1. Meta-Analyses, Guideline Development & Implementation
Latest Evidence on Nutrition in the ICU: Will it Change Existing Guidelines?
June 10th 2011
Rupinder Dhaliwal, RD
Clinical Evaluation Research Unit
Critical Care Nutrition
Kingston ON, Canada 1
Rupinder Dhaliwal

2. Outline of Session New RCTs in area of critical care nutrition (adult)
Updated analyses of Canadian Guidelines
Impact on evidentiary basis 1

3. Conflict of interest
Co-author of Canadian Clinical Practice Guidelines 1

4. Canadian CPGs 1980-2003 n > 200 RCTs 34 topics 17 recommendations
JPEN 2003
n > 200 RCTs
34 topics
17 recommendations 1

5. 2005 update
update
2009 update

6. Development of Guidelines
Validity
Homogeneity
Safety
Feasibility
Cost
evidence
integration of values +
practice
guidelines 1

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

8. New RCTs* per Topic (n =51)
Meta-Analyses, Guideline Development & Implementation
New RCTs* per Topic (n =51)
June 10th 2011
Topic
# RCTs 2009
# new RCTs
Early vs. delayed 14 2
Target dose EN
Fish Oils/Borage Oils 5 4
Protein/peptides 1
Fibre 6
Small Bowel vs. Feeding 11
Protocols/GRVs 3
Probiotics 12 7
Supplemental PN
PN Type of lipids
PN Glutamine 17 8
Antioxidants 16
PN Selenium
Total n = 58 of all RCTs
* from
Rupinder Dhaliwal

9. Probiotics 1

10. Probiotics 2009 Recommendation New RCTs = 7
There are insufficient data to make a recommendation on the use of Prebiotics/Probiotics/Synbiotics in critically ill patients
Knight 2009
Barraud 2010
Morrow 2010
Frohmader 2010
Ferrie 2011
Sharma Tan 2011
New RCTs = 7 1

11. Lower quality studies > effect vs. higher quality studies
Probiotics: effect on infections (n =11)
Lower quality studies > effect
vs. higher quality studies
p = 0.03
2009 update : RR 0.89 [0.68, 1.17] p = 0.4
Petrof et al in submission Critical Care 2012

12. Meta-Analyses, Guideline Development & Implementation
June 10th 2011
Probiotics: effect on VAP (n = 7)
Earlier: not enough studies to
Petrof et al in submission Critical Care 2012
Rupinder Dhaliwal

13. Meta-Analyses, Guideline Development & Implementation
June 10th 2011
Probiotics: effect on ICU mortality (n = 6)
Earlier: No effect
2009 update : RR 0.74 [0.50, 1.09] p = 0.12
Petrof et al in submission Critical Care 2012
Rupinder Dhaliwal

14. 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 1

15. Arginine 2009 Recommendation no effect on mortality
Based on 22 studies, we recommend arginine and other
select nutrients not be used for critically ill patients
no effect on mortality
no effect on infections 1

16. Meta-Analyses, Guideline Development & Implementation
June 10th 2011
significant reduction in infections p <0.0001
significant shorter HLOS p <0.0001
35 RCTs
No effect on mortality
Drover et al Am Coll Surg 2011
Rupinder Dhaliwal

17. (Product enhanced with fish oils +borage oils + antioxidants)*
Enteral Fish Oils* ?
(Product enhanced with fish oils +borage oils + antioxidants)* 1

18. Enteral Fish Oils 2009 Recommendation New RCTs = 4
(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 = 4

19. PREVENTION VS. TREATMENT
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
PREVENTION VS. TREATMENT
Pontes-Arruda Crit Care 2011;15:R144

20. Mostly due to reduced Cardio-resp failures
PRIMARY OUTCOME: DEVELOPMENT OF SEVERE SEPSIS AND SEPTIC SHOCK
Mostly due to reduced Cardio-resp failures
Pontes-Arruda Crit Care 2011;15:R144

21. No difference in survival between the groups
Secondary Outcomes
Variable
Study (n=53)
Control (n=53)
P Value
Use of mechanical ventilation, n (%)
Invasive
10 (18.9%)
18 (34%)
.03984
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
13 (9-18)
<.0001
Number of hospital days
9 (6-14)
19 (13-24)
No difference in survival between the groups
Pontes-Arruda Crit Care 2011;15:R144

22. Meta-Analyses, Guideline Development & Implementation
June 10th 2011
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
Control = ensure plus
Grau-Carmona Clin Nutr 2011
Rupinder Dhaliwal

