A Randomized Trial of Empiric Antibiotics and Invasive Diagnostic Techniques in the setting of Ventilator-Associated Pneumonia

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Iatrogenic Malnutrition in the ICU Time for a
Change!
Daren K. Heyland Professor of Medicine Queens
University, Kingston General Hospital Kingston,
ON Canada
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Learning Objectives

• Define iatrogenic malnutrition
• Describe the nature of the evidence related to
  optimal amount of calories/protein
• List key variables to consider in assessing
  nutritional risk in ICU patients
• List strategies to improve nutritional adequacy
  in the critical care setting.

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A different form of malnutrition?
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Health Care Associated Malnutrition

• Nutrition deficiencies associated with
  physiological derangement and organ dysfunction
  that occurs in a health care facility

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Optimal Amount of Protein and Calories for
Critically Ill Patients?
Early EN (within 24-48 hrs of admission) is
recommended!
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Increasing Calorie Debt Associated with worse
Outcomes
Adequacy of EN

• ? Caloric debt associated with
• ? Longer ICU stay
• ? Days on mechanical ventilation
• ? Complications
• ? Mortality

Rubinson CCM 2004 Villet Clin Nutr 2005 Dvir
Clin Nutr 2006 Petros Clin Nutr 2006
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• Point prevalence survey of nutrition practices in
  ICUs around the world conducted Jan. 27, 2007
• Enrolled 2772 patients from 158 ICUs over 5
  continents
• Included ventilated adult patients who remained
  in ICU gt72 hours

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Effect of Increasing Amounts of Calories from EN
on Infectious Complications
Multicenter observational study of 207 patients
gt72 hrs in ICU followed prospectively for
development of infection
for increase of 1000 cal/day, OR of infection at
28 days
Heyland Clinical Nutrition 2010
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Relationship between increased nutrition intake
and physical function (as defined by SF-36
scores) following critical illness
For every 1000 kcal/day received
Model Estimate (CI) P values
At 3 months
PHYSICAL FUNCTIONING 3.2 (-1.0, 7.3)   P0.14
ROLE PHYSICAL 4.2 (-0.0, 8.5) P0.05
STANDARDIZED PHYSICAL COMPONENT SCALE 1.8 (0.3, 3.4) P0.02
At 6 months
PHYSICAL FUNCTIONING 0.8 (-3.6, 5.1) P0.73
ROLE PHYSICAL 2.0 (-2.5, 6.5) P0.38
STANDARDIZED PHYSICAL COMPONENT SCALE 0.70 (-1.0, 2.4) P0.41
for increase of 30 gram/day, OR of infection at
28 days
Unpublished data from Multicenter RCT of
glutamine and antioxidants (REDOXS Study) n364
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Mechancially Ventd patients gt7days (average ICU
LOS 28 days)
Faisy BJN 20091011079
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• 113 select ICU patients with sepsis or burns
• On average, receiving 1900 kcal/day and 84 grams
  of protein
• No significant relationship with energy intake
  but

Clinical Nutrition 2012
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More (and Earlier) is Better!
If you feed them (better!) They will leave
(sooner!)
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Optimal Amount of Calories for Critically Ill
Patients Depends on how you slice the cake!

• Objective To examine the relationship between
  the amount of calories recieved and mortality
  using various sample restriction and statistical
  adjustment techniques and demonstrate the
  influence of the analytic approach on the
  results.
• Design Prospective, multi-institutional audit
• Setting 352 Intensive Care Units (ICUs) from 33
  countries.
• Patients 7,872 mechanically ventilated,
  critically ill patients who remained in ICU for
  at least 96 hours.

Heyland Crit Care Med 2011
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• Association between 12 day average caloric
  adequacy and
• 60 day hospital mortality
• (Comparing patients recd gt2/3 to those who recd
  lt1/3)

A. In ICU for at least 96 hours. Days after
permanent progression to exclusive oral feeding
are included as zero calories
B. In ICU for at least 96 hours. Days after
permanent progression to exclusive oral feeding
are excluded from average adequacy calculation.
C. In ICU for at least 4 days before permanent
progression to exclusive oral feeding. Days after
permanent progression to exclusive oral feeding
are excluded from average adequacy calculation.
D. In ICU at least 12 days prior to permanent
progression to exclusive oral feeding
Adjusted for evaluable days and
covariates,covariates include region (Canada,
Australia and New Zealand, USA, Europe and South
Africa, Latin America, Asia), admission category
(medical, surgical), APACHE II score, age, gender
and BMI.
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Association Between 12-day Caloric Adequacy and
60-Day Hospital Mortality
Heyland CCM 2011
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More (and Earlier) is Better!
If you feed them (better!) They will leave
(sooner!)
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Rice et al. JAMA 2012307
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Rice et al. JAMA 2012307
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Enrolled 12 of patients screened
Rice et al. JAMA 2012307
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Trophic vs. Full enteral feeding in critically
ill patients with acute respiratory failure

