IMPACT DE NOUVELLES ETUDES - Hôpital Erasme · IMPACT DE NOUVELLES ETUDES ... - Marins souffrant de scorbut - 2 mois de mer ... James Lind, 1747 . 10 29 avril 2015 ANALYSE OBJECTIVE

Jean-Charles Preiser

Service des soins intensifs

Hôpital Universitaire Erasme – Bruxelles

Congrès de diététique thérapeutique et de support nutritionnel

28 mars 2015 - Bruxelles

IMPACT DE NOUVELLES ETUDES

D’INTERVENTIONS NUTRITIONNELLES SUR NOTRE

PRATIQUE

PROCESSUS DE DECISION

29 avril 2015 2 2

PROCESSUS DE DECISION

29 avril 2015 3 3

Impact potentiel

de nouvelles

études

INFLUENCE DES LEADERS

D’OPINION!

29 avril 2015 5

29 avril 2015 6

ANALYSE OBJECTIVE DES

DONNEES Hiérarchie de l’Evidence-based Medicine

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29 avril 2015 9

Première étude clinique

- Marins souffrant de

scorbut

- 2 mois de mer

- 6 groupes

- cidre

- vinaigre

- vitriol

- eau de mer

- oranges, citrons

- épices, eau de barley

après 6 jours

- agrumes : tous guéris

- autres : pas de

changement..

James Lind, 1747

29 avril 2015 10

ANALYSE OBJECTIVE DES

DONNEES Hiérarchie de l’Evidence-based Medicine

29 avril 2015 11

Guidelines

Guidelines

Sont Des constats (statements) et

recommandations pour la

pratique clinique basées sur

l’état actuel des connaissances

dans un domaine spécifique

Un moyen de mettre évidence

les différences entre notre

pratique et l’état actuel des

connaissances

Ne sont pas Des contraintes légales

Des garanties de réussite

Un substitut au jugement

clinique

Par nature, les guidelines évoluent!

Très bien,

mais sont-elles applicables

ou réalisables avec les

ustensiles, outils et

ingrédients actuels?

Deux exemples d’application

Péri-opératoire

Soins intensifs – réanimation

Suppléments en glutamine

Mesure du résidu gastrique


Péri-opératoire




http://www.sfnep.org/

http://www.sfnep.org/


Péri-opératoire





Péri-opératoire




Did glutamine switch from angel to devil?

The REDOXS© Study REducing Deaths due to OXidative Stress

The REDOXS© Study REducing Deaths from OXidative Stress

Study Chair

Dr. Daren Heyland, MD, FRCPC

Project Leader

Rupinder Dhaliwal, BASc, RD

Can

a

dia

n C

rit

ical Ca

re

Tria

ls G

r

oup

Pourquoi avoir initié REDOXs?

Effect of Glutamine: A Systematic Review of the Literature

www.criticalcarenutrition.com

Mortality

Effect of Glutamine: A Systematic Review of the Literature

www.criticalcarenutrition.com

Infectious Complications

Warning # 1 :

GLUTAMINE : A LIFE-SAVING NUTRIENT, BUT WHY?

Preiser and Wernerman Crit Care Med 2003; 31:2555

Possible beneficial effects of glutamine supplementation

Metabolic

Protein synthesis

C / N transporter

Gluconeogenesis

Ammoniagenesis

Immunologic

Replication

T-cells function

IgA synthesis

HLA-DR on CD14

Gut protection

Replication

Maintenance of GALT

Anti-oxidant

Glutathione

Taurine

Potential Beneficial Effects of Glutamine

Fuel for

Enterocytes

Fuel for

Lymphocytes

Nucleotide

Synthesis

Maintenance of

Intestinal

Mucosal Barrier

Maintenance of

Lymphocyte

Function

Preservation

of TCA Function

Decreased Free

Radical availability (Anti-inflammatory action)

Glutathione

Synthesis

GLN

pool

Glutamine

Therapy

Enhanced Heat

Shock Protein

Anti-catabolic

effect

Preservation of

Muscle mass

Reduced

Translocation

Enteric Bacteria

or Endotoxins

Reduction of

Infectious

complications

Inflammatory Cytokine

Attenuation

NF- B

?

