What other beneficial effects might GLN exert in critical illness??

What other beneficial effects might GLN exert in critical illness??

Prevention of Enhanced Gut Permeability

Who believes bacteria translocate from the gut to blood and cause infection? Yes No

Bacteria DO NOT translocate from the gut to the blood! The data are relatively clear for this but gut failure is VITAL to prevent!

WHY???

Inflammatory Mediators/Toxins Transported by Lymph Lung and Other Organs (kidneys) Injured by Inflammatory Mediators Activation of Gut Immune System Gut Barrier Impaired by Malnutrition Bacteria Translocate

Animals Undergoing Trauma! If lymph duct is not ligated all animals get ARDS and die! If lymph duct is ligated,, no ARDS, all animals live!! Lymph from traumatized animals is toxic to cells Deitch E et al.

GLN s POTENTIAL BENEFITS Attenuation of sepsis/sirs associated lung injury -Enhanced pulmonary HSP expression -Preservation of cellular metabolic function (ATP content) -Prevents ARDS following sepsis/endotoxin in rats -Prevents Hyperglycemia/Insulin Resist. Attenuation of pro-inflammatory response from gut immune cells -Attenuation of cytokine release -Attenuated inos expression Lymph Maintenance of Gut Barrier Function -Enhanced gut IgA levels Protection of IEC from injury -Enhanced cellular HSP expression -Preservation of GSH -Gut energy source

Potential Beneficial Effects of Glutamine Enhanced insulin sensitivity Decreased Free Radical availability (Anti-inflammatory action) Enhanced Heat Shock Protein Inflammatory Cytokine Attenuation NF-KB P38 Glutamine Therapy Critical Illness Glutathione Synthesis GLN Plasma Pool GLN Fuel for Enterocytes Nucleotide Synthesis Maintenance of Intestinal Mucosal Barrier Reduced Translocation Enteric Bacteria or Endotoxins Reversal of Cytopathic Hypoxia Hexosamine Synthesis Fuel for Lymphocytes Maintenance of Lymphocyte Function Elimination of Translocating Bacteria Preserved Cellular Energetics- ATP content Control of NO formation (Anti-inflammatory action) Wischmeyer PE, Curr Opin Clin Nutr Metab Care 6: 217-222, 2003

New Paradigm Glutamine as a Vital Drug and Signaling Molecule In Critical Illness

Why You Should Use a New Therapy in Your ICU?! Therapy Makes Mechanistic Sense! Majority of Studies Support Use of Therapy (on clinically relevant endpoints)! Meta-Analysis Supports Use! No Evidence of Harm/Low Cost! Makes Sense in the Developmental History of Mankind?

What is a Clinically Relevant Endpoint in Critical Illness?! Survival! Infectious Morbidity! Length of Stay

Clinical Research Data Utilizing Glutamine in Critical Illness

Glutamine in Critical Illness Clearly a deficiency!!

Compensating a deficiency?? Glutamine as a Fuel!Non-essential amino acid!vital to gut, immune cells, and kidney!serves as metabolic fuel and precursor to purine and pyrimidine synthesis!gln concentrations fall precipitously after injury, illness, and stress (including exercise).!glutamine (GLN) deficiency at onset of critical illness/sepsis is correlated with increased mortality (Oudemans-van Straaten,, HM et al. Intensive Care Med, 2001

Glutamine

Older Randomized Clinical Trials Using Glutamine # Zeigler et al (1991) - GLN decreases infections in bone marrow transplant patients # Griffiths et al (1997)- GLN decreases mortality in critically ill patients # Houdijk et al (1998) - GLN decreases sepsis, bacteremia, pneumonia in trauma patients # Wischmeyer et al (2001) - GLN decreases gram (-) bacteremia in severe burn injury

$ Garrel et al. studied glutamine in severe burn injury (26 grams/day- enteral) $ Mortality: $ 12/22 Control Group $ 2/19 Glutamine Group (p < 0.05) $ Marked reduction in Pseudomonas infection $ Significant reduction of positive blood cultures Crit Care Med 31:2444-2449, 2003

Alanyl-Glutamine Dipeptide-Supplemented Parenteral Nutrition Decreases Nosocomial Infection in SICU patients: Differential Responses After Pancreatic Versus Non-Pancreatic Surgery. T. R. Ziegler 1, C. F. Estivariz 1, D. P. Griffith 1, N. Bazargan 1, M. Luo 1, N. Dave 1, D. P. Jones 1, P. Furst 2, B. Alteheld 2, C. R. Jonas 1, J. R. Galloway 3 ; 1 Dept. Medicine, Emory University, Atlanta, GA, USA, 2 Dept. Nutrition, University of Bonn, Bonn, Germany; 3 Dept.. Surgery, Emory University, Atlanta, GA, USA.

