Transcript A Randomized Trial of Empiric Antibiotics and Invasive

Nutrition therapy that modulates the
underlying disease process
Adjunctive
Supportive
Care
Proactive
Primary
Therapy
Nutrition therapy impacts clinical
outcomes
Adjunctive
Supportive
Care
Proactive
Primary
Therapy
Timeliness of administration of
nutritional therapy matters!
Adjunctive
Supportive
Care
Proactive
Primary
Therapy
endothelial dysfunction
activation of coagulation
• infection
• trauma
• I/R
• hypoxemic/
hypotensive
Role of
GIT
Activation of
PMN’s
Microcirculatory
Dysfunction
elaboration of cytokines,
NO, and other mediators
generation of OFR
(ROS + RNOS)
mitochondrial
dysfunction
=
oxidative stress
cellular = energetic
failure
Key nutrient deficiencies
(e.g. glutamine, selenium)
organ = failure
Death
Fish Oil supplemented diets?
Mechanisms by which fatty acids can affect
immune cell function
Copyright ©2007 The American SocietyWanten,
for Nutrition
G. J. et al. Am J Clin Nutr 2007;85:1171-1184
• 21 patients with sepsis requiring TPN
• Randomized to recieve PN with an n-3 or n6 lipid emulsion for 5 days
• Dose: 350 ml og s 10% n-3 lipid emulsion
(Omegevan)
Am J Respir Crit Care Med 2003; 167: 1321
TPN with N-3 vs n-6 FAs in severe sepsis.
Monocyte membrane FA composition: arachidonic,
EPA, DHA
N- 3 group
N- 6 group
Mayer K, Am J Respir Crit
Care med 2003; 167: 1321
TPN with N-3 vs n-6 FAs in severe sepsis.
Ex vivo monocyte cytokine release in response to LPS
N- 3 group
N- 6 group
Mayer AJRCCM 2003; 167: 1321
• 25 Patients with SIRS or
sepsis receiving PN
• Randomized to 50:50
MCT/soybean emulsion or
lipid emulsion with 50%
MCT, 40% soy, and 10%
Fish oil x 5 days
• Dose of fish oils:
– rec’d 6.4 gms/day
– .09 g/kg/d
Barbosa Critical Care 2010;14:R5
• Fish oil group resulted in:
• Greater attenuation of IL-1B, IL-6, and TNF
• Improved Pa02/FiO2 ration by day 6
• No difference in vent days, ICU stay
• Tendency to reduced hospital stay (22 vs 55 days, p=0.08)
and fewer deaths 31% vs 40% (p=ns).
Greater treatment effect with higher dose?
? treatment effect if control group not
receiving any lipids?
Barbosa Critical Care 2010;14:R5
• Retrospective study of 194 patients with intraabdominal infection
leading to sepsis
• Control group rec’d standard PN with soybean/olive oil (80%/20%).
• Treatment group had 10% FO (omegaven) infused on top of standard
PN over 30-60 mins
• No effect with fish oils on CRP, organ failure or any clinical outcomes
• Dose of fish oils: rec’d 0.12 g/kg/d over 1 hr! (infusion >0.05 g/kg/hr
may be harmful!)
Wohlmuth JPEN 2010
There appears to be a doseresponse curve with IV FO
However, in this small study of healthy
volunteers, no correlation with biological effect
Pittet Intensive Care Med 2010;36:289-295
Fish Oil optimal Dose Determination Study
The FOILED Study
• Phase 2 dose finding study
• Mechanically ven’t patients with sepsis with high IL-6 level
receiving EN (NO PN lipids)
• Open label use 10% Fish Oil (Omegaven) to 3 groups:
– Group 1: standard care only, no FO
– Group 2: 0.20 kg/day of IBW
– Group 3: 0.50 kg/day of IBW
• Outcomes:
– Safety- SOFA scores, complications, bleeding
– Systemic inflammation: IL-6 and IL-10
– Immunity: LPS ex-vivo stimulation of TNF and IL-6
– Clinical outcomes
What about enteral fish oils?