Preserved

Cellular

Energetics-

ATP content

GLN

Pool Critical Illness

Enhanced

insulin

sensitivity

Pharmaconutrition A New Emerging Paradigm

Old

Immunonutrition

New

Pharmaconutrients

Nutrition Nutrients

Combined nutrients Single nutrients

Heterogeneous

populations

Homogenous

Patients

Weak methods Rigorous

Small single center Large multicenter

Heyland Int Care Med 2005;31:501

Research Questions

In critically ill patients with severe organ

dysfunction, what is the effect of:

1) Glutamine supplementation compared to

placebo on 28-day mortality?

2) Antioxidant supplementation compared to

placebo on 28-day mortality?

Inferences

• 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

Parenterally Enterally

Glutamine/day 0.35 gms/kg 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

Optimizing the dose of glutamine dipeptides and

antioxidants in critically ill patients: a phase I dose-

finding study. Heyland et al JPEN 2007;31:109.

single-center, open-label, dose-escalating clinical trial.

Mechanically ventilated adult patients with clinical evidence

of hypoperfusion were sequentially enrolled to 1 of 5 groups: group 1 (n = 30): no supplementation;

group 2 (n = 7): 0.35 g/kg/d of glutamine IV;

group 3 (n = 7): same as group 2 plus 15 g/d of glutamine and 150

microg of selenium enterally;

group 4 (n = 7): same as group 2 plus 30 g/d of glutamine and 300

microg of selenium enterally;

group 5 (n = 7): same as group 4 plus an additional 500 microg of

selenium IV.

KNOWN POSSIBLE TOXICITY OF

GLUTAMINE

Related to metabolites (ammonia, glutamate?):

Hepatic encephalopathy / ammonium production

Lower glutamate levels

Precusor of arginine => NO

Ranges of doses used in critically ill patients: 0.35 g/kg.day

IV and/or 30 – 60 g orally/enterally

J Nutr 2001.

The unsolved issue is:

How safe were we with this phase I trial?

N = 7 per group

Relevance of outcome variables selected, in terms of safety?

Duration of follow-up

Critères d’inclusion et d’exclusion

1200 ICU patients

Evidence of

organ failure R

glutamine

placebo

R

R

antioxidants

placebo

Factorial 2x2 design

placebo

antioxidants

REDOXS© Study Design

Start of Supplements

Start ASAP within 24 hrs of admission to ICU within 2 hrs of randomization

Duration: 28 days or death or discharge min of 5 days

Parenteral supplements as soon as patient resuscitated 10 ml/hr dedicated central port (eg. one of a triple lumen) can run peripherally if needed (watch for phlebitis) Do NOT infuse with medications; IV fluids, albumin, nutrition OK

Enteral supplement NG tube OK or feeding tube 20 ml/hr, can be given via Y connector start regardless of whether docs want to start enteral nutrition

nutrients vs.

nutrition

SS Manual p 4-10

Interim analysis (n=600 patients)

FINAL RESULTS (II)

FINAL RESULTS (I)

POST-HOC ANALYSIS

45

Metaplus

European PRCT (14 centres)

Mechanically ventilated adults

Comparison of an immune-modulating formula enriched

in glutamine, vitamins C and E, selenium, zinc and

omega-3 fatty acids (EPA and DHA) with a control

isocaloric isonitrogenous solution

Van Zanten et al JAMA 2014; 312:514

46

Aims of the study

Primary outcome variable :

Incidence of nosocomial infections

Secondary outcome variables :

Score SOFA (Sepsis-related Organ Failure Assessment)

Length of ventilation,

Length of stay

Insulin requirements

ICU, hospital, 28-day and 6-mo mortality

Plasma concentrations of glutamine, Vit C, vit E, Sélénium, Zinc, DHA

at days 0,4 and 8.


