Daren K. Heyland MD Professor of Medicine Queen’s University, Kingston, ON Canada

The 2013 Canadian Critical Care Nutrition The 2013 Canadian Critical Care Nutrition Clinical Practice Guidelines: Clinical Practice Guidelines:

What are the Latest Recommendations?What are the Latest Recommendations?

Daren K. Heyland MD

Professor of MedicineQueen’s University, Kingston, ON Canada

On behalf of the Canadian Critical Care Nutrition Clinical Practice Guidelines Committee

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Disclosures

I have received speaker honoraria and/or I have been paid from grants from the following companies:

– Nestlé

– Fresenius Kabi

– Baxter

– Abbott

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Learning Objectives

Better understand the process by which CPGs are developed

Become familiar with recent randomized nutrition trials in critically ill adult patients

Enteral Fish oilsPN and type of Lipids New Sections

Review the updated analyses and recommendations of the Canadian CPGs

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www.criticalcarenutrition.com

Orginally published in 2003

Summarizes 198 trials studying 21283 patients

34 topics 17 recommendations

2005 update2005 update20072007 updateupdate20092009 updateupdate2013 update 2013 update

Guideline Development

Effect sizeConfidence Intervals

Validity Homogeneity

Adequacy of control groupBiological plausibility

GeneralizabilitySafety

FeasibilityCost

evidence integration of values+

practiceguidelines

Language of Recommendations

CONDITIONS LANGUAGE OF RECOMENDATION

No reservations about endorsing intervention.

“ strongly recommend”

Evidence supportive but minor uncertainties about safety, feasibility, or costs of intervention.

“recommend”

Supportive evidence weak and/or major uncertainties about safety, feasibility, or costs of intervention.

“ should be considered”

Inadequate or conflicting evidence.

“ insufficient data”

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Inclusion Criteria

Updated to 2013• Randomized controlled trials• Critically ill patients (not elective surgery)• Clinical Outcomes• EMBASE, Medline, Cinhal, reference lists

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New Evidence

67 new RCTs across 27 topics!

Topic 2009 2013 Total

Enteral vs Parenteral 12 2 14

Early vs. delayed 14 2 16

Indirect Calorimetry 1 1 2

Arginine containing 24 2 26

Fish Oils/Borage Oils 4 4 8

Protein/peptides 4 1 5

Fibre 6 2 8

Small Bowel vs. Feeding 11 4 15

Probiotics 11 12 23

New RCTs per Topic

Topic 2009 2013 Total

Combination EN + PN 5 3 8

PN Branched Chain A Acids 5 1 6

Intensive insulin 22 3 25

PN Type of lipids 5 4 9

PN Glutamine 17 11 28

Antioxidants 16 8 24

PN Selenium 11 7 18

New RCTs per topic

New Topic # RCTs

Intentional Underfeeding: Trophic vs Full Feeds 2

Intentional Underfeeding: Hypocaloric EN 1

Fish Oils only 1

Threshold of GRVs 2

Discarding GRVs 1

EN: ß Hydroxyl Methyl Butyrate (HMB) 1

Early Supplemental PN vs Late 1

PN + EN Glutamine 1

Optimal glucose control: CHO Restricted Formula + Insulin Therapy

1

Vitamin D 1

New Topics (n=10)

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 = 4New RCTs = 4

Rice 2011Grau-Carmona 2011Thiella 2011Elamin 2012+ Pontes Arruda 2011+ Stapleton 2011 (fish oil only)

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

bolus: dilute effect?50% pts underfed

(trophic)protein in placebo

include but analyze without

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)

First multicentre study to use “usual care” in control group…….no effect on

mortality

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)

Significant effect, no statistical heterogeneity!

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 Infections (2 RCTs): no effect Reduction in ICU LOS still significant (heterogeneity) Concerns of control group, negative results of large studies

2013 Recommendations

Fish Oils/borage oil: Downgraded recommendation to “should be considered”

Fish Oils alone: insufficient data

Use of PN and type of lipids

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EN + PN

No change from 2009we recommend that PN not be started

not be started at the same time as EN.

Insufficient evidence in those who are

not tolerating EN (case by case)

NEJM 2011Lancet 2012

Early Supplemental PN vs. LateCombined EN + PN

Strongly recommend that early PN & high IV

glucose not be used in low risk, short ICU stay

Insufficient evidence in those who are not

tolerating EN (case by case)

large multicentreearly PN: worse infections, LOSearly PN: no diff mortalityhigh glucose loadinglow risk patients

used indirect calorimetryNo difference mortalityreduced infections day 4-28

+ Abrishami 2010+ Chen 2011

Lipid Free PN?