• Average age 52
• Few comorbidities
• Average BMI 29-30
• All fed within 24 hrs (benefits of early EN)
• Average duration of study intervention 5 days

No effect in young, healthy, overweight patients
who have short stays!
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Nutritional Management of ICU Patients Are these
both the same?

• Low Risk
• 34 year former football player,
• BMI 35
• otherwise healthy
• involved in motor vehicle accident
• Mild head injury and fractured R leg requiring
  ORIF

• High Risk
• 72 women
• BMI 35
• PMHx COPD, poor functional status
• Admitted to hospital 1 week ago with CAP
• Now presents in respiratory failure requiring
  intubation and ICU admission

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ICU-acquired Weakness (ICUAW)

• Muscle weakness develops in 25-60 of patients
  who have been mechanically ventilated for gt 1
  week1
• Prolongs1-4
• mechanical ventilation
• weaning from the ventilator
• ICU stay
• ICUAW main clinical manifestation of critical
  illness neuromyopathy (CINM)5

1. de Jonghe B, et al. Crit Care Med.
   2004301117-1121.
2. Garnacho-Montero J, et al. Crit Care Med.
   200533349-354.
3. van den Berghe G, et al. Crit Care Med.
   200331359-366.
4. Hermans G, et al. Am J Respir Crit Care Med.
   2007175480-489.
5. de Jonghe B, et al. Crit Care Med.
   200937(suppl.)S309-S315.

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Determinants to Lean Body Mass
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Muscle Matters!Skeletal muscle mass predicts
ventilator-free days, ICU-free days, and
mortality in elderly ICU patients

• Patients gt 65 years with an admission abdominal
  computed tomography scan and requiring intensive
  care unit stay at a Level I trauma center in
  2009-2010 were reviewed.
• Muscle cross-sectional area at the 3rd lumbar
  vertebra was calculated and sarcopenia identified
  using sex-specific cut-points.
• Muscle cross-sectional area was then related to
  clinical parameters including ventilator-free
  days, ICU-free days, and mortality.

Kozar (in submission)
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Body Composition Lab CT Imaging Analysis
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Physical Characteristics of Patients

• N149 patients
• Median age 79 years old
• 57 males
• ISS 19
• Prevalence of sarcopenia 71

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BMI Characteristics
All Patients Sarcopenic Patients (n106) Non-sarcopenic Patients (n43)
BMI (kg/m2) 25.8 (22.7, 28.2) 24.4 (21.7, 27.3) 27.6 (25.5, 30.4)
Underweight, 7 9 2
Normal Weight, 37 44 19
Overweight, 42 38 51
Obese, 15 9 28
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Low muscle mass associated with mortality
Proportion of Deceased Patients P-value
Sarcopenic patients 32 0.018
Non-sarcopenic patients 14 0.018
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Muscle mass is associated with ventilator-free
and ICU-free days
All Patients Sarcopenic Patients Non-Sarcopenic Patients P-value
Ventilator-free days 25 (0,28) 19 (0,28) 27 (18,28) 0.004
ICU-free days 19 (0,25) 16 (0,24) 23 (14,27) 0.002
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• Prospective multicenter observational trial of
  136 patients requiring min 5 days of mechanical
  ventilation
• After day 5, when awake, performed muscle
  testing

Am J Respir CCM 2008178261-268
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ICU patients are not all created equalshould we
expect the impact of nutrition therapy to be the
same across all patients?
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How do we figure out who will benefit the most
from Nutrition Therapy?
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Health Care Associated Malnutrition

• Do Nutrition Screening tools help us discriminate
  those ICU patients that will benefit the most
  from artificial nutrition?

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Albumin a marker of malnutrition?

• Low levels very prevalent in critically ill
  patients
• Negative acute-phase reactant such that
  synthesis, breakdown, and leakage out of the
  vascular compartment with edema are influenced by
  cytokine-mediated inflammatory responses
• Proxy for severity of underlying disease
  (inflammation) not malnutrition
• Pre-albumin shorter half life but same limitation

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Subjective Global Assessment?
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• When training provided in advance, can produce
  reliable estimates of malnutrition
• Note rates of missing data

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• mostly medical patients not all ICU
• rate of missing data?
• no difference between well-nourished and
  malnourished patients with regard to the serum
  protein values on admission, LOS, and mortality
  rate.