(Product enhanced with fish oils
+borage oils
+ antioxidants)
EPA + GLA Modulate Inflammation
Borage Oil
Arachidonic Acid
Fish Oil
EPA
GLA
DGLA
Cyclooxygenase
Lipoxygenase
Replacing AA with
DGLA results in
PGE1 and eicosanoids
that are less
inflammatory
Decreased
proinflammatory
eicosanoids
(LTB4, TXA2, PGE2)
Replacing AA with
EPA results in
Eicosanoids
that are less
inflammatory
(TXA3, PGE3, LTB5)
Effect of Enteral Fish Oils/Borage
Oils and antioxidants
in Critically Ill with ALI
• RCT of 146 critically ill
patients with ALI and BAL+
for WBCs
• Double-blinded; ITT
• Experimental: Oxepa®
• Control: high fat diet
• Groups well matched at
baseline
After 3-4 days
• Reduction in AA and
increase in EPA in lung and
alveolar macrophage
• Decrease in neutrophils
recovered in BAL fluid
• Improved oxygenation
Gadek Crit Care Med 1999;27:1409
Effect of Enteral Fish Oils/Borage
Oils and antioxidants
in Critically Ill with ALI
25
• RCT of 146 critically ill
patients with ALI and BAL+
for WBCs
• Double-blinded; ITT
• Experimental: Oxepa®
20
15
Oxepa
control
10
• Control: high fat diet
5
• Groups well matched at
baseline
0
Vent
Days
ICU
ICU
Days Deaths
P=0.03 P=0.02 P=0.17
Gadek Crit Care Med 1999;27:1409
Overall Effect on Mortality
www.criticalcarenutrition.com
Diets Supplemented with fish oils,
borage oils, and antioxidants
• Recommendation:
Based on 1 level 1 studies and 4 level 2 studies, we
recommend the use of enteral formula with fish oils,
borage oils, and antioxidants in patients with ALI/ARDS.
Canadian Clinical Practice Guidelines JPEN
2003;27:355-373
Updated 2009; www.criticalcarenutrition.com
Investigating Nutritional Therapy with EPA, GLA and
Antioxidants Role in SEPsis Treatment
(INTERSEPT)
 Multicenter, Randomized, Double-blinded trial (14 Clinical
Sites – Brazil)
 200 Patients in the early stages of sepsis (no organ failures;
within 36 hrs from onset of sepsis)
 Fish oil/borage oil/antioxidant vs standard polymeric
 Primary Outcome: Evolution to more severe forms of sepsis
(severe sepsis or septic shock)
 Secondary Outcome: 28 day all-cause mortality, organ failure
development, hyper/hypoglycemic events, insulin use,
hospital stay, ICU stay
Pontes-Arruda Crit Care 2011;15:R144
PRIMARY OUTCOME: DEVELOPMENT OF
SEVERE SEPSIS AND SEPTIC SHOCK
30
NUMBER OF PATIENTNS
25
p=0.0217
13.3%
20
Severe Sepsis
Septic Shock
15
5.7%
37.7%
10
20.7%
5
0
Study
Mostly due to
reduced Cardioresp failures
Control
Pontes-Arruda Crit Care 2011;15:R144
SECONDARY OUTCOMES
Variable
Study
(n=53)
Control
(n=53)
P Value
Invasive
10 (18.9%)
18 (34%)
.03984
Non-invasive
5 (9.4%)
6 (11.3%)
NS
Number of days using mechanical
ventilation*
Number of ICU days*
7 (4-12)
15 (9-21)
.0033
7 (4-12)
13 (9-18)
<.0001
Number of hospital days*
9 (6-14)
19 (13-24)
<.0001
Use of mechanical ventilation, n (%)
No Difference in survival between
the groups?
EDEN-OMEGA:
NIH NHLBI
Factorial Trial Design
Timing of Feeding
S
U
P
P
N-3 +
L Antioxidants
E
(Module delivered
M
as bolus bid)
E
N
Control
T
Standard EN
(480 cal/ 20 g pro)
“Early
Full”
“Early
Trophic”
Fast ramp up
(10 ml/hr)
n = 250
n = 250
n = 250
n = 250
OMEGA: 60-Day Mortality
P=0.05
P=0.14
30
25
20
% 15
10
5
26.6%
24.6%
16.3%
17.9%
25.5%
OMEGA
Observed
OMEGA
Adjusted
Control
Observed
Control
Adjusted
FACTT
Conservative
0
JAMA on line Oct 2011
Plasma Fatty Acids (%)
OMEGA: Plasma Eicosapentaenoic Acid
(EPA) Levels (%)
10
5
Omega
Control
Gadek-EPA/GLA
Gadek-Control
0
0
3 or 4
Day
6 or 7
Problems with OMEGA
• Hard to attribute excess mortality to FO when the EPA levels
were half of what Gadek achieved, what would the biological
mechanism for harm be?