Recommendation: • Based on 2 level 2 studies, in critically ill patients who are not

malnourished, are tolerating some EN, or when parenteral nutrition is indicated for short term use (< 10 days), withholding soy bean emulsions should be considered.

• There are insufficient data to make a recommendation about withholding lipids high in soybean oil in critically ill patients who are malnourished or those requiring PN for long term (> 10 days).

• Practitioners will have to weigh the safety and benefits of withholding lipids high in soybean oil on an individual case-by-case basis in these latter patient populations.

There are no new randomized controlled trials since the 2009 update and hence there are no changes to the recommendation.

Vanek VW, et al. Nutr Clin Pract 2012; 27: 150.

High LCT

ω-6

MCT/LCT

50:50

High MUFA

Ω-9

High PUFA

Ω-3Mixtures

Soybean Oil

(SO)SO + Coconut

Olive Oil

(OO) + SOFish Oil (FO)

SO, FO,

Coconut, OO

Intralipid®

Lipofundin®

(MCT/LCT)® ClinOleic®

Omegaven® SMOF®

Lipoplus®

Study or Subgroup1.1.1 LCT + MCT vs LCT

Garnacho-MonteroIovinelliLindgrenNijveldtSubtotal (95% CI)

Total eventsHeterogeneity: Tau² = 0.00; Chi² = 0.94, df = 3 (P = 0.82); I² = 0%Test for overall effect: Z = 0.53 (P = 0.59)

1.1.2 Fish oil containing emulsions vs LCT or LCT + MCT

BarbosaFrieseckeGrecuWang 2009Subtotal (95% CI)


1.1.3 Olive oil containing emulsions vs LCT or LCT + MCT

Garcia de LorenzoHuschakPontes-Arruda 2012UmperrezSubtotal (95% CI)


Total (95% CI)

Total eventsHeterogeneity: Tau² = 0.00; Chi² = 4.19, df = 11 (P = 0.96); I² = 0%Test for overall effect: Z = 1.27 (P = 0.20)Test for subgroup differences: Chi² = 0.25, df = 2 (P = 0.88), I² = 0%

Events

8212

13

418

20

24

44

195

32

69

Total

3512151274

13832828

152

1118

10351

183

409

Events

11301

15

422

32

31

41

218

34

80

Total

371215

872

10822628

146

1115

10149

176

394

Weight

13.4%3.2%0.8%1.7%

19.1%

6.6%27.9%

2.8%0.9%

38.3%

6.7%1.9%

26.5%7.5%

42.7%

100.0%

M-H, Random, 95% CI

0.77 [0.35, 1.69]0.67 [0.13, 3.30]

3.00 [0.13, 68.26]1.33 [0.14, 12.37]0.84 [0.43, 1.61]

0.77 [0.25, 2.34]0.81 [0.47, 1.39]0.62 [0.11, 3.41]0.20 [0.01, 3.99]0.76 [0.48, 1.21]

1.00 [0.33, 3.02]3.33 [0.42, 26.72]

0.89 [0.51, 1.55]0.60 [0.21, 1.71]0.90 [0.58, 1.39]

0.83 [0.62, 1.11]

Omega-6 Reducing LCT or LCT+MCT Risk Ratio Risk RatioM-H, Random, 95% CI

0.01 0.1 1 10 100Favours omega-6 reducing Favours LCT or LCT+MCT

Manzanares W, et al. Int Care Med 2013 (in press)

Ω-6 Sparing Strategies were associated with a reduction in Mortality (RR= 0.83, 95 % CI 0.62, 1.11, P= 0.20, heterogeneity I2 =0%)

Ω-6 Sparing Strategies were associated with a reduction in Mortality (RR= 0.83, 95 % CI 0.62, 1.11, P= 0.20, heterogeneity I2 =0%)

Study or Subgroup1.4.1 Fish oil containing emulsions vs LCT or LCT + MCT

GrecuFrieseckeBarbosaSubtotal (95% CI)

Heterogeneity: Tau² = 0.00; Chi² = 1.84, df = 2 (P = 0.40); I² = 0%Test for overall effect: Z = 1.63 (P = 0.10)