23. Meta-Analyses, Guideline Development & Implementation
Clinical Outcomes
June 10th 2011
Fish Oils: Trend towards lower SOFA scores (NS)
Non signficant trend for lower SOFa scores
Overall: Do not benefit from fish oils in sepsis
Grau-Carmona Clin Nutr 2011
Rupinder Dhaliwal

24. ARDSnet n = 250 “Early Trophic” “Early Full” N-3 + GLA + Antioxidants
NIH NHLBI
Timing of Feeding
“Early Trophic”
(10 ml/hr)
“Early Full”
Fast ramp up S U P L E M N T
N-3 + GLA +
Antioxidants
(Module delivered
as bolus bid)
n = 250
EDEN OMEGA Trial Factorial design OMEGA and Early enteral (trophic) feeds
OMEGA: 21 days, 120 mls X 2/day
Stopped for futility
No benefit on outcomes or biomarkers of inflammation and may be harmful
Control
Standard EN
(480 cal/ 20 g pro) 24

25. Meta-Analyses, Guideline Development & Implementation
June 10th 2011
OMEGA: 60-Day Mortality
P=0.05
P=0.14
P=0.14
Adjusted for baseline demographics differences
Rice et al JAMA Oct 2011
Rupinder Dhaliwal

26. Meta-Analyses, Guideline Development & Implementation
June 10th 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
Fish Oils ONLY
Bolus
Separate from EN
Fish oils
Stapleton CCM 2011
Rupinder Dhaliwal

27. Meta-Analyses, Guideline Development & Implementation
June 10th 2011
Clinical Outcomes
No differences
NO diff in biomarkers of inflammation
Stapleton CCM 2011
Rupinder Dhaliwal

28. Update this slide with the JAMA editorial
……..Because of different study design, difficult to combine with other studies of continuous administration in moderately well fed patients…..
Cook, Heyland JAMA Oct 2011

29. Meta-Analyses, Guideline Development & Implementation
June 10th 2011
Fish Oils: Effect on mortality (n = 7)
INTERSEPT data not included
No effect , statistical heterogeneity!
2009: RR 0.67, 95% CI 0.51, 0.97, p = 0.003
Rupinder Dhaliwal

30. Fish oils: effect on mortality removing bolus RCTs
Meta-Analyses, Guideline Development & Implementation
June 10th 2011
Fish oils: effect on mortality removing bolus RCTs
Mortality still significant
No infections data
ICU LOS (significant) and HLOS (significant)..same as before 1
Rupinder Dhaliwal

31. EN fish oils: with new RCTs
Meta-Analyses, Guideline Development & Implementation
June 10th 2011
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
New RCTs did not report on LOS in mean and SD
Rupinder Dhaliwal

32. Parenteral Fish Oils
IV lipid
emulsion 1

33. Meta-Analyses, Guideline Development & Implementation
June 10th 2011
Type of Lipids (PN)
IV lipid
emulsion
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
Fish oil + LCT vs LCT alone or LCT/MCT
LCT + MCT vs LCT
Olive Oil + LCT vs LCT + MCT
LCT vs LCT
Fish Oil containing vs LCT/MCT or LCT
Olive Oil containing vs LCT/MCT or LCT
LCT + MCT vs LCT
LCT vs LCT
New RCTs = 4
Rupinder Dhaliwal

34. Meta-Analyses, Guideline Development & Implementation
June 10th 2011
p = 0.004
N = 25 septic pts
PN + Fish Oil
vs. PN + soybean oil
Barbosa Crit Care 2010
Rupinder Dhaliwal

35. Meta-Analyses, Guideline Development & Implementation
June 10th 2011
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
Sabater: safe
Wang: pilot study, no differences in outcomes
Wang Inflammation 2009
Rupinder Dhaliwal

36. Supplementation with Fish Oils 100 mls/day X 5 d vs. Placebo (saline)
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 = )
Khor Asian J Surg 2011

37. Meta-Analyses, Guideline Development & Implementation
June 10th 2011
Procalcitonin levels
Procalcitonin levels are a marker of inflammatory response
No difference in hospital or length of stay between the groups
PCT levels decrased significanty suggesting that fish oils attenuate the infl process.
Khor Asian J Surg 2011
Rupinder Dhaliwal

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

39. Meta-Analyses, Guideline Development & Implementation
June 10th 2011
Fish Oil vs LCT + MCT: Updated Effect on mortality (n = 7)
Was no effect, now there is
2009: RR 0.76, [0.46, 1.26], p = 0.29 1
Rupinder Dhaliwal

