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 area of critical care nutrition (adult)

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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Canadian CPGs

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1980-2003 n > 200 RCTs 34 topics 17 recommendations

JPEN 2003

www.criticalcarenutrition.com

2005 update2005 update20072007 updateupdate2009 update 2009 update

Development of Guidelines

Validity Homogeneity

SafetyFeasibility

Cost

evidence integration of values+

practiceguidelines

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Inclusion Criteria

Updated to 2011• Randomized controlled trials• Critically ill patients (not elective surgery)• Clinical Outcomes• EMBASE, Medline, Cinhal, reference lists

Topic # RCTs 2009 # new RCTs

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 8

Antioxidants 16 5

PN Selenium 11 5

New RCTs* per Topic (n =51)

* from 2009-2011

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 = 7

Probiotics: effect on infections (n =11)

2009 update : RR 0.89 [0.68, 1.17] p = 0.4

Petrof et al in submission Critical Care 2012

Lower quality studies > effect vs. higher quality studies

p = 0.03

Probiotics: effect on VAP (n = 7)

Petrof et al in submission Critical Care 2012

Probiotics: effect on ICU mortality (n = 6)

Petrof et al in submission Critical Care 2012

2009 update : RR 0.74 [0.50, 1.09] p = 0.12

Probiotics with new RCTs

stronger signal for reduction in infections– higher quality studies do NOT show a reduction in

infections

significant reduction in VAP still trend towards reduction in ICU mortality

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Arginine

2009 Recommendation

Based on 22 studies, we recommend arginine and other

select nutrients not be used for critically ill patients

no effect on mortalityno effect on infections

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Drover et al Am Coll Surg 2011

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

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 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 = 4New RCTs = 4

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

PREVENTION VS. TREATMENT

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

OMEGA: 60-Day MortalityOMEGA: 60-Day Mortality

P=0.05P=0.14P=0.14

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

Fish Oils ONLYBolus

Separate from EN

Clinical Outcomes

Stapleton CCM 2011

……..Because of different study design, difficult to combine with other studies of continuous administration in moderately well fed patients…..

Cook, Heyland JAMA Oct 2011

Fish Oils: Effect on mortality (n = 7)

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

No effect , statistical heterogeneity!

INTERSEPT data not included

Fish oils: effect on mortality removing bolus RCTs

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EN fish oils: with new RCTs

Effect on mortality disappears when bolus studies are included

clinical heterogeneity-studies using bolus fish oils are methodologically different

- one RCT does not have GLA, antioxidants

statistical heterogeneity with the addition of the bolus studies

Parenteral Fish Oils

IV lipid

emulsion

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Type of Lipids (PN)

2009 Recommendation

There are insufficient data to make a recommendation

on the type of lipids to be used in critically ill patients

receiving parenteral nutrition

IV lipid

emulsion

Fish Oil containing vs LCT/MCT or LCTOlive Oil containing vs LCT/MCT or LCTLCT + MCT vs LCTLCT vs LCT

New RCTs = 4New RCTs = 4

N = 25 septic pts

PN + Fish Oil vs. PN + soybean oil

p = 0.004

Barbosa Crit Care 2010

Wang Inflammation 2009

N = 56 patients with SAP, China

PN with Fish Oils (+ LCT) vs PN (LCT) X 5 days

Fish Oils improved plasma IL-10 levels, decreased HLA= anti-inflammatory

No effect on clinical outcomes

N= 28 patients with Severe Sepsis, Taiwan

Supplementation with Fish Oils 100 mls/day X 5 d vs. Placebo (saline)

Reduction in APACHE 3 score:• improved more in Fish oil group Days 3, 5 & 7 (p =0.03-0.004)

Khor Asian J Surg 2011

Procalcitonin levels

Procalcitonin levels are a marker of inflammatory response

No difference in hospital or length of stay between the groups

Khor Asian J Surg 2011

N = 61 patients with ARDS, India

Supplementation with Fish Oils + EN vs. EN alone X 14 days

Oxygenation •P/F ratio: no differences• worsening in P/F ratio: higher in control group (p=0.0004)

