age: - It is about 14% for patients >70 yr, and • - only 7% for patients between the ages of 60 to 70 yr • - The other significant factor was duration of delirium • Valsan et al, Cognitive impairment in critically ill. Indian Journal of Applied Research. Feb. 2017

25. CAUSES and RISK FACTORS • Whether delirium is associated with, or leads to cognitive dysfunction is unknown. • As delirious patients are more likely to be sicker, older, mechanicallyventilated, require more sedation, the association between delirium and cognitive impairment may reflect the relationship between these risk factors and poor cognitive outcomes • Miller RR 3rd, Ely EW. Delirium and cognitive dysfunction in the intensive care unit. Curr Psychiatry Rep 2007; 9:26–34

26. CAUSES and RISK FACTORS • 6 months after hospital discharge: • Mechanical ventilation:1/3 patients showed signs of neurocognitive impairment • Jackson JC, Hart RP, Gordon SM, et al. Six-month neuropsychological outcome of medical intensive care unit patients. Crit Care Med 2003; 31:1226–34

27. PATHOGENESIS • The neurotransmitter acetylcholine is thought to be involved in cognitive functionas well as neuroplasticity of the motor cortex. • After stroke, activity of cholinergic system is reduced • Dopamine augmentation enhances simple motor memories and improves procedural learning. • Understanding of these neurochemical alterations opens opportunities for investigation of drug therapies. • WerginR and Modrykamien A. Cognitive impairment in ICU survivors: Assessment and therapy. Cleveland clinic J of Medicine, Oct 2012; vol 78: 10 • Court JA, Perry EK. Neurotransmitter abnormalities in vascular dementia. Int Psychogeriatr 2003; 15(suppl 1):81–7

28. MECHANISM • It seems that mentalhorrors (memories of delusions) experienced by ICU patients are more traumatizing than actual physical ones • Jones et al: Rehabilitation after critical illness: a randomized controlled trial. Crit Care Med 2003, 31:2456- 61

29. MECHANISM • There’re 2 hypotheses regarding relation between delirium in ICU and cognitive dysfunction in the coming years: • 1) Default hypothesis: • ICU delirium and post-ICU cognitive impairment have a commoncause, the nature of which is not yet discovered • 2) Heretical alternative hypothesis: • Delirium might, in some instances, be responsible for the low neuropsychological test scores in post-ICU patients. • Both hypotheses could be true: • - in some instances, there may be a common cause and • - in some instances, delirium may be a confounding factor in testing for cognitive impairment • Jackson et al: Research issues in the evaluation of cognitive impairment in intensive care unit survivors. Intensive Care Med 2004, 30: 2009-16

30. MECHANISM • Post-ICU cognitive impairment might represent, at least in part, a psychological reaction not only to stress of ICU delirium but also to the whole phenomena that arise from critical illness. • Reduced reserves, fatigue, extreme weakness, and decreased quality of life might have an impact on results of tests for post-ICU cognitive impairment • Misak. Critical Care 2009, 13:312

31. MECHANISM • Confidence and moral outcomes: • Thinking you are likely to be cognitively impaired may affect your performance on cognitive function tests. • When medical community is interested in one’s neurocognitive status, it’s an alert that there is an expectation of cognitive damage. • Misak. Critical Care 2009, 13:312

32. MECHANISM • Practical and ethical upshots • Poor performance may be induced either by: • - organic/biochemical problem (such as hypoxia or liver failure) or • - functional problem (such as psychological fallout from delirium, fatigue, or a lack of confidence) • Whatever the cause, the brain is not working properly and there is impairment. • However, the difference in what induces poor performance is important in terms of interventions and ethical outcomes • Misak. Critical Care 2009, 13:312

33. EFFECTS • Cognitive impairment during hospitalization is associated with complications: • - hypotension, • - hyperglycemia, • - hypoxemia, and • - delirium • Valsanet al, Cognitive impairment in critically ill. Indian Journal of Applied Research. Feb. 2017

34. MECHANISM • So, inquiry needs to be conducted to: • - Physicalfactors that might influence neurocognitive outcomes for those critically ill • - Individuals factors such as: increasing age, prior cognitive reserve, genetic factors that might influence responses to injury, and capacity to repair • - Externalfactors such as extent, duration, and nature of specific metabolic events and sedative regimens. • - Emotional and psychological factors that might influence neurocognitive outcomes for these patients. • Then, the question, whether these factors influence test scores • Misak. Critical Care 2009, 13:312 • Jackson et al: Research issues in the evaluation of cognitive impairment in intensive care unit survivors. Intensive Care Med 2004, 30: 2009-16