• Multpile tests of significance and baseline imbalances in
patients disadvantaging FO group.
• More likely, problem with delivery and utilization in the context
of bolus fed patients who were semi starved (fat used for fuel!)
• Improved outcomes in control group may be due to 20 grams
extra/day of protein
• Because of different study design, difficult to combine with
other studies of continuous administration in moderately well
fed patients
Bottom Line:
Continue with FO/AOX continuously
administered in optimally fed ICU
patients
Cook, Heyland
JAMA Oct 2011
Glutamine supplementation?
Glutamine: A conditionally
essential amino acid
Glutamine levels drop:
- following extreme physical exercice
- after major surgery
- during critical illness
Low glutamine levels are associated with:
- immune dysfunction
- higer mortality in critically ill patients
Novak F, Heyland DK, A Avenell et al., Crit Care Med 2002
Oudemans-van Straaten HM, Bosman RJ, Treskes Met al., Intensive Car Med 2001
The “Oudemans-van Straaten-Study”
“high”
“low”
=> Low plasma glutamine at
ICU admission is related to
mortality.
Potential Beneficial Effects of Glutamine
Enhanced
insulin
sensitivity
Enhanced Heat
Shock Protein
Decreased Free
Radical availability
(Anti-inflammatory action)
Increased Autophagy
Glutamine
Therapy
Glutathione
Synthesis
Critical Illness
Preservation
of TCA Function
Preserved
Cellular
EnergeticsATP content
GLN
GLN
Pool
pool
Fuel for
Enterocytes
Maintenance of Reduced
Translocation
Intestinal
Enteric Bacteria
Mucosal Barrier or Endotoxins
Nuclotide
Synthesis
Maintenance of
Fuel
for
Anti-catabolic
Lymphocyte
Lymphocytes
effect
Function
Preservation of
Muscle mass
Reduction of
Infectious
complications
Effect of Glutamine:
A Systematic Review of the Literature
Infectious Complications
Updated Jan 2009, see www.criticalcarenutrition.com
Effect of Glutamine:
A Systematic Review of the Literature
Hospital Length of Stay
Updated Jan 2009, see www.criticalcarenutrition.com
Effect of Glutamine:
A Systematic Review of the Literature
Mortality
Updated Jan 2009, see www.criticalcarenutrition.com
Effect on Mortality
High Dose
Low Dose
.01
0.1
1
10
100
Novak CCM 2002;30:2022
Results of Phase I Dosing Study
Glutamine/day
Antioxidants
per day
Parenterally
Enterally
0.35 gms/kg
30 gms
500 mcg
Selenium
Vit C 1500 mg
Vit E 500 mg
B carotene 10 mg
Zinc 20 mg
Se 300 ug
• High dose appears safe
• High dose associated with
–
–
–
–
no worsening of SOFA Scores
greater resolution of oxidative stress
greater preservation of glutathione
Improved mitochondrial function
Heyland JPEN Mar 2007
Inadequate Dose and
Wrong Patient Population?
 RCT 368 heterogeneous
critically ill patients
 Double-blind
 Enteral nutrition supplemented
glutamine: 20 grams/L
 Control: Glycine 20g/L
 Well matched groups
 Glutamine group rec’d average
19 g/day of glutamine
20
15
Glutamine
Control
10
5
0
Mortality
No differences noted
Hall Intensive Care Med 2003;29:1710
No difference in outcome for
patients who stayed <9 days
but significant survival
advantage for those who
stayed >9 days
The longer you stay, the greater duration of
exposure, the greater the benefit
CCM 2002;30:2032
Canadian Critical Care Nutrition
Clinical Practice Guidelines
• “If using parental nutrition, we strongly
recommend supplementing with parenteral
glutamine.”
• “Enteral Glutamine should be considered
for Burns and Trauma Patients.”
• “There are insufficient data to support the
routine use of enteral glutamine in other
critically ill patients.”
• Benefit of Parenteral Glutamine in Patients
on EN?
