Latest Evidence on Nutrition in the ICU:
Will it Change Existing Guidelines?
Rupinder Dhaliwal, RD
Clinical Evaluation Research Unit
Critical Care Nutrition
Kingston ON, Canada
1
Outline of Session
New RCTs in select area of critical care nutrition
(adult)
Fish oils
Parenteral glutamine
Antioxidants
Probiotics
Updated analyses of Canadian Guidelines
Impact on evidentiary basis
1
Conflict of interest
Co-author of Canadian Clinical Practice Guidelines
1
JPEN 2003
 1980-2003
 n > 200 RCTs
 34 topics
 17 recommendations
2005 update
2007 update
2009 update
www.criticalcarenutrition.com
Development of Guidelines
evidence
+ integration of values
Validity
Homogeneity
Safety
Feasibility
Cost
practice
guidelines
1
Inclusion Criteria
Updated to 2012
• Randomized controlled trials
• Critically ill patients (not elective surgery)
• Clinical Outcomes
• EMBASE, Medline, Cinhal, reference lists
New RCTs per Topic (n = 66)
Topic
# RCTs 2009
# new RCTs 2012
Early vs. delayed
14
2
Target dose EN
2
2
Fish Oils/Borage Oils
5
4
Protein/peptides
4
1
Fibre
6
1
Small Bowel vs. Feeding
11
5
Protocols/GRVs
3
2
Probiotics
12
7
Supplemental PN
5
5
PN Type of lipids
5
4
PN Glutamine
17
11
Antioxidants
16
6
PN Selenium
11
5
New Topics (n=8) and RCTs
New Topic
# new RCTs
Trophic vs. Full feeds
2
Hypocaloric EN
1
Fish Oils only
1
PN + EN Glutamine
1
Threshold of GRVs
1
Discarding GRVs
1
Early Supplemental PN vs Late
1
Vitamin D
1
Enteral Fish Oils*
*Product enhanced with fish oils +borage oils +
antioxidants
1
Enteral Fish Oils*
*Product enhanced with fish oils +borage oils + antioxidants
2009 Recommendation
Based on 5 studies, we recommend the use of
enteral formula with fish oils, borage oils, and
antioxidants in patients with ALI/ARDS
New RCTs = 3
Rice 2011
Grau-Carmona 2011
Thiella 2011
+ Pontes Arruda 2011
+ Stapleton 2011 (fish oil only)
 Multicenter, RCT, 14 ICUs in Brazil
 N = 200, early stages of sepsis (no organ failures; within 36 hrs from onset
of sepsis).
 Fish oil/borage oil/antioxidant vs. standard polymeric X 7 days
 Outcomes:
• Evolution to more severe forms of sepsis (severe sepsis or septic
shock
• 28 day all-cause mortality, organ failure development,
hyper/hypoglycemic events, insulin use, hospital stay, ICU stay
Pontes-Arruda Crit Care 2011;15:R144
Outcomes
Variable
Study
(n=53)
Use of mechanical ventilation, n (%)
Control
(n=53)
P Value
Development of sepsis
5.7%
13.3%
Development of septic shock
20.7 %
37.7%
0.022
Invasive
10 (18.9%)
18 (34%)
.039
Non-invasive
PREVENTION
5 (9.4%)
6 (11.3%)
NS
VS.
TREATMENT
Number of days using
7 (4-12)
15 (9-21)
.0033
< 50 % patients
ventilated
mechanical ventilation
Exclude from
Number of ICU days
7 (4-12)CPGs
13 (9-18)
<.0001
Number of hospital days
No difference in survival between
the groups
9 (6-14)
19 (13-24)
<.0001
Pontes-Arruda Crit Care 2011;15:R144
 11 Spanish ICUs
 89 patients with diagnosis of Sepsis on admission
 Randomized to:
• Fish Oil/Borage Oil formula OR
• Standard polymeric formula
 Outcomes: new organ dysfunction
Grau-Carmona Clin Nutr 2011
Clinical Outcomes
Fish Oils: Trend towards lower SOFA scores (NS)
Grau-Carmona Clin Nutr 2011
NIH
NHLBI
Timing of Feeding
S
U
P
P
L
E
M
E
N
T
“Early
Full”
N-3 + GLA +
Antioxidants
(Module delivered
as bolus bid)
Control
Standard EN
(480 cal/ 20 g pro)
Fast ramp up
“Early
Trophic”
(10 ml/hr)
n = 250
n = 250
n = 250
n = 250
……..Because of different study design, difficult to
combine with other studies of continuous
administration in moderately well fed patients…..