35. EFFECTS • These impairments lead to: • - ↓ quality of life: especially its physical component • - layoffs, • - absenteeism • - rising health care expenditure • - Post-traumatic stress disorder, depression, and sexual dysfunction are reported years after discharge • Herridge, et al. Functional disability 5 years after acute respiratory distress syndrome. N Engl J Med 2011; 364:1293–304 • Timmers, et al. Long-term quality of life after surgical intensive care admission. Arch Surg 2011; 146:412–8 • Griffiths, et al. Sexual dysfunction in intensive care survivors. Br J Hosp Med (Lond) 2007; 68:470–3

36. EFFECTS • Poor outcomes from rehabilitation: • Strokepatients with cognitive alterations are less likely to be discharged home or to be living at home 6 months after discharge • They cannot fully participate in rehabilitation activities, due to: • - impairment in executive function, • - inability to remember therapy instructions, or • - disruption of implicit and explicit learning. • So, manipulation or enhancement of cognition may directly affect rehabilitation outcomes • Whyte et al. Cognitive impairment in acquired brain injury: a predictor of rehabilitation outcomes and an opportunity for novel interventions. PMR 2011; 3(suppl 1):S45–S51 • HenonH, et al. Confusional state in stroke: relation to preexisting dementia, patient characteristics, and outcome. Stroke 1999; 30:773–9

37. PREVENTIVE STRATEGIES • Because data are few about therapies for this complication, prevention is the main strategy • During ICU stay: • - optimizing hemodynamics, glucose, and oxygenation • - Apply “ABCDE” bundle of strategies (due to the association between sedation, delirium, and consequent cognitive impairment) • ABCDE stands for Awakening and Breathing, Choice of sedatives with fewer adverse effects, Daily delirium monitoring, and Early mobility exercise. • These strategies can prevent delirium; however, they are not proved to prevent cognitive impairment. • Wergin R and Modrykamien A. Cognitive impairment in ICU survivors: Assessment and therapy. Cleveland clinic J of Medicine, Oct 2012; vol 78: 10 • van den Boogaard et al. Delirium in critically ill patients: impact on long-term health-related quality of life and cognitive functioning. Crit Care Med 2012; 40:112–8 • Morandiet al. Sedation, delirium and mechanical ventilation: the ‘ABCDE’ approach. CurrOpinCrit Care 2011; 17:43–9

38. PREVENTIVE STRATEGIES • i - Awakening and breathing: • ie, sedatives are interrupted every morning to awaken the patients, and if so, see if they can breathe on their own): • - They are extubated 3 days earlier • - ICU and hospital stay are 4 days shorter • - over 1 year, mortality rate is lower by 14 % • Girard et al. Efficacy and safety of a paired sedation and ventilator weaning protocol for mechanically ventilated patients in intensive care (Awakening and Breathing Controlled trial): a randomised controlled trial. Lancet 2008; 371:126–34

39. PREVENTIVE STRATEGIES • ii- Choice of sedatives: • Often, mechanically ventilated patients are given benzodiazepines, opiates, and propofol • Dexmedetomidine(Precedex) may offer advantages over the others • (MENDS) trial: Dexmedetomidine patients had 4 more days alive without delirium or coma than lorazepam(Ativan) (7 vs 3 days, P = .01) • (SEDCOM) trial: Dexmedetomidine patients had a lower incidence of delirium (54% vs 76%, P < .001), and 2 fewer days on mechanical ventilation than Midazolam • Riker et al. Dexmedetomidine vs midazolam for sedation of critically ill patients: a randomized trial. JAMA 2009; 301:489–99 • Pandharipandeet al. Effect of sedation with dexmedetomidinevslorazepam on acute brain dysfunction in mechanically ventilated patients: the MENDS randomized controlled trial. JAMA 2007; 298:2644–53 • Arroligaet al. Use of sedatives, opioids, and neuromuscular blocking agents in patients with acute lung injury and acute respiratory distress syndrome. Crit Care Med 2008; 36:1083–8

40. PREVENTIVE STRATEGIES • ii- Choice of sedatives: • Dexmedetomidinepatients had shorter time to extubation and shorter ICU stay than haloperidol (Haldol) • Acute Neuroscience Intensive Care Sedation Trial: While on propofol, patients’ adjusted scores went down by 12.4 points, whereas they went up by 6.8 points while on dexmedetomidine • Mirskiet al. Cognitive improvement during continuous sedation in critically ill, awake and responsive patients: the Acute Neurological ICU Sedation Trial (ANIST). Intensive Care Med 2010; 36:1505–13 • Reade et al. Dexmedetomidine vs. haloperidol in delirious, agitated, intubated patients: a randomised open-label trial. Crit Care 2009; 13:R75

