Transcript A Randomized Trial of Empiric Antibiotics and Invasive
Daren K. Heyland Professor of Medicine Queen’s University, Kingston, ON Canada
The First Ever Recorded Clinical Trial [Nebuchadnezzar, king of Babylon, carried away children of Israel, into his court ] 5 And the king appointed them a daily provision of the king's meat, and of the wine which he drank: 8 Daniel would not defile himself with the portion of the king's meat, nor with the wine 10 Prince of the eunuchs said unto Daniel, I fear the king, who hath appointed your meat and your drink: for why should he see your faces worse liking than the children which
are
of your sort? then shall ye make
me
endanger my head to the king.
Book of Daniel 1:1-15
The First Ever Recorded Clinical Trial 11 Then said Daniel to Melzar, whom the prince of the eunuchs had set over Daniel, 12 Prove thy servants, I beseech thee, ten days; and let them give us pulse to eat, and water to drink.
13 Then let our countenances be looked upon before thee, and the countenance of the children that eat of the portion of the king's meat: and as thou seest, deal with thy servants.
14 So he consented to them in this matter, 15 And at the end of ten days their countenances appeared fairer and fatter in flesh than all the children which did eat the portion of the king's meat.
Book of Daniel 1:1-15
Translating Research Findings into Practice !
16 [from all the children of Israel in the King’s Court] Thus Melzar took away the portion of their meat, and the wine that they should drink; and gave them pulse.
Book of Daniel 1:1-16
Number of RCTs and Multicenter Trials over Time 2 0 6 4 16 14 12 10 8 RCTs Multicenter RCTs 198 RCT’s Reviewed in Critical Care Nutrition Guidelines
RCT Average Patient Population Size per Year 250 200 150 100 50 0 1976 1983 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 198 RCT’s Reviewed in Critical Care Nutrition Guidelines
Average Yearly Quality Score
12 6 4 10 8 2 0 1976 1983 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 198 RCT’s Reviewed in Critical Care Nutrition Guidelines
2000 1800 1600 1400 1200 1000 800 600 400 200 0 Caloric Debt 1 3 5 Prescribed Engergy Energy Received From Enteral Feed 7 9 11
Days
13 15 17 19 21 Prolonged ICU stay, discharged weak and debilitated. Dies on day 43 in hospital from massive PE
Why such poor adoption?
Suboptimal Patient Care?
Information Overload
Impractical for individual clinicians to assimilate massive amounts of information to make unaided judgments about complex decisions
Clinical Practice Guidelines
• “systematically developed statements to assist practitioner and patient decisions about appropriate health care for specific clinical circumstances” – U.S. Institute of Medicine • applies to the average patient • improve process of care and patient outcomes
Development of CPGs
Evidence
+
Integration of Values Practice Guidelines
Validity Homogeneity Safety Feasibility Cost
Updated January 2009 Summarizes >200 trials studying 15080 patients 34 topics 17 recommendations www.criticalcarenutrition.com
Guidelines: Topics
• • • • •
EN vs PN Early vs delayed EN Dose of EN Composition of EN
– – –
Arginine, fish oils Glutamine
– –
CHO/fat, Pro, fibre pH Strategies to optimize EN
– –
Feeding protocols Motility agents
– –
Small bowel feeding Body position www.criticalcarenutrition.com
• • • • • •
EN other EN in combination with PN PN vs. standard care Composition of PN
– –
BCAA Type of lipids
– –
Zinc Glutamine Strategies to optimize PN and minimize risks
–
Use of lipids/hypocaloric
– –
Mode of lipid delivery Intensive insulin therapy Antioxidants
– –
combined selenium
Nutrients vs. Nutrition
Impacts morbidity EN vs PN Early EN small bowel feeding Impacts mortality!
arginine glutamine antioxidants omega-3 fatty acids
Overall Effect of Glutamine supplementation
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
Enteral vs Parenteral Glutamine supplementation?
Why Parenteral Glutamine
Pro predictable daily dose can be added to all patients regardless gut intolerance
higest level
of glutamine is observed with
parenteral infusion
compared to enteral infusion
greater treatment effect
is observed with
parenteral
compared to
enteral glutamine
supplmentation Con unstable amino acid solutions solved with synthetic glutamine containing dipeptides costs Griffiths RD, Intensive Care Med 2001 Powell-Tuck J, Gut 1999 Lian-An World J Gastroenterol 2003 Novak F,. Crit Care Med 2002 Melis BrL Nutrition2005;94:19 Grimm H, Kraus A, Langenbeck’s Arch Surg 2001 Goeters C, Wenn A, Mertes N et al., Crit Care Med 2002
Why Enteral Glutamine?
