An introductory talk to Chronic Critical Illness: A state of immune, endocrine, nutritional and metabolic dysfunction leading to significant mortality and morbidity in modern ICUs. Please feel free to use slides with appropriate attribution/acknowledgement. *Not medical advice* *Updated review of evidence advised independently* Follow on Twitter: @virenkaul

1. Chronic
Critical Illness (CCI)
Beyond the first 8 days …
Viren Kaul
Fellow, PCCM
Sinai / Elmhurst
Case Conference 01/14/2019

2. Research Triangle Institute (2014)
At least 8 days in an ICU PLUS 1 out of the 5 conditions:
1. MV for at least 96 hr in a single episode
2. Tracheotomy
3. Sepsis / other severe infections
4. Severe wounds
5. Multiple organ failure, ischemic CVA, ICH, or TBI
Kandilov AM, Ingber MJ, Morley M, et al.: Chronically Critically Ill Population Payment Recommendations. Research Triangle Park, NC, RTI International, 2014

3. Epidemiology
Kahn. CCM (2015): 7.6% out of 3,235,741
cases
Marchioni. ERJ (2018): 37% patients
➔ Commonest conditions:
Prolonged MV: 72% and Sepsis: 64%
➔ 55% cases
Had 3 comorbid conditions
➔ Differences across hospital
types
Minimal. Patients in larger hospitals
were younger and more likely to have
Medicaid
Kahn, Jeremy M., et al. "The epidemiology of chronic critical illness in the United States." Critical care medicine 43.2 (2015): 282-287.

4. Epidemiology
Kahn, Jeremy M., et al. "The epidemiology of chronic critical illness in the United States." Critical care medicine 43.2 (2015): 282-287.

5. Cost of CCI
Kahn, Jeremy M., et al. "The epidemiology of chronic critical illness in the United States." Critical care medicine 43.2 (2015): 282-287.

6. Long term
outcomes?
❏ 1 yr mortality: 48-68%
❏ Functional autonomy / living at
home at 1 yr: < 10%
CCI Trivia
Originally defined and
described by Girard
and Raffin in 1985!!
Carson et al. "A prognostic model for one-year mortality in patients requiring prolonged mechanical ventilation." Critical care medicine 36.7 (2008): 2061.

7. Clinical
Features
of CCI
Immune
compromise
Lossof
anatomical
integrity
Deconditioning

8. Risk Factors and
trajectory of CCI are
poorly understood
Derangements in
inflammation and
endocrine pathways
suggested
Question is
Why do some patients
with the same acute
illnesses progress to CCI
while others do not?

9. Proposed
pathophysiology of
CCI
Marchioni, Alessandro, et al.
"Chronic critical illness: the
price of survival." European
journal of clinical investigation
45.12 (2015): 1341-1349.

10. Acute
illness →
CCI
➔ Severity of initial insult:
Eg: Florid sepsis or ARDS
➔ Non resolution of
inflammatory responseOften require MV
And hence likely to
develop CCI
Higher
inflammation at
onset →
Worse prognosis
More multi organ
failure (1)
Old age associated
with higher IL‐6,
TNF, IL‐1 receptor
antagonist and CPR
Resolution of
inflammation
Clearance
of trigger
Apoptosis of
acute
inflammatory
cells +
macrophages
Anti
inflammatory
cytokine
release:
TGF-b, IL10

11. Immunosuppressive model
Some patients experience an “Immunosuppression phase” characterized by:
Apoptosis +
Cell loss of the innate and adaptive immune system involving
CD4, CD8, B-type and dendritic cells
Leaves them susceptible and hence, contributes to CCI

12. Predictors of CCI
Marchioni. ERJ (2018): CCI in Acute Respiratory Failure
APACHEII > 26: 71%sensitivity and 89% specificity in identifying CCI
High CRP through the first 7 days from admission = Strongly associated with development of CCI
Marchioni, Alessandro, et al. "Chronic critical illness in patients with acute respiratory failure admitted to a respiratory intensive care unit." (2018): PA320.

13. UNDERSTANDING
PATHOPHYSIOLOGY
OF CHRONIC
CRITICAL ILLNESS

14. Endocrinology of acute inflammation:
Provide immediately available energy sources for vital functions!
↑TSH and T4 but ↓ in T3
Likely to prevent energy expenditure
GH levels ↑, peripheral effector
hormone levels ↓
Peripheral GH resistance: Increased
catabolism
Energy substrates available
↑CRH → ACTH → Hypercortisolism
Energy substrates available
↑IV fluid retention
↑response to pressors / intortopes
including AT II
Inflammation limiting effect
Pituitary gland
Secretion pulse & peaks ↑