HuschakGarcia de LorenzoSubtotal (95% CI)


Total (95% CI)

Heterogeneity: Tau² = 3.00; Chi² = 5.36, df = 4 (P = 0.25); I² = 25%Test for overall effect: Z = 1.72 (P = 0.09)Test for subgroup differences: Chi² = 2.87, df = 1 (P = 0.09), I² = 65.2%

Mean

2.8322.8

10

1311

SD

1.6222.914.4

8.911.93

Total

88313

104

181129

133

Mean

5.2320.5

11

20.413

SD

2.819

12.64

716.25

Total

7821099

151126

125

Weight

50.5%16.4%

6.4%73.3%

21.1%5.6%

26.7%

100.0%

IV, Random, 95% CI

-2.40 [-4.76, -0.04]2.30 [-4.12, 8.72]

-1.00 [-12.07, 10.07]-1.81 [-3.98, 0.36]

-7.40 [-12.83, -1.97]-2.00 [-13.91, 9.91]

-6.47 [-11.41, -1.53]

-2.57 [-5.51, 0.37]

Year

200320082010

20052005

Omega-6 Reducing LCT or LCT+MCT Mean Difference Mean DifferenceIV, Random, 95% CI

-100 -50 0 50 100Favours omega-6 reducing Favours LCT or LCT+MCT

Ω-6 Sparing Strategies were associated with a trend towards a reduction in

Ventilation Days(WMD -2.57, 95% CI -5.51, 0.37, P=0.09)

Ω-6 Sparing Strategies were associated with a trend towards a reduction in

Ventilation Days(WMD -2.57, 95% CI -5.51, 0.37, P=0.09)

Manzanares W, et al. Int Care Med 2013 (in press)

Study or Subgroup1.3.1 LCT + MCT vs LCT

NijveldtGarnacho-MonteroSubtotal (95% CI)


1.3.2 Fish oil containing emulsions vs LCT or LCT + MCT

GrecuFrieseckeBarbosaSubtotal (95% CI)



Garcia de LorenzoHuschakUmperrezSubtotal (95% CI)


Total (95% CI)

Heterogeneity: Tau² = 10.21; Chi² = 21.87, df = 7 (P = 0.003); I² = 68%Test for overall effect: Z = 1.53 (P = 0.13)Test for subgroup differences: Chi² = 0.46, df = 2 (P = 0.80), I² = 0%

Mean

13.816.6

3.322812

32.917.9

17

SD

2.96.1

1.4825

14.4

10.611.2

18

Total

123547

88313

104

11185180

231

Mean

17.415.8

9.282313

41.825.115.2

SD

37

3.0820

12.6

16.37

14

Total

83745

7821099

11154975

219

Weight

19.1%18.3%37.4%

19.4%10.2%

5.5%35.1%

5.2%11.2%11.2%27.6%

100.0%

IV, Random, 95% CI

-3.60 [-6.25, -0.95]0.80 [-2.23, 3.83]

-1.46 [-5.77, 2.85]

-5.96 [-8.46, -3.46]5.00 [-1.90, 11.90]

-1.00 [-12.06, 10.06]-1.13 [-8.96, 6.69]

-8.90 [-20.39, 2.59]-7.20 [-13.47, -0.93]

1.80 [-4.51, 8.11]-4.08 [-10.97, 2.81]

-2.31 [-5.28, 0.66]

Year

19982002

200320082010

200520052012

Omega-6 Reducing LCT or LCT+MCT Mean Difference Mean DifferenceIV, Random, 95% CI

-100 -50 0 50 100Favours omega-6 reducing Favours LCT or LCT+MCT

Ω-6 Reducing Strategies were associated with a trend towards a reduction in ICU

LOS (WMD -2.31, 95% CI -5.28, 0.66, P=0.13)

Ω-6 Reducing Strategies were associated with a trend towards a reduction in ICU

LOS (WMD -2.31, 95% CI -5.28, 0.66, P=0.13) Manzanares W, et al. Int Care Med 2013 (in press)

FO containing lipid emulsions were associated with a trend towards a

reduction in mortality RR= 0.71, 95 %CI 0.49-1.04, P= 0.08

FO containing lipid emulsions were associated with a trend towards a

reduction in mortality RR= 0.71, 95 %CI 0.49-1.04, P= 0.08

0.71 (0.49,1.04)

P= 0.08

Manzanares W, et al. JPEN 2013, in press.