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Mostly surgical patients 100 data available for
SGA
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We must develop and validate diagnostic criteria
for appropriate assignment of the described
malnutrition syndromes to individual patients.
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A Conceptual Model for Nutrition Risk Assessment
in the Critically Ill
Starvation
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The Development of the NUTrition Risk in the
Critically ill Score (NUTRIC Score).
Variable Range Points
Age lt50 0
50-lt75 1
gt75 2
APACHE II lt15 0
15-lt20 1
20-28 2
gt28 3
SOFA lt6 0
6-lt10 1
gt10 2
Comorbidities 0-1 0
2 1

Days from hospital to ICU admit 0-lt1 0
1 1

IL6 0-lt400 0
400 1
AUC 0.783 0.783
Gen R-Squared 0.169 0.169
Gen Max-rescaled R-Squared  0.256 0.256
BMI, CRP, PCT, weight loss, and oral intake were
excluded because they were not significantly
associated with mortality or their inclusion did
not improve the fit of the final model.
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The Validation of the NUTrition Risk in the
Critically ill Score (NUTRIC Score).
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The Validation of the NUTrition Risk in the
Critically ill Score (NUTRIC Score).
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The Validation of the NUTrition Risk in the
Critically ill Score (NUTRIC Score).
Interaction between NUTRIC Score and nutritional
adequacy (n211)
P value for the interaction0.01
Heyland Critical Care 2011, 15R28
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P0.008
P0.04
P0.04

• Multicenter prospective study of nutrition
  practice in abdominal surgery
• All patients had nutrition screening, not all
  patients had peri op nutrition support
• Benefit of nutrition support seen in NRSgt5
  compared to controls, no benefit seen in low risk
  patients (NRSlt5).

Patients with NRS gt5
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Who might benefit the most from nutrition therapy
in the ICU?

• High NUTRIC Score?
• Clinical
• BMI
• Projected long length of stay
• Others?

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Do we have a problem?
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Preliminary Results of INS 2011Overall
Performance Kcals
84
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N211
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Nutritional Adequacy of High Risk Patients
compared to Low Risk Patients
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Failure Rate
high risk patients who failed to meet minimal
quality targets (80 overall energy adequacy)
91.2
87.0
79.9
78.1
75.6
75.1
69.8
Unpublished observations. Results of 2011
International Nutrition Survey (INS).
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Strategies to Maximize the Benefits and Minimize
the Risks of EN
weak evidence

• feeding protocols
• motility agents
• elevation of HOB
• small bowel feeds

stronger evidence
Canadian CPGs www.criticalcarenutrition.com
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Use of Nurse-directed Feeding Protocols
Start feeds at 25 ml/hr

• lt 250 ml
• advance rate by 25 ml
• reassess q 4h

• gt 250 ml
• hold feeds
• add motility agent
• reassess q 4h

Check Residuals q4h
Should be considered as a strategy to optimize
delivery of enteral nutrition in critically ill
adult patients.
2009 Canadian CPGs www.criticalcarenutrition.com
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The Impact of Enteral Feeding Protocols on
Enteral Nutrition DeliveryResults of a
multicenter observational study
Plt0.05

• Time to start EN from ICU admission 41.2 in
  protocolized sites vs 57.1 hours in those without
  a protocol
• Patients recing motility agents 61.3 in
  protocolized sites vs 49.0 in those without

Plt0.05
Heyland JPEN 2010
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Can we do better?
The same thinking that got you into this mess
wont get you out of it!
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The Efficacy of Enhanced Protein-Energy Provision
via the Enteral Route in Critically Ill Patients
The PEP uP Protocol!

• Different feeding options based on hemodynamic
  stability and suitability for high volume
  intragastric feeds.
• In select patients, we start the EN immediately
  at goal rate, not at 25 ml/hr.
• We target a 24 hour volume of EN rather than an
  hourly rate and provide the nurse with the
  latitude to increase the hourly rate to make up
  the 24 hour volume.
• Start with a semi elemental solution, progress to
  polymeric
• Tolerate higher GRV threshold (300 ml or more)
• Motility agents and protein supplements are
  started immediately
• Nurse reports daily on nutritional adequacy.