Total # of New Infections * # 70 60 50 40 30 20 10 0 64 37 30 Total group Pancreatic Non-Pancreatic Surgery Surgery P = 0.140 0.968 0.005 25 34 29 30 17 15 12 15 * CDC criteria Control Glutamine 12 N (2.8 vs. 0.8 infections/patient)

Patients With New Bloodstream Infections # 10 8 6 4 28% 13% 18% 27% 42% Control Glutamine 2 0 Total group Pancreatic Non-Pancreatic Surgery Surgery 7 0 P= 0.174 0.687 0.010

Nosocomial Infections Attributed to Staphylococcus aureus 15 12 Control Glutamine # 9 6 3 0 Total group Pancreatic Non-Pancreatic Surgery Surgery P= <0.01 <0.05 <0.05

Nosocomial Infections Attributed to Fungal Species 15 12 Control Glutamine # 9 6 3 0 Total group Pancreatic Non-Pancreatic Surgery Surgery P= <0.05 0.890 <0.0002 0

Hospital Mortality 10 8 Control Glutamine # 6 4 17% 42% * 2 0 3% 7% 0% 0% Total group Pancreatic Non-Pancreatic Surgery Surgery P= 0.103 1.000 0.060 * An additional control subject died on study day 4 (intent-to-treat P<0.05)

Why You Should Use a New Therapy in Your ICU?! Therapy Makes Mechanistic Sense! Majority of Studies Support Use of Therapy (on clinically relevant endpoints)! Meta-Analysis Supports Use! No Evidence of Harm/Low Cost! Makes Sense in the Developmental History of Mankind?

Overall Glutamine: Effect on Mortality (As of January 8th, 2007)

Glutamine Reduces LOS in ICU Patients

Glutamine Reduces Infectious Complications in ICU

GLN-supplementation of TPN Reduces Mortality (As of January 8th, 2007)

Effect of Glutamine in Critically Ill: A Systematic Review of the Literature (Criticalcarenutrition.com) %Results of subgroup analyses: &Reduced mortality in ICU patients (particularly in ICU patient on TPN) &Less complications and shorter LOS in ICU patients &Greater treatment effect with parenteral, high dose

Effect of Glutamine in Critically Ill: A Systematic Review of the Literature (Criticalcarenutrition.com) There are virtually no other drugs in the ICU that can make this claim

Glutamine and Bone Marrow Transplant Patients $Recent Cochrane Review of nutrition support for bone marrow transplant patients $Extremely rigorous review of all available data comparing TPN supplemented with glutamine versus TPN alone

Glutamine Supplementation Reduces Hospital Length of Stay in BMT Patients Receiving Parenteral Nutrition

Glutamine Supplementation Reduces Number of Patients with Positive Blood Cultures in BMT Patients Receiving Parenteral Nutrition

Glutamine and Bone Marrow Transplant Patients 'Concluded that bone marrow transplant patients with gastrointestinal failure (unable to enterally feed) should receive TPN (parenteral nutrition) supplemented with glutamine

Good in Theory and Good in Practice??

Inducing Glutamine Hsp 70 Protein in Critically Ill Patients Could this be the answer???

Methods "Randomized, controlled, double blind trial assessing effect of 7-days of ALA-GLN- supplemented parenteral nutrition (PN) versus iso-nitrogenous control PN on serum HSP-70 "Critically ill patients who require admission to SICU following surgery for cardiac sugery, vascular surgery, gastrointestinal surgery or necrotizing pancreatitis

ALA-GLN Enhances Serum HSP-70 in Critically Ill Patients with Sepsis/SIRS GLN Patients Control Patients Serum HSP 70 (ng/ml) 6 5 4 3 2 1 * 0 Baseline 1 week Study Date

Conclusions ALA-GLN treatment leads to significant enhancement of serum HSP-70 with 7 days of treatment ALA-GLN mediated enhancement of HSP-70 correlates with decreased ICU length of stay and time on ventilator Ziegler T, Wischmeyer P et al Intensive Care Medicine, 31:1079-1086, 2005

Heat Shock Protein and Critical Illness! Critical Illness leads to a maladaptive (?) deficit in HSP expression! This may be due to acute GLN deficiency! Aging and Diabetes worsen defect in HSP expression! Critically ill patient is at great risk for severe deficit in HSP expression which leads to:! Defect in organ protection! Defect in control of inflammatory response via increased IkBa degradation