JPEN 2003;27:355 see www.criticalcarenutrition.com for current version
Admitted to ICU
? PN
Glu
Se
Glu + Se
None
Andrews BMJ 2011:342
The SIGNET Trial - Design
• 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
• Main Outcomes:
– New infections
– Mortality (ICU/HDU and at 6 months)
• Prespecifed analysis of people having ≥ 5
• Median duration of study PN was 4-5 days
The SIGNET Trial – RESULTS
Effect of Glutamine
Mortality
No significant differences
Confirmed infections within 14 days
No significant differences
The SIGNET Trial – RESULTS
Effect of Selenium
Mortality
No significant differences
Confirmed infections within 14 days
P=0.12
P=0.02
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)
• 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 rec’d only 5-6 days of PN
Grau CCM 2011; 39
P=0.10
P=0.03
Grau CCM 2011; 39
Scandinavian Glutamine Trial:
a Pragmatic Clinical Multi-Centre RCT of ICU patients
• 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 (Placebo was saline in identical bottles.)
• Primary endpoint SOFA; infections not recorded
• All included patients were considered as intention-to-treat (ITT) patients.
• Patients given supplementation for > 3 days (68%) were considered as
predetermined per protocol (PP) patients.
No effect on
SOFA
Scandinavian Glutamine Trial (prel results)
jw -10
Updated Meta-Analysis
Effect on Mortality
According to control group mortality highest to lowest
April 2011
Updated Meta-Analysis
Effect on Infection
April 2011
Updated Meta-Analysis
Effect on Hospital LOS
April 2011
Antioxidant
supplementation?
Underlying Pathophysiology
of Critical Illness (2)
• preserved ATP
•Recovery of mt DNA
•Regeneration of mito
proteins
Genetic down
regulation
Tissue
hypoxia
cytokine
effect
Prolonged
inflammation
NO
Endocrine
effects
Survivors
↓ mitochondrial
activity
•↓mt DNA
•↓ ATP, ADP,
NADPH
•↓ Resp chain
activity
•Ultra structural
changes
Metabolic
Shutdown
Death
mtDna/nDNA Ratio by Day 28 Survival
mtDna/nDNA Ratio
2.0
P=0.04
Alive Individuals
Expired Individuals
Alive Reg line
Expired Reg Line
1.5
1.0
0.5
0.0
0
5
10
15
20
25
Day
Heyland JPEN 2007;31:109
Effect of Antioxidants on Mitochondrial Function
Heyland JPEN 2007;31:109
Mitochondrial Damage
Cell
mitochondria
Respiratory
chain
ROS
nDNA
mtDNA
RNS
nucleus
LPS exposure leads to GSH depletion and
oxidation of mtDNA within 6-24 hours
Potentially Irreversible by 48 hours
Levy Shock 2004;21:110 Suliman CV research 2004;279
N-Acetylcysteine Treatment to Prevent the
Progression of Multisystem Organ Failure:
A prospective, randomized, placebo-controlled study
• 100 patients admitted to
ICU with MODS
• Randomized to NAC (150
mg/kg bolus followed by
12 mg/hr) vs placebo
• No difference in clinical
outcomes
• Median time to treatment
24 hrs
% mortality
P=0.05
What do the clinical studies show?
Influence of early antioxidant supplements on clinical
evolution and organ function in critically ill cardiac surgery,
major trauma and subarachnoid hemorrhage patients.
250
 RCT
 200 patients
 IV supplements for 5 days
after admission (Se 270
mcg, Zn 30 mg, Vit C 1.1 g,
Vit B1 100 mg) with a
double loading dose on
days 1 and 2 (AOX group),
or placebo.
 No affect on clinical
outcomes
200
150
Cardiac
Trauma
SAH
100
50
0
0
1
2
3
4
5
CRP levels daily in the Control groups
Significant reduction with AOX in Cardiac and
Trauma but not SAH
Berger Crit Care 2008
Randomized, Prospective Trial of Antioxidant
Supplementation in Critically Ill Surgical Patients
 Surgical ICU patients,
mostly trauma
 770 randomized; 595
analysed
 alpha-tocopherol 1,000 IU
(20 mL) q8h per naso- or
orogastric tube and 1,000
mg ascorbic acid IV q8h or
placebo

Tendency to less
pulmonary morbidity and
shorter duration of vent
days
Nathens Ann Surg 2002;236:814
Treatment Stratgy For Sepsis?