A Major Paradigm Shift in How we Feed Enterally
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The Efficacy of Enhanced Protein-Energy Provision
via the Enteral Route in Critically Ill Patients
The PEP uP Protocol!
Adequacy of Calories from EN (Before Group vs.
After Group on Full Volume Feeds)

Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Total
P-value 0.08 0.0003 0.10 0.19 0.48 0.18 0.11 lt0.0001
Heyland Crit Care 2010
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Change of nutritional intake from baseline to
follow-up of all the study sites (intervention
group only)
calories received/prescribed
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Health Care Associated Malnutrition

• What if you cant provide adequate nutrition
  enterally?
• to add PN or not to add PN,
• that is the question!

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Early vs. Late Parenteral Nutrition in Critically
ill Adults

• 4620 critically ill patients
• Randomized to early PN
• Recd 20 glucose 20 ml/hr then PN on day 3
• OR late PN
• D5W IV then PN on day 8
• All patients standard EN plus tight glycemic
  control

• Results
• Late PN associated with
• 6.3 likelihood of early discharge alive from ICU
  and hospital
• Shorter ICU length of stay (3 vs 4 days)
• Fewer infections (22.8 vs 26.2 )
• No mortality difference

Cesaer NEJM 2011
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Early vs. Late Parenteral Nutrition in Critically
ill Adults

• ? Applicability of data
• No one give so much IV glucose in first few days
• No one practice tight glycemic control
• Right patient population?
• Majority (90) surgical patients (mostly
  cardiac-60)
• Short stay in ICU (3-4 days)
• Low mortality (8 ICU, 11 hospital)
• gt70 normal to slightly overweight
• Not an indictment of PN
• Early group only recd PN for 1-2 days on average
• Late group only ¼ recd any PN

Cesaer NEJM 2011
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Lancet Dec 2012
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Lancet Dec 2012
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Lancet Dec 2012
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Adult patients were eligible for enrollment
within 24 hours of ICU admission if they were
expected to remain in the ICU on the calendar
day after enrollment, were considered ineligible
for enteral nutrition by the attending clinician
due to a short-term relative contraindication and
were not expected to PN or oral nutrition
Doig, ANZICS, JAMA May 2013
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Who were these patients?
Overall, standard care group remained unfed for
2.8 days after randomization 40 of standard
care group never recd any artificial nutrition
remained in ICU 3.5 days
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Intervention not intense enough?

• 40 of both groups got EN (delayed)
• 40 of standard care group got PN for an average
  of 3.0 days
• Average PN use in early PN group was 6.0 days

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Main inference No harm by early PN (in contrast
to EPaNIC)
Doig, ANZICS, JAMA May 2013
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• What if you cant provide adequate nutrition
  enterally?
• to TPN or not to TPN,
• that is the question!

• Case by case decision
• Maximize EN delivery prior to initiating PN
• Use early in high risk cases

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At 72 hrs gt80 of Goal Calories?
YES
Anticipated Long Stay?
High Risk?
Carry on!
No
Maximize EN with motility agents and small bowel
feeding
YES
Tolerating EN at 96 hrs?
No
Supplemental PN?
No problem
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The TOP UP Trial
PN for 7 days
Primary Outcome
Stratified by Site BMI Med vs Surg
ICU patients
R
BMI lt25
60-day mortality
BMI gt35
Fed enterally
Control
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Muscle Outcome Assessments in TOP UP

• Measures of muscle mass and function
• mitochondrial complex I activity
• US of femoral quad (baseline and follow up CTs
  when available)
• Hand grip strength
• 6 min walk test
• SF 36 (RP and PCS)

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Reliability of US measure of Quad Muscle Layer
Thickness

• 46 pairs of within operator measurements with an
  ICC of .98
• 73 pairs of operator 1 to operator 2
  measurements with an ICC of .94.
• There was a small but statistically significant
  difference between the operator 1 and 2 results
  Mean (operator 1-2) (95 CI) -0.061 cm (-0.100
  to -0.022), p 0.0028. 

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Lancet 2009273
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In Conclusion

• Health Care Associate Malnutrition is rampant
• Not all ICU patients are the same in terms of
  risk
• Iatrogenic underfeeding is harmful in some ICU
  patients or some will benefit more from
  aggressive feeding (avoiding protein/calorie
  debt)
• BMI and/or NUTRIC Score is one way to quantify
  that risk
• Need to do something to reduce iatrogenic
  malnutrition in your ICU!
• Audit your practice first! (JOIN International
  Critical Care Nutrition Survey in 2013)
• PEP uP protocol in all
• Selective use of small bowel feeds then sPN in
  high risk patients

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Questions?