41. PREVENTIVE STRATEGIES • ii- Choice of sedatives: • So, all sedatives are not the same in their short-term and intermediate-term outcomes: • Dexmedetomidine can be used as first-line sedation • With hemodynamic instability, benzodiazepines are recommended • Propofol can be used for very short periods of intubation or for hemodynamically stable patients who cannot be sedated with dexmedetomidine • Wergin R and Modrykamien A. Cognitive impairment in ICU survivors: Assessment and therapy. Cleveland clinic J of Medicine, Oct 2012; vol 78: 10

42. PREVENTIVE STRATEGIES • iii- Daily delirium monitoring • Delirium is highly under recognized if valid tests are not used. • Confusion Assessment Method for ICU (CAM- ICU) is probably the best, with a sensitivity of 93% - 100% and a specificity of 98% - 100% • Luetzet al. Different assessment tools for intensive care unit delirium: which score to use? Crit Care Med 2010; 38:409–18

43. PREVENTIVE STRATEGIES • iv- Early mobilization • Early mobilization through physical and occupational therapy leads to: • -shorter duration of mechanical ventilation and delirium, • - higher rate of return to independent functional status upon hospital discharge • Schweickertet al. Early physical and occupational therapy in mechanically ventilated, critically ill patients: a randomised controlled trial. Lancet 2009; 373:1874–82

44. PROGNOSIS • Cognition may improvein the first 6 to 12 months after ICU discharge • So, if we can detect it early, and promptly refer patients for cognitive therapy, we may improve the prognosis of this disabling complication • Hopkins et al. Two-year cognitive, emotional, and quality-of-life outcomes in acute respiratory distress syndrome. Am J RespirCritCare Med 2005; 171:340–7

45. TREATMENT • Most of evidence on treating cognitive impairment after ICU is extrapolated from studies in patients with mild cognitive impairment or traumatic brain injury. • Wergin R and Modrykamien A. Cognitive impairment in ICU survivors: Assessment and therapy. Cleveland clinic J of Medicine, Oct 2012; vol 78: 10

46. TREATMENT • If no physical damage to the brain, but a reversible metabolic injury →to engage in cognitive and cardiovascular exercises to improve mental functioning. • If injury is due to prolonged hypoxia or cessation of blood flow to brain, resulting in cell death or loss of nerve cell connectivity→ such rehabilitative interventions may be still appropriate. • If there is anything to the idea of plasticity of the brain→ otherintensive rehabilitations might also help • If the brain works properly physically, but psychological or emotional problems disrupt cognitive functioning → appropriate interventions might include cognitive behavior or drug therapy. • Misak. Critical Care 2009, 13:312

47. TREATMENT • Post-ICU psychological rehabilitation: • Connection between confidence, fear of failure, motivation, and success - needs to be carefully considered. • Griffiths R, Jones C: Delirium, cognitive dysfunction and posttraumatic stress disorder. CurrOpinAnaesthesiol2007, 20: 124-129

48. TREATMENT • Cognitive training is the most described cognition-focused intervention: • - It is delivered in individual or group sessions • - Patient practices tasks targeting different domains, such as memory, language, and attention. • Cognitive training shows positive results in improving memory, especially immediate recall • Because of heterogeneity among cognitive training interventions and studied populations, still no strong evidence-based recommendations for clinical practice. • Wergin R and Modrykamien A. Cognitive impairment in ICU survivors: Assessment and therapy. Cleveland clinic J of Medicine, Oct 2012; vol 78: 10

49. TREATMENT • Martin et al (2011) reviewed 36 relevant studies about cognition based interventions for healthy older people (33 studies) and people with mild cognitive impairment (3 studies), and found. • Only available data were related to the memory domain, and outcomes were mostly associated with immediate recall of words, paragraphs, and stories. • Based on this, cognitive therapy is currently considered justified, as most patients with cognitive impairment after ICU have memory problems • Martin et al. Cognition-based interventions for healthy older people and people with mild cognitive impairment. Cochrane Database SystRev 2011:1

50. COGNITIVE THERAPIES • Zelinski et al, conducted a randomized, controlled, double-blind study comparing outcomes in a computerized cognitive training program group with control group that viewed videos on a variety of topics such as literature, art, and history. • Overall memory (such as immediate and delayed recall) andcomposite memory (included letter number sequencing and the digit span backwards test) favored the intervention group. • Zelinskiet al. Improvement in memory with plasticity-based adaptive cognitive training: results of the 3-month follow-up. J Am GeriatrSoc 2011; 59:258–65