 Multicenter RCT in
Germany
 double-blinded
 non-ITT analysis
 249 patients with
severe sepsis
 standard nutrition plus
1000 ug bolus
followed by 1000
ug/day or placebo x14
days
p=0.11
100
90
80
70
60
50
40
30
20
10
0
Selenium
Placebo
28 day Mortality
Greater treatment effect observed in those
patients with:
•supra normal levels vs normal levels of selenium
•Higher APACHE III
•More than 3 organ failures Crit Care Med 2007;135:1
•
•
•
•
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.
•Confirms observation of
SIGNET trial and Berger
study in burns
•Mechanism related to:
• increase neutrophil and
macrophage function?
• reversible inhibition of NF-kB
binding to DNA
• induction of apoptosis and
cytotoxicity in activated proinflammatory cells
• a direct virucidal or bactericidal
effect
No serous adverse
events noted
• 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 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).
P=0.10
Greater treatment effect in sicker patients!
Supplementation with Antioxidants in
the Critically Ill: A meta-analysis
o 16 RCTs
o Single nutrients (selenium) and combination
strategies (selenium, copper, zinc, Vit A, C, & E,
and NAC)
o Administered various routes (IV/parenteral,
enteral and oral)
o Patients:
o
o
o
o
o
Critically ill surgical, trauma, head injured
SIRS, Pancreatitis, Pancreatic necrosis
Burns
Medical
Sepsis, Septic Shock
Heyland Int Care Med 2005:31;327;updated 2011
Effect of Combined Antioxidant
Strategies in the Critically Ill
Effect on Mortality
Updated April 2011
Effect of Combined Antioxidant
Strategies in the Critically Ill
Effect on Infection
Updated April 2011
Biological Plausibility!
Mitochondrial + Microvascular
dysfunction
Antioxidants
Inflammation/oxidative stress
Antioxidants
Organ dysfunction
Antioxidants
Supplemental Antioxidant
Nutrients
• Recommendation:
Based on 3 level 1 studies and 13 level 2 studies, the use
of supplemental vitamins and trace elements should be
considered.
Canadian Clinical Practice Guidelines JPEN
2003;27:355-373
Updated 2009; www.criticalcarenutrition.com
Pharmaconutrients Impact Outcomes!
Effect on Mortality
Glutamine
Antioxidants
Fish/Borage Oils
Plus AOX
.01
0.1
1
10
100
www.criticalcarenutrition.com
enteral / parenteral
supply
Urea
L-Ornithine
L-Arginine
L-Citrulline
Polyamine Synthesis
Hormone release
Nitrogenous compounds
• Putrescine
• Spermidine
• Spermine
• GH
• IGF
• Insulin
• Glucagon
• Prolactin
• catecholamines
• Nitric oxide
• Nitrite
• Nitrate
Arginine Metabolism after Trauma in Mice
Figert… Ochoa Surg Forum 1998
Optimal NO-Balance
cNOS
- Microcirculation 
- Immune augmentation 
Harmful
Arginine / NO
availability
cNOS + iNOS
- Hemodynamic instability
- Immune Suppression
- Cytotoxicity
- Organe dysfunction
Suchner Brit J Nutrition 2001
Overall Effect on Mortality (2009)
www.criticalcarenutrition.com
Overall Effect on Infection (2009)
www.criticalcarenutrition.com
Diets Supplemented with arginine
and select other nutrients
• Recommendation:
Based on 4 level 1 studies and 18 level 2
studies, we recommend that diets supplemented
with arginine and other select nutrients not be
used for critically ill pts.
Canadian Clinical Practice Guidelines JPEN
2003;27:355-373
Updated 2009; www.criticalcarenutrition.com
Critically Ill patient not the same
as Elective Surgery patient!
=
Heyland JAMA 2001;286:944
Elective Surgical Patient
• cellular immune
dysfunction
–
T-cell
• decrease cytokine
activation
– IL-2, IFN
Elective Surgical Patient
arginase
arginine
expression of zeta chain
Taheri Clin Cancer Res 2001 ;7:958
Summary
• Nutrients/Nutritional strategies
– Modulate underlying pathphysiological processes
– Improve clinical outcomes, particularly in sickest
patients
– Disease processes and treatment effects are time
dependent
Nutrition Therapy for Critically ill Patients of the Future
Pare n t e r a l Pharmaconutrition
? parenteral nutrition
1. enteral nutrition
Enteral Pharmaconutrition
ICU length of stay
Assement of nutritional risk
Measurement of biomarker to determine which pharmaconutrient
Set of tools to monitor response to nutrition/nutrient therapy
Questions?