1. SLAM Sepsis Symposium 2018 Quality and Patient Safety UMass Memorial Medical Center
Post Sepsis Syndrome
Sarah McGee MD, MPH
Clinical Chief, Division of Geriatric Medicine
October 31, 2018

2. I have no actual or potential conflict of interest
Disclosure statement
I have no actual or potential conflict of interest
in relation to this program/presentation.

3. Terms Post sepsis syndrome Sepsis associated encephalopathy (SAE)
Post ICU syndrome
Post intensive care syndrome (PICS)
Cognitive impairment
Physical impairment
Affects to caregivers
THRIVE: Redefining Recovery Video

4. Given the known high mortality of sepsis the main goal of sepsis care and research has been to reduce short term mortality Assumption: If a person is able to survive the initial insult of sepsis the crisis has been averted and the patient should do well

5. Irreversible cognitive and physical impairment following acute illness are feared outcomes and weigh heavily on patient decision making Cognitive and physical disability place burdens on family and informal caregivers

6. No clear mechanism to explain these findings
Sepsis survivors had double the risk of death in the following 5 years compared with hospital controls
Thought that elderly and those with underlying disease had a higher risk of sepsis and that the late increased risk of mortality was unrelated to the sepsis episode and due to poor preexisting health condition
Later studies controlled for preexisting conditions found similar results with long term increased risk of death
Others reported that sepsis survivors and other survivors of related conditions ie ARDS developed physical cognitive and affective problems in the months to years following d/c
No clear mechanism to explain these findings
Often these studies were done following the onset of critical illness, not prospectively with no info re function and cognition prior to the event, therefore the underlying health status as a cause of subsequent decline could not be ruled out
Magnitude and duration of the effect of sepsis on survival Quartin 1997

7. Health Retirement Study of community dwelling US residents >age 50
Objective : Determine the change in cognitive impairment and physical functioning among pts surviving severe sepsis controlling for pre sepsis function
Health Retirement Study of community dwelling US residents >age 50
Began in 1992, >27,000 adults with >200,000 hours of interviews, q2y
90-95% follow up rate
Linked to Medicare data for claims
Study of those with baseline cog and physical info with subsequent claim for severe sepsis and subsequent interview
Long term Cognitive Impairment and Functional Disability JAMA 2010, Iwashyna

8. 90 day mortality after severe sepsis 41.3%
5 year mortality after severe sepsis 81.9%
516 pts survived 623 episodes of severe sepsis and had at least 1 interview
FINDINGS
Incident sepsis associated with a clinically and statistically significant increase in mod to severe cognitive impairment among survivors
Prevalence of mod–severe cog impairment pre sepsis 6.1%, post sepsis 16.7%, OR 3.34
Severe sepsis associated with development of 1.57 new limitations among pts with no limitations prior to sepsis
Those with mild to mod limitations had similar increase of new ADL/IADL limitations
Negative effects of severe sepsis were greater in pts with better physical functioning
New deficits were not concentrated in any particular subset of functioning measures

9. Changes in physical function occurred at all levels of cognitive impairment at baseline
Changes in cognitive and physical impairment were worse for those with severe sepsis comp to those hospitalized for other reasons
Subgroup analysis – no difference in findings for those that had mechanical ventilation comp to those without mech vent
BOTTOM LINE: 1st time shown that severe sepsis was independently associated with lasting cognitive and physical limitations with a tripling of the odds of development of mod to severe cognitive impairment and independently associated with 1.5 new functional limitations in pts with no/mild/mod preexisting functional limitations

10. Caveats: Observational study and cannot prove causality
Many plausible possible causal pathways by which sepsis and treatment can lead to significant declines in physical and cognitive impairment
Weakness and chronic illness myopathy and poly neuropathy may be related to inflammatory and hypoperfusion mediated degradation of muscle fibers and neurons which may be exacerbated by prolonged immobility and lack of PT
Hypotension and relative Hypoperfusion may directly contribute to brain injury and subsequent cog impairment
Inflammation can contribute to vascular dementia and Alzheimer's Disease
Delirium is common in sepsis and associated with increased cog decline with AD pts awa Iong term cog impairment in mechanically ventilated ed pts
Some pts died before 1st interview
Not able to determine pts who developed dementia
Included Medicare pts only
Limited to claims definition of sepsis and further subgroup analysis not possible

11. Factors associated with poor long-term functional outcomes after sepsis
Burden of chronic health conditions Duration of delirium during hospital stay Hearing impairment Immobility Frailty No spouse
Older age Premorbid disability Prior nursing home care Severity of acute illness Vision impairment