Mortality: trend towards lower in Fish Oil group (p = 0.10)

Ventilation, ICU LOS: no difference

Gupta Ind J Crit Care Med 2011

Fish Oil vs LCT + MCT: Updated Effect on mortality (n = 7)

2009: RR 0.76, [0.46, 1.26], p = 0.29

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Fish Oil vs LCT or LCT + MCT: Effect on infections (n = 3)

2009: RR 0.77 [0.39, 1.49], p = 0.43

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PN lipids: with new RCTs

Other lipids: no changes fish oils: studies with different designs

2 studies of lipids in PN 2 studies of supplemental fish oils

fish oils: signal for reduction in mortality fish oils: still no effect on infections

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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

Chinese Chinese RCTsRCTs

New RCTs = 2New RCTs = 2

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

Grau 2011Grau 2011Andrews 2011Andrews 2011Wernerman 2011Wernerman 2011Eroglu 2009Eroglu 2009Perez Barcena 2010Perez Barcena 2010+ possibly 3 Chinese RCTs+ possibly 3 Chinese RCTs

New RCTs = 5New RCTs = 5

• 10 centres in Scotland • 502 Patients expected to be in ICU for at least 48h and required PN

meet at least half their requirements• 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» 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

• Right patient population?– Only about half getting PN at time of randomization

• Timing of intervention?– Started too late (2.6 days plus time to get PN running)

• Inadequate exposure to intervention?– Too small of dose– Too short of duration (4-5 days)

The SIGNET Trial – The SIGNET Trial – QuestionsQuestions!!

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

PN GLN: mortality revised (n = 20)

2009 RR 0.71 [0.55, 0.52] p = 0.008

PN GLN: infections revised (n = 12)

2009 RR 0.76 (0.62, 0.93) p = 0.008

less effect on mortality, still a trend less effect on infections, still significant

PN GLN with new RCTs

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Awaiting results

The REDOXS© Study REducing Deaths due to OXidative Stress

The REDOXS© StudyREducing Deaths from OXidative Stress

Study ChairDr. Daren Heyland

Enrolment completed, n =1200Results expected Summer 2011

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 Selenium2009 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

New RCTs = 5 New RCTs = 5

• Randomized, open-label, single-centre clinical trial

• 150 patients with SIRS/sepsis and a SOFA score of >5

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• Patients in the Se group received 1,000 ug on day 1 followed by 500 ug/day on days 2–14

• Administered daily over 30 mins

• Patients in both groups received a standard Se dose (75 ug/day)

Lower mortality in patients with a higher APACHE p =0.10

Phase II study building on previous dosing work

35 Patients with SIRS and APACHE II >15

Randomized within 24 hrs of admission Received either placebo or IV Se as a

bolus-loading dose of 2,000 ug followed by continuous infusion of 1,600 ug/ day for 10 days.

Lower VAP (p =0.04) Lower SOFA at day 10 (p=0.01)

The SIGNET Trial – RESULTSThe SIGNET Trial – RESULTS

Effect of SeleniumEffect of Selenium

No significant differences

Confirmed infections within 14 days

P=0.12 P=0.02

Mortality

AOX combined mortality, n =20

2009 0.76 RR [0.64, 0.91], p = 0.002

Manazares et al in submission 2012

AOX combined Infections, n=10

2009 RR 0.94 [0.75, 1.17], p = 0.56

Manazares et al in submission 2012

still significant effect on reduction on mortality stronger reduction on infections reduction stronger signal in sicker patients selenium associated with a trend towards lower mortality

& infections

Antioxidants with new RCTs

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Conclusion

• Many recent RCTs in area of critical care nutrition • Careful review of the articles is recommended• Recommendations for following not expected to change:

– Arginine– EN glutamine– PN glutamine– IV fish oils

• Recommendations for following may be upgraded:

Probiotics and AOX• Recommendations for the following pending discussion

– EN Fish Oils

• Other Societies for critical care: harmonize the evidence