Heat Shock Protein and Critical Illness! Thus the patient deficient in HSPs can not protect themselves from stress and inflammation! If you allow your patients to lose their ability to make HSPs you are putting them at serious risk of a bad outcome! The only known treatment for this defect is GLN

Replacing a Deficiency And Inducing a Pharmacologic Effect

Why You Should Use a New Therapy in Your ICU?! Therapy Makes Mechanistic Sense! Majority of Studies Support Use of Therapy (on clinically relevant endpoints)! Meta-Analysis Supports Use! No Evidence of Harm/Low Cost! Makes Sense in the Developmental History of Mankind?

No Study of Glutamine in Critical Illness has Shown any Significant Evidence of Harm!!

Far Cheaper Then Activated Protein C!! Or any other new pharmacologic agent in the ICU!

So We Have Shown Glutamine! Makes Mechanistic Sense! Majority of Studies Support Use of Therapy (on clinically relevant endpoints)! No Evidence of Harm! Meta-Analysis Supports Use! Makes Sense in the Developmental History of Mankind?

How do we Explain Glutamine s s Effects in History of Human Development??

How Do We Explain GLN s Role in Stress and Illness? We know that GLN levels fall precipitously following stress and injury The magnitude of this fall is predictive of mortality in critical illness It appears we have only evolved the ability to store 24-48 hours worth of this vital stress signal and substrate This would make sense, as the ER and ICU are recent developments

How Do We Explain GLN s Role in Stress and Illness? If you did not survive your initial trauma or injury in the first 24-72 hours you died no ambulance came and scooped you up Thus significant stores of stress substrates and signaling molecules would not be necessary This is supported by the fact that battlefield mortality rates have changed little in the least 150 years. Champion HR et al. A profile of combat injury. J Trauma. 54:S13-19, 2003

How Do We Explain GLN s Role in Stress and Illness? Currently many of the therapies we consider standard of care, are having their risk/benefit ratio questioned (I.e. antibiotics) Singer M et al. Treating Critical Illness: The importance of first doing no harm. PLOS medicine, 2;e167, 2005. Perhaps we should be looking to the bodies own stress substrates as our drugs of the future for critical illness and injury This is particularly true for substrates that may have a limited supply such as glutamine, which demands replacement as we know deficiency s lead to increased death in ICU

Clinical Indications and Suggestions

Enteral versus Parenteral GLN Enteral GLN: Recommendation: Based on 2 level 1 and 5 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. Canadian Critical Care Nutrition Guidelines Criticalcarenutrition.com

Enteral versus Parenteral GLN Parenteral GLN Based on 4 level 1 studies and 5 level 2 studies, when parenteral nutrition is prescribed to critically ill patients, parenteral supplementation with glutamine, where available, is recommended. Canadian Critical Care Nutrition Guidelines Criticalcarenutrition.com

Burn/Trauma Patients! Strongest data in this group-! 4 randomized trials showing decreased infections, mortality.! Enteral Dose: 5-10 grams 3-5 times a day to achieve (0.3-0.5 gr/kg/day)! Parenteral GLN may be better- Dose: 0.5 gr/kg/day

Medical/Surgical Intensive Care! Data is strongly in favor! Best data with intravenous use as supplement to TPN! 0.5 gr/kg/day parenterally with standard enteral feeds if possible! Until proven otherwise! GLN-supplementation should be standard of care for all critically ill patients requiring PN

Special Considerations Renal Failure:! Rise in Blood Urea Nitrogen is normal and not toxic per worlds leading critical care nephrologists! Urea used to be given widely (and safely) as diuretic in head injured patients! If you BUN is < 100 you should not be concerned! No concern on continuous dialysis Liver Failure! Follow Ammonia! If Ammonia 2 x normal consider reducing GLN dose

Overall Conclusions! Parenteral, high dose glutamine appears more beneficial the oral glutamine! Until proven otherwise, TPN supplemented with GLN in the ICU! Early administration may be important!! But! The longer you are in the ICU the lower your GLN levels will go! So consider strongly in any ICU patient early early or late

Why You Should Change Your Practice?! Therapy Makes Mechanistic Sense! Majority of Studies Support Use of Therapy (on clinically relevant endpoints)! Meta-Analysis Supports Use! No Evidence of Harm/Low Cost! Makes Sense in the Developmental History of Mankind?

Questions??