Latest Evidence on Nutrition in the ICU: Latest Evidence on Nutrition in the ICU: Will it Change Existing Guidelines?Will it Change Existing Guidelines?

Rupinder Dhaliwal, RD

Clinical Evaluation Research Unit

Critical Care Nutrition

Kingston ON, Canada

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Outline of Session

New RCTs in select area of critical care nutrition (adult)

Fish oilsParenteral glutamineAntioxidantsProbiotics

Updated analyses of Canadian Guidelines

Impact on evidentiary basis

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Conflict of interest

Co-author of Canadian Clinical Practice Guidelines

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www.criticalcarenutrition.com

JPEN 2003

1980-2003 n > 200 RCTs 34 topics 17 recommendations

2005 update2005 update20072007 updateupdate2009 update 2009 update

Development of Guidelines

Validity

HomogeneitySafety

FeasibilityCost

evidence integration of values+

practiceguidelines

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Inclusion Criteria

Updated to 2012• Randomized controlled trials• Critically ill patients (not elective surgery)• Clinical Outcomes• EMBASE, Medline, Cinhal, reference lists

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 RCTs per Topic (n = 66)

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

New Topics (n=8) and RCTs

Enteral Fish Oils*

*Product enhanced with fish oils +borage oils + antioxidants

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Enteral Fish Oils**Product enhanced with fish oils +borage oils + antioxidants

2009 RecommendationBased on 5 studies, we recommend the use of

enteral formula with fish oils, borage oils, and

antioxidants in patients with ALI/ARDS

New RCTs = 3New RCTs = 3

Rice 2011Grau-Carmona 2011Thiella 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

Variable Study (n=53)

Control (n=53)

P Value

Use of mechanical ventilation, n (%)

Development of sepsis 5.7% 13.3%0.022

Development of septic shock 20.7 % 37.7%

Invasive 10 (18.9%) 18 (34%) .039

Non-invasive 5 (9.4%) 6 (11.3%) NS

Number of days using mechanical ventilation

7 (4-12) 15 (9-21) .0033

Number of ICU days 7 (4-12) 13 (9-18) <.0001

Number of hospital days 9 (6-14) 19 (13-24) <.0001

Outcomes

No difference in survival between the groups

Pontes-Arruda Crit Care 2011;15:R144

PREVENTION VS. TREATMENT< 50 % patients ventilated

Exclude from CPGs

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

Grau-Carmona Clin Nutr 2011

Fish Oils: Trend towards lower SOFA scores (NS)

Timing of FeedingTiming of Feeding

SSUUPPPPLLEEMMEENNTT

““Early Early Full”Full”Fast ramp upFast ramp up

““Early Early Trophic”Trophic”(10 ml/hr)(10 ml/hr)

N-3 + GLA +N-3 + GLA +AntioxidantsAntioxidants(Module delivered (Module delivered as as bolusbolus bid) bid)

ControlControlStandard ENStandard EN(480 cal/ 20 g pro)(480 cal/ 20 g pro)

n = 250 n = 250

n = 250 n = 250

NIH NHLBI

……..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 MortalityOMEGA: 60-Day Mortality

P=0.05P=0.14P=0.14

Rice et al JAMA Oct 2011

bolusnot formula

select patients

include but analyze without

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

Stapleton CCM 2011

Fish Oils ONLYBolus

Separate from EN

X aggregate with RCTs of fish oil,

borage oil

Fish Oils: Effect on mortality (n = 6)

2009: RR 0.67, 95% CI 0.51, 0.97, p = 0.003

No effect , statistical heterogeneity!

INTERSEPT, Stapleton data not included

Fish oils: effect on mortality removing bolus RCT (n =5)

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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

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New RCTs = 0New RCTs = 0 Elective surgery patients many RCTs

Drover et al Am Coll Surg 2011

significant reduction in infections p <0.0001 significant shorter HLOS p <0.0001

Glutamine supplementation?

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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

No changes in No changes in recommendationrecommendation

New RCTs = 0New RCTs = 0

PN Glutamine2009 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 Ozgultekin 2008 Eroglu 2009Eroglu 2009Perez Barcena 2010Perez Barcena 2010Grau 2011Grau 2011Andrews 2011Andrews 2011Wernerman 2011Wernerman 2011Cekman 2011Cekman 2011Zeigler 2012 (in press)Zeigler 2012 (in press)+ 3 Chinese RCTs+ 3 Chinese RCTs+ Heyland 2012 REDOXS (EN + PN)+ Heyland 2012 REDOXS (EN + PN)

New RCTs = 11 New RCTs = 11

• 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 – RESULTSThe SIGNET Trial – RESULTS

Effect of GlutamineEffect of Glutamine

No significant differences

Confirmed infections within 14 daysMortality

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 Ala-Gln dipeptide

Enrolled patients received only 5-6 days of PN

Grau CCM 2011; 39

P=0.10 P=0.03Grau 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

Wernerman Acta Anesthesiology 2011

PN glutamine group: lower mortality PP p = 0.046ITT p = 0.098

Ahmet Eroglu Anesthesia Anal 2009

Critical Care 2010

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© StudyREducing Deaths from OXidative Stress

Dr. Daren Heyland et al

N = 1223 patients with 2 or more organ failuresRandomized to high GLN EN + PN vs. placebo

within 24 hrs admission to ICUFactorial design: Antioxidants vs. placebo

Glutamine given via PN plus EN

Patients at least 2 Organ failure

X aggregate with other studies

PN GLN: mortality revised (n = 24)

2009 RR 0.71 [0.55, 0.52]

p = 0.008

2012weakernow a trend

PN GLN: infections revised (n = 12)

2009 RR 0.76 (0.62, 0.93) p = 0.008

2012still significantweaker

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

PN GLN with new RCTs

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Antioxidant supplementationParenteral Selenium

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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

El Attar 2009Montoya 2009Andrews 2011Manzanares 2011Valenta 2011

New RCTs = 5

+ REDOXS Study 2012

Manzanares Critical Care 2012

AOX combined: mortality, n =22

2009 0.76 RR [0.64, 0.91]

p = 0.002

2012still significantweaker signal

AOX combined: infections, n=11

2009 RR 0.94 [0.75, 1.17]

p = 0.56

2012stronger signal

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 ?

Antioxidants/PN Se with new RCTs

Probiotics

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Probiotics

2009 Recommendation

There are insufficient data to make a recommendation on the use of Prebiotics/Probiotics/Synbiotics in critically ill patients

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Knight 2009Barraud 2010Morrow 2010Frohmader 2010Ferrie 2011Sharma 2011Tan 2011

New RCTs = 7Petrof 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

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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 downgradedEN Fish Oils/borage oils

PN Glutamine

PN + EN Glutamine (NEW TOPIC)

• Recommendations for following will probably be upgraded Probiotics

• Recommendations for following are pendingCombined AOX

PN Selenium

Updated recommendations will have an impact on practices in ICU