12. ICU-Acquired Weakness
Observational studies noting meds may exacerbate ICU weakness through direct toxicity to nerves, muscles or both
Corticosteroids
Aminoglycosides
Neuromuscular blocking agents (NMBs)
Other studies with limited use of NMBs have not shown an increase in ICU weakness.
Limited use of NMBs for sickest pts with sepsis related ARDS

13. ICU-Acquired Weakness
Early Activity and Mobility (even during mechanical ventilation)
Safe and effective in reducing short term disability as well as reducing delirium
Results in better physical function while in ICU and upon hospital d/c
More likely to be d/c’d home ( 1 randomized study) 43% vs 24% d/c’d to home
Improved functional status at d/c should translate to better long term outcomes
Timing is critical as skeletal muscle wasting begins within 24 h
Interventions begun later in ICU stay, after ICU d/c or after hosp d/c are not as successful

14. ICU-Acquired Weakness
Exercise and Rehabilitation
One RCT with 126 ICU pts had improved physical function at 8 weeks and 6 mo with a 6 week self directed rehab manual
Another RCT of 286 ICU pts with 3 mo self directed rehab manual and f/u in nurse led ICU follow up clinic showed no improvement in physical function at 6 mo and 1 year
Other studies with older adults recently d/c’d from hosp with self directed exercise program have resulted in greater mobility but also with increased falls

15. Sepsis associated encephalopathy (SAE)
Cognitive dysfunction associated with sepsis without the presences of sepsis in the CNS or structural brain injury after excluding metabolic causes
May be acute, sub acute or chronic
Acute – lasting as long as episode of sepsis
Sub acute- symptoms last weeks to months
Chronic-symptoms last over a year

16. 577 potential articles, 16 studies met criteria for review
6 prospective cohort with control, 6 prospective without control, 3 retro without control and 1 case control study
74,000,000+ patients
Age range 19-81, mean age of most 60+
Comparison across studies was limited b/o differences in definition of sepsis, severe sepsis and septic shock and cognitive assessments
Post-sepsis cognitive impairment and associated risk factors: A systematic review AJ Calsavara et all. Aust Crit care (2018) 242

17. Risk factors for cognitive impairment after sepsis: CNS infection
# of hospital visits due to infection
LOS due to infection
Family hx of infection
Temporal proximity to latest episode of infection
Risk factor for diagnosis of dementia within 3 years
Critical illness in presence of infection, esp severe sepsis
Sepsis a risk factor for the development and longer duration of delirium
Diagnosis of sepsis increased the mortality of pts with delirium
Post-sepsis cognitive impairment and associated risk factors: A systematic review AJ Calsavara et all. Aust Crit care (2018) 242

18. Cognitive deficits related to sepsis were not affected by:
LOS in ICU
ICU discharge time
# of days on vent
APACHE II scores
Sequential Organ Failure Assessment (SOFA) score
Patient age
Family hx of psychiatric illness
Substance abuse
Post-sepsis cognitive impairment and associated risk factors: A systematic review AJ Calsavara et all. Aust Crit care (2018) 242

19. Factors with unclear effect: Sedatives Hypnotics Antipsychotics
Antibiotics
Glycemic control
Corticosteroids
Post-sepsis cognitive impairment and associated risk factors: A systematic review AJ Calsavara et all. Aust Crit care (2018) 242

20. Considerations:
The mechanism of action of cognitive of impairment not able to be determined Cerebrovascular damage, metabolic disorders, brain inflammation may be due: Disruption of blood brain barrier Microglial activation Altered neurotransmission – can be diffuse or limited Most studies included pts >60 years of age There is increased incidence and mortality in the elderly due to sepsis but important to evaluate the impact on younger individuals who are still in the workforce Greater cognitive reserve in younger patients may be a protective factor for cognitive impairment and may relate to the lower incidence of development of cognitive impairment
Post-sepsis cognitive impairment and associated risk factors: A systematic review AJ Calsavara et all. Aust Crit care (2018) 242

21. Management Strategies- still evolving
Delirium, acute distress and immobility are key ICU factors associated with long term cognitive and physical disability, limiting these risk factors in addition to rapid treatment of infection and support of vital organs should be helpful
ABCDEF bundle
A collection of multidisciplinary practices for mechanically ventilated pts
Aspects of the bundle in its entirety or paired bundle components have been shown to double the odds of walking and halving the odds of delirium without a subsequent risk of self extubation or reintubation
ABCDEF bundle associated with more days alive and free of delirium and coma