-
Pro
enteral feeding is preferred route of nutrition in critically ill glutamine accounts for 35% of total metabolic requirements of the enterocytes trophic effect on the small bowel and colonic mucose preserving gut barrier function by augmenting immune response reduced bacterial translocation benefficial effect on radical scavenger production (glutathione) preserving intestinal blood flow -
Con
difficult to predict and achieve daily dose because of gut intolerance problems difficult to achieve high enough plasma and tissue levels of glutamine reduction in affinity or number of transport proteins for glutamine on the surfice of the gut during sepsis reduced flow in the intestinal microcirculation impairs export of absorbed substrate across basolateral membrane decrease of absobtion function due to rapid turnover of enterocytes Griffiths, Proceedings of the nutrition Society 2001; Hall J et al., Intensive Care Med 2003 Arndt H, Kullmann F, Reub F et al., JPEN 1999 Houdijk APJ, Rijnsburger ER, Jansen J et al., Lancet 1998 Conejero R, Bonet A, Grau T et al., Nutrition 2002
Enteral v Parenteral Glutamine Supplementation - animal model
enteral glutamine
supplementation reduced the severity of the methotrexsate - induced enterocolitis, maintained barrier function of the gut with reduced bacterial translocation and resulted in a decreased mortality
parenteral glutamine
same model supplement had no benifit in the Fox AD, Kripke SA, De Paula J et al.: Effect of glutamine supplemented enteral diet on methotrexate induced enterocolitis.
JPEN 1988
Results of Subgroup Analysis
Mortality Infection EN (n=9) PN (n=17) 0.81 (0.48-1.34) P=0.41
0.71 (0.55-0.92) P=0.008
0.83 (0.64-1.08) P=0.16
0.76(0.62-0.93) P=0.008
PN>>>EN?
Metabolic effects of enteral versus parenteral alanyl-glutamine dipeptide administration in critically ill patients receiving enteral feeding: A pilot study • RCT, double-blind • IV ala-glut (0.5) vs EN ala-GLN (0.32 gm/kg/day) vs placebo • 32 critically ill patients rec’ing EN • No difference in : – Antioxidant capacity (vit C, Glutathione) – Oxidative stress (malondialdehyde) – T lymphocytes – Intestinal permeability – Nitrogen balance Luo, Clinical Nutrition (2008) 27, 297-306
Effect of Glutamine in Critically Ill: Individual Studies Concealed randomization Double-blind 72 Trauma (ISS>20) Reported on 60 successful feed patients (non-ITT) Gln added to EN vs isonitrogenous control (12 days) Results • Less pneumonia, bacteremia, and sepsis (majority in first week) • Plasma glutamine levels elevated in Gln group in first week • Lower levels of p55 and p75 soluble TNF receptors • No difference in mech ventilation, LOS, mortality Houdijk Lancet 1998;352:772
Effect of Enteral Glutamine in Burns • 3 RCTs of enteral glutamine • Burns patients – Increased plasma glutamine – Improved permeability – Decreased endotoxin levels – Reduced GNB infections – Reduced hospital LOS – Reduced mortality Garrell CCM 2003;31:2444, Zhou JPEN 2003 27;241; Peng Burns 2004;30:135
Effect of EN Glutamine on Hospital LOS
www.criticalcarenutrition.com
What about Glutamine in Head Injury?
Safety of Glutamine in Head Injury?
30 25 20 15 10 -5 -10 5 0 Brain Glutamine Levels
Arterial-jugular vein Glu difference Control Ala-Gln
Brain Glutamate Levels
Arterial-jugular vein Gln difference
-40 -50 -60 -70 -80 -90 10 0 -10 -20 -30
Control Ala-Gln
31 Berg et al, Clin Nutr 2008 (in press)
Efficacy of Glutamine in Head Injury?
• 46 patient with severe TBI randomized to IV ala-gln vs standard care • ?dose
• All patients fed PN on day 3 with EN to follow P<0.05
Yang Chinese Journal of Traumatology 2007; 10:145
What about Glutamine in Pancreatitis?
Efficacy of Glutamine in Pancreatitis?
• 4 RCTs of IV Glutamine supplemented PN • ? relevance when EN standard of care www.criticalcarenutrition.com
What about Glutamine in Shock?
• 20 severely traumatized patients • RCT • Enteral glut 0.5 gm/kg/day vs control • All patients rec’d Impact • Started within 24 hrs and continued for 10 days JPEN 2008;32:28
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
What about dose of Glutamine?
Inadequate Dose and Wrong Patient Population?
RCT 368 heterogeneous
20
critically ill patients
15
Double-blind Enteral nutrition supplemented
10
glutamine: 20 grams/L
5
Control: Glycine 20g/L Well matched groups Glutamine group rec’d average 19 g/day of glutamine
0 Mortality
No differences noted
Glutamine Control
Hall Intensive Care Med 2003;29:1710
Optimal Dose?
Normal Healthy range
Tjader ICM 2004
REDOXS Dosing Study
Glutamine/day Parenterally 0.35 gms/kg Enterally 30 gms Antioxidants per day 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
Higher Dose Needed in CRRT?
Glutamine loss in the filtration fluid during CRRT in ICU patients.
Lower dose in patient with renal dysfunction pre-dialysis Berg et al, ICM 2007;33:660-6
Conclusions Glutamine Therapy : Modulating the underlying disease process and Improving Patient Outcomes
Adjunctive Supportive Care Proactive Primary Therapy
Results of 2008 International Nutrition Survey Use of PN glutamine in Patients receiving PN
2008 Attitudes to Nutrition CPGs Survey N=500 In patients prescribed parenteral nutrition, supplementation with glutamine should be used
Strongly Recommend Recommend Should be Considered Insufficient data Disagree Don't know
Cost Considerations –
Major barrier to uptake
–
Our fiduciary responsibility is to our patients- acting in their best interests first.
–
Consider the costs saving of reduced infectious complications and 2.5 days in hospital!
–
Formal economic analysis may be helpful?