40. Fish Oil vs LCT or LCT + MCT: Effect on infections (n = 3)
Meta-Analyses, Guideline Development & Implementation
June 10th 2011
Fish Oil vs LCT or LCT + MCT: Effect on infections (n = 3)
No changes as infections not reported
2009: RR 0.77 [0.39, 1.49], p = 0.43 1
Rupinder Dhaliwal

41. 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 1

42. Glutamine supplementation?
Meta-Analyses, Guideline Development & Implementation
June 10th 2011
Glutamine supplementation?
Low plasma levels at icu admission = mortality 1
Rupinder Dhaliwal

43. Meta-Analyses, Guideline Development & Implementation
June 10th 2011
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
2 Chinese RCTs
Chinese RCTs
New RCTs = 2
Rupinder Dhaliwal

44. Meta-Analyses, Guideline Development & Implementation
June 10th 2011
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
2 Chinese RCTs
Grau 2011
Andrews 2011
Wernerman 2011
Eroglu 2009
Perez Barcena 2010
+ possibly 3 Chinese RCTs
New RCTs = 5
Rupinder Dhaliwal

45. Randomized 2.6 days after admission to ICU
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

46. The SIGNET Trial – RESULTS
Effect of Glutamine
Confirmed infections within 14 days
Mortality
No significant differences
No significant differences

47. The SIGNET Trial – Questions!
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)

48. 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

49. P=0.10
P=0.03
Grau CCM 2011; 39

50. 413 Patients given nutrition by EN and/or PN route
Within 72 hrs of ICU admission
Supplemented as IV L-Ala-Glutamine, g/kg/day administered separate from PN vs. placebo (saline)
Primary endpoint SOFA; infections not recorded
No effect on SOFA
Wernerman Acta Anesthesiology 2011

51. PN glutamine group: lower mortality PP p = 0.046 ITT p = 0.098
Wernerman Acta Anesthesiology 2011

52. Meta-Analyses, Guideline Development & Implementation
June 10th 2011
Ahmet Eroglu Anesthesia Anal 2009
Critical Care 2010
Eroglu Turkey ~ 40 patients.no diff
Perez-Barcena Spaon 40 patients, no diff
Rupinder Dhaliwal

53. PN GLN: mortality revised (n = 20)
2009 RR 0.71 [0.55, 0.52] p = 0.008

54. PN GLN: infections revised (n = 12)
2009 RR 0.76 (0.62, 0.93) p = 0.008

55. Meta-Analyses, Guideline Development & Implementation
June 10th 2011
PN GLN with new RCTs
less effect on mortality, still a trend
less effect on infections, still significant
HLOS: no changes 1
Rupinder Dhaliwal

56. Awaiting results

57. REDOXS Training: RD & Pharmacy
The REDOXS© Study
REducing Deaths from OXidative Stress
Study Chair
Dr. Daren Heyland
Enrolment completed, n =1200
Results expected Summer 2011
November 2008
November 2008 57

58. Antioxidant supplementation Parenteral Selenium1

59. 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
New RCTs = 5

60. Meta-Analyses, Guideline Development & Implementation
June 10th 2011
Randomized, open-label, single-centre clinical trial
150 patients with SIRS/sepsis and a SOFA score of >5
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)
No differences in mortality
Lower mortality in patients with a higher APACHE p =0.10
Rupinder Dhaliwal

61. 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)

62. The SIGNET Trial – RESULTS
Effect of Selenium
Confirmed infections within 14 days
Mortality
P=0.12
P=0.02
No significant differences

63. Meta-Analyses, Guideline Development & Implementation
June 10th 2011
Scneider, Germany, n =58 : Intestamin: GLN + Se, no difference
El Attar, Egypt, n = 80, Se, Mg, Zinc: reduction in ventilation
Rupinder Dhaliwal

64. Manazares et al in submission 2012
AOX combined mortality, n =20
RR [0.64, 0.91], p = 0.002
Manazares et al in submission 2012

65. Manazares et al in submission 2012
AOX combined Infections, n=10
2009 RR [0.75, 1.17], p = 0.56
Manazares et al in submission 2012

66. Meta-Analyses, Guideline Development & Implementation
June 10th 2011
AOX: did decrease vent days
No effect on LOS
Rupinder Dhaliwal

67. Antioxidants with new RCTs
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 1

68. 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