22. ABCDEF Bundle Components
Assess, Prevent and Manage Pain Both Spontaneous Awakening and Spontaneous Breathing Trials Choice of Analgesia and Sedation Delirium Monitoring and Management Early Mobility and Exercise Family Engagement and Empowerment

23. Intensive Care Unit Follow up clinics
Common in UK (1/3 of ICUs)
Growing interest in US, Critical Care Recovery Center at Indiana University and Vanderbilt ICU Recovery Center
No optimal model has been identified
Evidence of effectiveness is limited
Largest study to date
Self directed PT program
Visits to nurse-led f/u clinic at 3 and 9 mo
Med review, discussion of ICU course, physiologic screen, eval for need for specialty referral, visit to ICU and letter to PCP
No improvement in QOL, PTSD, depression, costs or mortality
Trial included unselected pts, family not included in intervention, first clinic visit not till 3 mo post ICU d/c and intervention not interprofessional

24. Enhancing Recovery from sepsis A Review JAMA 2018;319 Prescott
No tools to predict recovery from sepsis
Pts with preexisting disability, frailty or NH use are less likely to regain functional independence
Those previously healthy have a higher chance of recovery
Severity of cognitive impairment shortly after hospitalization does not predict subsequent impairment well
Enhancing Recovery from sepsis A Review JAMA 2018;319 Prescott

25. Enhancing Recovery from sepsis A Review JAMA 2018;319 Prescott
Causes of functional decline multifactorial
Myopathy
Neuropathy
Cardiorespiratory impairment
Cognitive impairment
Combination
Swallowing difficulty
Pts in ICU with sepsis more likely to have aspiration noted on endoscopy than those without sepsis ( 63% vs 23%)
Older US adults sepsis survivors have risk of 90day readmission rate for aspiration 1.8% vs 1.2% for pts hosp for other reasons
Enhancing Recovery from sepsis A Review JAMA 2018;319 Prescott

26. Enhancing Recovery from sepsis A Review JAMA 2018;319 Prescott
Physical function typically improves following hospital d/c
Prospective study of sepsis survivors
Clinically significant improvements 6 min walk distance, quad strength, handgrip strength at 3 mo
At 3 mo 60% (n = 51) could walk for 30 min /day
Physical function remained below population norms and often did not return to presepsis levels
Cognitive impairment
Long term impairment in memory, attention, verbal fluency and executive function
Prospective observational study of 516 pts with sepsis
Mod to severe impairment increased from 6.1% to 16.7 % ( before to after hosp stay)
Prevalence of mild impairment is unknown
Enhancing Recovery from sepsis A Review JAMA 2018;319 Prescott

27. Enhancing Recovery from sepsis A Review JAMA 2018;319 Prescott
Mental health impairment
High prevalence of anxiety, depression and PTSD sx following an ICU stay
2 studies pts with sepsis note high rates of mental health impairment
Sepsis was an independent risk factor of stress disorders after critical illness in observational studies
Somatic sx of depression ie weakness, appetite change and fatigue common
Extent to which sepsis exacerbated anxiety, depression or PTSD is not clear or if these are more common in pts that develop sepsis
These dx are important to recognize as they are associated with a more complicated clinical course
Some studies have shown that by providing a diary completed by bedside nurses and family provided at 1 mo was associated with lower rates of PTSD in pts and relatives at 3 mo
Diaries more commonly used in Scandinavia and Western Europe
Descriptions of hospital course in simple terms may provide similar benefit and is commonly done in a number or ICU follow-up clinics
Enhancing Recovery from sepsis A Review JAMA 2018;319 Prescott

28. Medication reconciliation
Chronic meds may be held or forgotten
Acute meds may be continued inadvertently
One study 24% of pts with an atypical antipsychotic for acute delirium during critical illness had med continued at d/c
Need to consider dosage adjustment for chronic meds that need to be made as a result of physiologic changes during sepsis hospitalization ie reduced muscle mass or decline in renal function

29. Enhancing Recovery from sepsis A Review JAMA 2018;319 Prescott
Exacerbation of chronic medical conditions
Sepsis survivors have high rates of hospital readmissions with CHF, ARF and COPD exacerbation
Risk of CV events and ARF increased compared to age matched controls
Unclear if sepsis relates to progression of these conditions
Enhancing Recovery from sepsis A Review JAMA 2018;319 Prescott