Cook, Heyland JAMA Oct 2011
OMEGA: 60-Day Mortality
P=0.05
P=0.14
bolus
not formula
select patients
include but analyze
without
Rice et al JAMA Oct 2011
 89 patients from 5 centres in US
 Mechanically ventilated patients with Acute lung injury (ALI)
 Randomized to (separate from EN):
• BOLUS fish oils 7.5 mls q 6 hrs, 9.75g EPA & 6.75 gm DHA/day
OR
• placebo i.e. normal saline X 14 days
 EN or PN as per MDs discretion
Stapleton CCM 2011
Clinical Outcomes
Fish Oils ONLY
Bolus
Separate from EN
X aggregate with RCTs
of fish oil, borage oil
Stapleton CCM 2011
Fish Oils: Effect on mortality (n = 6)
INTERSEPT, Stapleton data not included
No effect , statistical heterogeneity!
2009: RR 0.67, 95% CI 0.51, 0.97, p = 0.003
Fish oils: effect on mortality removing
bolus RCT (n =5)
1
EN fish oils: with new RCTs
 Effect on mortality disappears when bolus study is included
• statistical heterogeneity present
 Effect on mortality is significant when bolus study excluded
2012 Recommendation
Fish Oils/borage oil:
Downgrade recommendation to “should be considered”
Fish Oils alone: insufficient data
Arginine
2009 Recommendation
Based on 22 studies, we recommend arginine and other
select nutrients not be used for critically ill patients
New RCTs = 0
1
Elective surgery patients
many RCTs
 significant reduction in infections p <0.0001
 significant shorter HLOS p <0.0001
Drover et al Am Coll Surg 2011
Glutamine supplementation?
1
EN Glutamine
2009 Recommendation
Based on 2 level 1 and 7 level 2 studies, enteral glutamine
should be considered in burn and trauma patients. There
are insufficient data to support the routine use of enteral
glutamine in other critically ill patients
New RCTs = 0
No changes in
recommendation
PN Glutamine
2009 Recommendation
Based on 17 studies, when parenteral nutrition is prescribed to critically
ill patients, parenteral supplementation with glutamine, where available,
is strongly recommended. There are insufficient data to generate
recommendations for intravenous glutamine in critically ill patients
receiving enteral nutrition
Ozgultekin 2008
Eroglu 2009
Perez Barcena 2010
Grau 2011
New RCTs = 11
Andrews 2011
Wernerman 2011
Cekman 2011
Zeigler 2012 (in press)
+ 3 Chinese RCTs
+ Heyland 2012 REDOXS (EN + PN)
• 10 centres in Scotland
• 502 Patients expected to be in ICU for at least 48h and required PN
meet at least half their requirements (only 50% received PN)
• Randomized 2.6 days after admission to ICU
• Trial PN isocaloric and isonitrogenous, given for up to 7 days unless
died or stopped PN
» Glutamine 20g/d ( too small of a dose?)