15. Endocrinology of CCI:
Acute: Darwinian; Chronic: Dystopian? → and not clearly understood
↓TSH, T4, T3
Muscle weakness, bone loss
GH levels ↓, IGF and related binding
protein levels ↓
Accounts for the wasting seen in CCI
↓ ACTH but ↑cortisol levels
1. Non ACTH dependent
hypercortisolism 2/2 chronic
inflammation and cytokine
cascade
2. Decreased cortisol metab
Leads to: Poor wound healing,
susceptibility to infections,
myopathy, adrenal insufficiency
Pituitary gland
Secretion pulse and peaks
DECREASED w/
Resultant WASTING syndrome

16. Hyperglycemia in CCI:
Glucose tolerance
Presence of comorbidities
Need for parenteral nutrition
Obesity
Severity of underlying disease
1
During acute stress:
1. Activation of
gluconeogenesis
2. Reduction of peripheral
insulin sensitivity
2
Persistence of
hyperglycemia in CCI:
Associated with
increased mortality
1
Krinsley, James S. "Glycemic control in the critically ill-3 domains and diabetic status means one size does not fit all!." Critical care 17.2 (2013): 131.

17. (Mal) nutrition in CCI
The modern day Kwashiorkor
ENTERAL FEEDING IS KEY! (2,3)
L-cells in distal ileum → GLP -1 when
they see food →
1. Stimulate insulin secretion
2. Slow gastric emptying
3. Influence cell‐mediated
immunity
Feeding improves immune function
through the endocrine system!
↑ Proteolysis + ↓ hepatic albumin
synthesis → Hypoalbuminemia
HYPO-ONCOTIC STATE
This Protein > Calorie deficient state
resembled Kwashiorkor!!
FLUIDS DON’T HELP EITHER :-(
EFFECTS OF LOW PROTEIN STATE:
1. Poor wound healing
2. Increased risk of infections
3. Increased hospital stay
Schulman, Rifka C., and Jeffrey I. Mechanick. "Metabolic and nutrition support in the chronic critical illness syndrome." Respiratory care 57.6 (2012): 958-978.

18. Cerebral dysfunction in CCI
More than meets the eye
No great solution to Delirium once it
sets in but key is in PREVENTION !
Don’t underestimate:
1. Pain
2. Immobility
3. Sleep
4. Reorientation
5. Interaction
Role of ICU diaries!
Complex play of:
1. Delirium: Hyper / hypo
2. Analgesics / sedatives
3. Sleep deprivation
4. Psychological trauma
5. PTSD
6. Residual effects of primary
neurological insult
What causes delirium:
1. Imbalance b/w dopamine
production and Ach depletion
2. Cytokines cross BBB →:
a. Endothelial damage
b. Vascular permeability
c. Reduced blood flow
d. Microaggregate
formation
e. Neurotransmitter
alteration (increase
uptake of Trp and
Phenylalanince, both
Dopa precursors)
Schulman, Rifka C., and Jeffrey I. Mechanick. "Metabolic and nutrition support in the chronic critical illness syndrome." Respiratory care 57.6 (2012): 958-978.

19. Neuromuscular dysfunction in CCI
Underappreciated and underaddressed
CIP + CIM coexist = CIPM
RISK FACTORS:
1. Drugs (Steroids, NMBs)
2. Hyperglycemia
3. Immobility
4. Deep sedation
Remember: After 6 days of MV,
diaphragmatic strength drops by
30% !!
I HOPE BY NOW YOU HAVE
NOTICED A PATTERN!!!
CRITICAL ILLNESS
POLYNEUROPATHY (CIP):
Limb + respiratory muscles
Distal axonal sensory-motor
PNpathy
Etiopath: Microvascular injury →
Damaged blood nerve barrier →
Neuronal injury
EP: ↓ in CMAP with normal SNAP
CRITICAL ILLNESS MYOPATHY:
Acute primary muscle atrophy
Muscle Bx: Selective loss of myosin
Activation of ubiquitin–proteasome
(UPS) & autophagy–lysosome systems
However, inhibitition of autophagy
ALSO leads to degeneration
Therefore, it is an imbalance b/w
muscle breakdown and synthesis
Batt, Jane, et al. "Intensive care unit–acquired weakness: clinical phenotypes and molecular mechanisms." American journal of respiratory and critical care medicine 187.3 (2013): 238-246.

20. Effects on surrogates of CCI patients
PTSD: Risk Factors
High Hospital Anxiety and
Depression Scale Scores
Patient unresponsiveness on
MV at DAY 10
Risk
factors for
PTSD in
surrogates
at Day 90
Wendlandt, Blair, et al. "Risk Factors for Post-Traumatic Stress Disorder Symptoms in Surrogate Decision-Makers of Patients with Chronic Critical Illness."
Annals of the American Thoracic Society 15.12 (2018): 1451-1458.