FO containing emulsions showed a trend towards reduction in the duration

of MV days WMD -1.41, 95% CI -3.43, 0.61, P=0.17

FO containing emulsions showed a trend towards reduction in the duration

of MV days WMD -1.41, 95% CI -3.43, 0.61, P=0.17

P= 0.17

-1.41 (-3.43,0.61)

Manzanares W, et al. JPEN 2013, in press.

Which Alternative Lipid Emulsion to Use?

• No head to head trials (and not likely to be)

• We analyzed our International Nutrition Survey database to evaluate effect of Alt Lipids on outcomes.

• Analyzed adjusted for key confounding variables.

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Edmunds, Heyland (in submission)


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Characteristic Lipid-free(n=70)

Soybean oil(n=223)

MCT oil(n=65)

Olive oil(n=74)

Fish oil(n=19)

pa

Age (yrs), mean±SD 64.8 ±16.6 63.5 ±15.9 61.9 ±16.9 64.0 ±16.4 66.2 ±18.3 0.81

Sex, n (%)MaleFemale

50 (71.4)20 (28.6)

135 (60.5)88 (39.5)

42 (64.6)23 (35.4)

45 (60.8)29 (39.2)

9 (47.4)10 (52.6)

0.31

Body mass index (kg/m2), mean±SD 26.1 ±9.8 28.4 ±8.0 23.8 ±3.3 25.6 ±4.7 27.4 ±6.4 <0.001

Admission category, n (%)MedicalEmergency surgicalElective Surgical

34 (48.6)23 (32.9)13 (18.6)

65 (29.1)118 (52.9)40 (17.9)

20 (30.8)31 (47.7)14 (21.5)

21 (28.4)35 (47.3)18 (24.3)

3 (15.8)15 (78.9)

1 (5.3)0.011

APACHE II score, mean±SD 23.8 ±9.5 22.4 ±7.9 22.7 ±9.3 21.1 ±8.0 24.3 ±6.8 0.30

Mean daily calories from PN, mean±SD 1036 ±428 1466 ±372 1287 ±313 1553 ±388 1517 ±385 <0.001

Mean daily calories from propofol, mean±SD 39 ±89 28 ±97 14 ±37 43 ±65 13 ±30 0.005

Mean daily total calories (PN + propofol), mean±SD 1084 ±472 1499 ±387 1306 ±326 1625 ±406 1532 ±398 <0.001


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Soybean

Fish Oil

Olive Oil

Lipid FreeMCT

PN Type of Lipids

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.

2013 Recommendation: IV lipids that reduce the load of omega-6 fatty acids/soybean

oil emulsions should be considered. There are

insufficient data on type of soybean reducing lipids

New Topic RCTs Recommendation

Intentional Underfeeding: Hypocaloric EN

1 Insufficient data

Threshold of GRVs 1 Insufficient data (250-500ml)

Discarding GRVs 1 Insufficient data

EN: ß Hydroxyl Methyl Butyrate (HMB)

1 Insufficient data

Optimal glucose control: CHO Restricted Formula + Insulin Therapy

1 Insufficient data

Vitamin D 1 Insufficient data

Other Topics

Summary• Many recent RCTs in area of critical care nutrition • Careful review of the articles is recommended• Recommendations downgraded

EN Fish Oils/borage oils

PN Glutamine

• Recommendations upgraded Probiotics

Type of PN lipids

• Recommendations do not changeCombined AOX

PN Selenium and others

• New RecommendationsPN + EN Glutamine: strongly recommended NOT to be used

Early PN vs Delayed PN: Strongly recommend NOT be used

Other: Trophic vs full feeds: should NOT be considered

Updated recommendations will have an impact on practices in ICU

Acknowledgment

Co Chair Daren HeylandLeah GramlichJohn DroverBrian JurewitschCarmen Christman Chelsea CorbettJan Greenwood Michele McCallGwynne MacdonaldGuiseppe PagliarelloJim Kutsogiannis

John MuscedereKhursheed JeejeebhoyCourtney Somers-BalotaDominique GarrelAdam Rahman

William ManzanaresPaul WischmeyerRene StapletonTodd RiceAndrew Davies Emma Ridley

Canadian Clinical Practice Guidelines Committee

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Documents

Daren K. Heyland MD Professor of Medicine Queen’s University, Kingston, ON Canada