» Selenium 500μg/d
» Both
» Neither
• Median duration of study PN was 4-5 days
Andrews BMJ 2011:342
The SIGNET Trial – RESULTS
Effect of Glutamine
Mortality
No significant differences
Confirmed infections within 14 days
No significant differences
 Multicenter trial in Spain
 127 patients with APACHE II score >12 and requiring PN
for 5–9 days
 Standard PN vs. Supplemented with 0.5 g/kg/d of AlaGln dipeptide
 Enrolled patients received only 5-6 days of PN
Grau CCM 2011; 39
P=0.10
P=0.03
Grau CCM 2011; 39
 413 Patients given nutrition by EN and/or PN route
 Within 72 hrs of ICU admission
 Supplemented as IV L-Ala-Glutamine, 0.283 g/kg/day administered
separate from PN vs. placebo (saline)
 Primary endpoint SOFA; infections not recorded
No effect on SOFA
Wernerman Acta Anesthesiology 2011
PN glutamine group: lower mortality
PP p = 0.046
ITT p = 0.098
Wernerman Acta Anesthesiology 2011
Ahmet Eroglu
Critical Care 2010
Anesthesia Anal 2009
GLND Ziegler et al (in press)
n =150 surgical ICU patients
needing PN after cardiac,
vascular, colonic surgery
no differences in mortality
trend towards increase in
infections
©
The REDOXS Study
REducing Deaths due to OXidative Stress
The REDOXS© Study
REducing Deaths from OXidative Stress
Glutamine given via
Dr. Daren Heyland et al
PN plus EN
Patients
least
2 failures
N = 1223 patients
with 2at
or more
organ
Randomized toOrgan
high GLNfailure
EN + PN vs. placebo
within 24 hrs admission to ICU
Factorial design: Antioxidants vs. placebo
t ic
a l C ar e
ials G
ro
i
d
a
Tr
a n Cri
X aggregate with other
studies
up C an
PN GLN: mortality revised (n = 24)
2009
RR 0.71
[0.55, 0.52]
p = 0.008
2012
weaker
now a trend
PN GLN: infections revised (n = 12)
2009
RR 0.76
(0.62, 0.93)
p = 0.008
2012
still significant
weaker
PN GLN with new RCTs

less effect on mortality, now only a trend
 less effect on infections, still significant
2012 Recommendation:
PN Glutamine
Downgrade to recommend or should be considered
CAUTION: do not use high dose PN in patients with acute MOF
PN + EN Glutamine (REDOXS)
Strongly recommend that high dose IV GLN + EN NOT be used in
patients with MOF
1
Antioxidant supplementation
Parenteral Selenium
1
Supplemental Antioxidant Nutrients
2009 Recommendation:
Based on 16 studies, the use of supplemental vitamins and trace
elements should be considered
Parenteral Selenium
2009 Recommendation:
There are insufficient data to make a recommendation
regarding IV/PN selenium supplementation, alone or in
combination with other antioxidants, in critically ill patients
AOX/PN Se new RCTs
New RCTs = 5
El Attar 2009
Montoya 2009
Andrews 2011
Manzanares 2011
Valenta 2011
+ REDOXS Study 2012
Manzanares
Critical Care
2012
AOX combined: mortality, n =22
2009
0.76 RR [0.64,
0.91]
p = 0.002
2012
still significant
weaker signal
AOX combined: infections, n=11
2009
RR 0.94
[0.75, 1.17]
p = 0.56
2012
stronger
signal
Antioxidants/PN Se with new RCTs
AOX combined
 weaker significant effect on reduction on mortality
 stronger reduction in infections
 stronger signal for both in sicker patients
PN selenium
 still trend towards reduction in mortality
 stronger reduction in infections
2012 Recommendation (TO BE FINALIZED):
AOX: no change ?
PN Se: no change ?
Probiotics
1
Probiotics
2009 Recommendation
There are insufficient data to make a recommendation
on the use of Prebiotics/Probiotics/Synbiotics in critically
ill patients
New RCTs = 7
1
Knight 2009
Barraud 2010
Morrow 2010
Frohmader 2010
Ferrie 2011
Sharma 2011
Tan 2011
Petrof et al
Critical Care
2012
Critical Care Medicine 2012
Probiotics with new RCTs

stronger signal for reduction in infections (2009: no
reduction)
– higher quality studies do NOT show a reduction in infections
 significant reduction in VAP
 still trend towards reduction in ICU mortality
2012 Recommendation:
Upgrade to should be considered
1
Summary
• Many recent RCTs in area of critical care nutrition
• Careful review of the articles is recommended
• Recommendations for following will probably not change
Arginine
EN glutamine
• Recommendations for the following will probably be downgraded
EN Fish Oils/borage oils
PN Glutamine
PN + EN Glutamine (NEW TOPIC)
• Recommendations for following will probably be upgraded
Probiotics
• Recommendations for following are pending
Combined AOX
PN Selenium
Updated recommendations will have an impact on practices in ICU