21. The single biggest problem in
communication is the illusion that it has
taken place.
- George Bernard Shaw
The single biggest problem in critical care
is that we are reactive, not proactive.

22. Prevention and
Treatment of CCI
No specific Rx
But advancement in team based,
multidisciplinary, proactive critical care can help
in avoiding continued dysregulation of the
immuno-neuro-hormonal axis
From the SCCM
President and every
smart intensivist
EVER:
LESS IS MORE

23. Prevention and Treatment of CCI
LTVV in ARDS (4)01
● ↓ inflammation
● Mortality benefit!
Early rehabilitation (5, 6)02
● ↓ cytokine levels
● ↓ ventilator free days
● ↓ delirium, ↑functional independence
Control of stress-induced
hyperglycemia (7,8)03
● ↓ MV, AKI, sepsis, CIPM
● ↓ mortality
● Benefits may be offset by hypoglycemia ?
Daily sedation vacation (9,10,11)04
● ↓ duration of MV → ↓ diaphragm weakness
● ↓ ICU LOS
Early enteral nutrition (within 48
hours of ICU admission)05
● ↓ immunological dysfunction, bacterial dyslocation
● ↓ septic complications, hospital LOS
PADIS (Pain, Agitation/Sedation,
Delirium, Immobility, Sleep)06 ● 37 directions in the 2018 PADIS update!

24. The Ethics and
Legalities of CCI
Care VS futility
Quantity of life VS quality of life
Cost of care w/ societal impact
Mental distress on families
Moral distress on providers
90%
seriously ill patients indicated that they would
rather die than survive with severe
impairments and disabilities
Hopkins, Ramona O., and James C. Jackson. "Long-term neurocognitive function after critical illness." Chest 130.3 (2006): 869-878.

25. Areas of research / conflict
Dealing with a man- made problem: Longevity with a twist
Palliative care
services for all CCI
patients
Carson / JAMA 2016:
Increased PTSD, routine
involvement not advised
Predicting CCI
Better understanding is
needed to how to predict
patients that develop CCI
including intervenable RFs
Treating CCI
Benchmarking standards of care for such
patients
Clarification of role of immunomodulators /
endocrine factors eg: Estrogen
Preventing CCI
“Playing G*d” comes at a
price. Ethical question: Just
because we can, should we?

26. References / further reading
1. Meduri, G. Umberto, et al. "Persistent elevation of inflammatory cytokines predicts a poor outcome in ARDS: plasma IL-1β and IL-6 levels are
consistent and efficient predictors of outcome over time." Chest 107.4 (1995): 1062-1073.
2. Deane, Adam, et al. "Bench-to-bedside review: The gut as an endocrine organ in the critically ill." Critical Care 14.5 (2010): 228.
3. Bakiner, Okan, et al. "Impact of early versus late enteral nutrition on cell mediated immunity and its relationship with glucagon like peptide-1 in
intensive care unit patients: a prospective study." Critical Care 17.3 (2013): R123.
4. Ranieri, V. Marco, et al. "Effect of mechanical ventilation on inflammatory mediators in patients with acute respiratory distress syndrome: a
randomized controlled trial." Jama 282.1 (1999): 54-61.
5. Schweickert WD, Pohlman MC, Pohlman AS, et al. Early physical and occupational therapy in mechanically ventilated, critically ill
patients: a randomised controlled trial. Lancet 2009;373:1874–82.
6. Winkelman C, Higgins PA, Chen YJ, Levine AD. Cytokines in chronically critically ill patients after activity and rest. Biol Res Nurs
2007;8:261–71.
7. Van den Berghe, Greet, et al. "Intensive insulin therapy in the medical ICU." New England journal of medicine 354.5 (2006): 449-461.
8. Nice-Sugar Study Investigators. "Intensive versus conventional glucose control in critically ill patients." New England Journal of Medicine
360.13 (2009): 1283-1297.
9. Levine, Sanford, et al. "Rapid disuse atrophy of diaphragm fibers in mechanically ventilated humans." New England Journal of Medicine 358.13
(2008): 1327-1335.
10. Jaber, Samir, et al. "Rapidly progressive diaphragmatic weakness and injury during mechanical ventilation in humans." American journal of
respiratory and critical care medicine 183.3 (2011): 364-371.
11. Girard, Timothy D., 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." The Lancet371.9607 (2008): 126-134.
12. Nomellini, Vanessa, et al. "Chronic Critical Illness and Persistent Inflammation: What can we Learn from the Elderly, Injured, Septic, and
Malnourished?." Shock: Injury, Inflammation, and Sepsis: Laboratory and Clinical Approaches49.1 (2018): 4-14.

27. Questions?
Of note, this ties into the other area of critical
care that really intrigues me:
The Post ICU Syndrome!
So, surprise, surprise, that’s up next!