30. Enhancing Recovery from sepsis A Review JAMA 2018;319 Prescott
Quality of Life (QOL), return to work and social relationships
Survivors report lower QOL compared to general population and cannot resume prior roles or activities
1 study 35% of older pts d/c’d to a post acute facility
43% previously employed pts were able to return to work within 1 year of sepsis
33% living at home prior were able to return to independent living by 6 mo after d/c
Pts with new dependence on caregivers and loss of independence with resultant of anger, helplessness and embarrassment
Spouses at increased risk of depression with 20% with depressive sx before sepsis vs 34% after sepsis
Enhancing Recovery from sepsis A Review JAMA 2018;319 Prescott

31. Enhancing Recover from sepsis A Review JAMA 2018;319 Prescott
Current guidelines emphasize interventions to reduce short term mortality with little info to minimize long term outcomes
Strategies for short term benefits may be at odds with those for longer term benefits
Conservative fluid administration during sepsis shown to decrease vent-free days but was associated with worse late cognitive function
Limited data for prevention of long term sequalae after sepsis
High quality early sepsis care
Fluids, abx
Management of pain, agitation and delirium
Assessment of pain, analgesia with IV narcs as first line, short acting sedatives over benzos, light sedation if needed with interruption, regular assessment for delirium
Early mobilization and progressive to prevent or minimize muscle atrophy ( ABCDEF)
Results in shorter time to PT, time to ambulation and duration of delirium
Improved physical function at hosp d/c and increased likelihood of being d/c’d directly home
Early mobility has not been proven to improve late physical function but short term improvements in physical function may result in long term improvements
Enhancing Recover from sepsis A Review JAMA 2018;319 Prescott

32. Post d/c assessment and treatment of survivors
RCTs of nurse led ICU f/u clinic, in person exercise rehab programs, self guided exercise rehab manuals and case management interventions have yielded small and inconsistent benefits in short and moderate term physical function by pt report or physical assessment
One RCT 6 and 12 mo multicomponent primary care management intervention vs usual care ( included education for pts and PCPs, case management by nurses with ICU experience and decision support by MDs knowledgeable about primary and critical care) some + findings for functional status
Despite lack of high quality evidence several expert panels suggest rehab with PT, OT and ST benefits pts with new weakness following sepsis – starting in ICU and continuing post hosp
Observational study in 30,000 sepsis survivors with a rehab referral within 90 days of hosp d/c associated with a lower risk of 10 year mortality compared with controls
Small RCT of multicomponent post ICU rehab with cog, functional and physical rehab showed improved cognitive and functional recovery at 3 mo using assessment of planning and strategic thinking suggesting that neuro cognitive deficits may be amenable to treatment

33. Post d/c assessment and treatment of survivors
Few pts are aware of sepsis diagnosis and realize its association with long term disability
Education needs to start in hosp and continue in post d/c setting
Few aware of long term sequalae
Pt’s risk for poor long term outcomes does not end with d/c from ICU
Care on wards needs to focus on mobility, preparing pts and caregivers for d/c
ICU diaries, peer to peer support groups may help with this
SCCM has in person, on line and telephone –based support groups for pts and families surviving critical illness
Pts and families may benefit from sharing their stories

34. Online resources sepsisalliance.org signs/sx sepsis
description of common sequalae
Faces of Sepsis written tributes to lost loved ones and stories of survivors
myicucare.org/thrive
White board videos for pts and families including videos on preparing for d/c following critical illness, post intensive care syndrome, wellness post critical illness
Info on virtual and in-person support groups for critical illness survivors
icusteps.org
Info on in-person support groups in the UK
healthtalk.org
Video interviews describing pt and family experiences of the ICU
icudelirium.org/patients
Info re common sequalae of critical illness including patient testimonials
Info re Vanderbilt ICU recovery center

35. Quality and availability of resources to facilitate being a patient
Patient experience
Patient workload:
Work of being a pt including effort to understand, access and use medical care
Capacity:
Quality and availability of resources to facilitate being a patient
Challenges of adherence to medical care, complex treatment plans have limitations and pts have new limitations ie new weakness, cognitive impairment, fatigue, lost income and stressed caregivers

36. Additional questions/considerations
Which aspects of illness and treatment contribute to which post sepsis sequelae?
Long term sequalae may be associated with both disease ( ie infection and organ dysfunction) and treatment (ie sedation)
Measuring the individual contributions of characteristics of sepsis and sepsis treatment is challenging but needed in order to target interventions to the most important mediators of long term adverse sequalae
The most common outcome in RCTs of sepsis is mortality. Interventions to reduce short term mortality may increase long term mortality or worsen other patient centered outcomes such as physical disability. As survival from sepsis improves the effects of interventions on long term effects is increasingly important
Multidisciplinary clinics for post ICU care have been established in several countries and now in the US. Benefit is unknown. A multicenter collaborative was recently established to study this and to refine best practices for post ICU clinics