47

Metaplus : composition

Nutritional composition of IMHP and HP enteral nutrition (per 1500 ml)

Nutriments IMHP HP

Energie(kcal) 1920 1920

Protéine (g) 112.5 112.5

Glutamine (g) 30 9

Hydrate de Carbone (g) 141.0 231.0

Lipides (g) 96.0 55.5

MCT (g) 19.5 0

EPA + DHA (g) 7.5 0

Anti-oxidants

vitamine C (mg) 690 195

vitamine E (mg alpha tocopherol) 266 23

Sélénium (mcg) 285 113

Zinc (mg) 30 23

Autres vitamines, et éléments traces Valeurs standards Valeurs standards

Fibres (g) 22.5 22.5

48

Metaplus : Résultats (groupe)

Total Group Medical Patients Surgical patients Trauma patients

IMHP HP IMHP HP IMHP HP IMHP HP

n=152 n=149 n=54 n=55 n=81 n=75 n=55 n=54

Age, mean (SD), y 57 (19) 59 (18) 64 (15) 65 (14) 54 (21) 57(19) 45(20) 48(20)

Sex, No (%) 100 (66) 102 (68) 35 (65) 32 (58) 54 (67) 52 (69) 41 (75) 46 (85)

Weight, mean (SD), kg 77.3 (14.1) 78.8 (15.9) 74.2 (13.6) 79.0 (14.5) 79.1 (13.7) 78.7 (17.2) 81.4 (13.4) 80.1 (17.8)

BMI, mean (SD), kg/m2 26.1 (4.5) 26.5 (4.8) 25.2 (4.6) 27.0 (4.7) 26.4 (4.1) 26.3 (5.0) 26.9 (4.9) 26.6 (5.1)

APACHE-II score, mean (SD)

22.0 (8.5) 21.3 (7.7) 26.7 (8.0) 24.9 (7.8) 20.4 (7.6) 19.7 (6.8) 17.0 (7.4) 17.5 (6.4)

Adjusted predicted mortality, mean (SD), %

39.8 (27.3) 37.4 (12.9) 56.3 (25.2) 50.8 (26.2) 33.8 (24.0) 31.4 (23.0) 22.5 (21.9) 22.5 (16.8)

SOFA score, mean (SD) 8.5 (2.3) 8.4 (2.3) 8.9 (2.3) 8.4 (2.4) 8.5 (2.4) 8.3 (2.2) 8.5 (2.5) 8.9 (2.2)

Results : primary outcome variable

IMHP

(152)

HP

(149) P

IMHP

(54)

HP

(55) P

IMH

P

(81)

HP

(75) P

IMHP

(55)

HP

(54) P

Incidence of infections * (n, (%)) 80

(53%)

78

(52%)

.96 21

(39%)

26

(47%)

.38 50

(62

%)

38

(51%)

.16 32

(58%)

36

(67%)

.36

Total number of infections (n) 119 122 32 40 75 58 47 58

Number of infections per patient 0.78 0.82 .73 0.59 0.73 .39 0.93 0.77 .30 0.85 1.07 .24

Entire

population

Medical

admissions

Surgical

admissions

Trauma

admissions


6-mo mortality

Su

rviv

al

pro

bab

iity

HP ---- IMHP

6-mo mortality S

urv

iva

l p

rob

ab

lity

Su

rviv

al

pro

bab

ilit

y

Type de nutrition ---- HP ---- IMHP Type de nutrition ---- HP ---- IMHP

Type de nutrition ---- HP ---- IMHP

Results – 6-mo mortality

Warning # 2:

REDOXS and META-PLUS :

more questions than answers Preiser JC, Wernerman J.

JPEN J Parenter Enteral Nutr. 2013 Sep;37(5):566-7

Hope to confirm the beneficial

effect of glutamine replaced by a

frightening discovery

of potential toxicity!!!

Hospital

6-mo

mortality

http://ccforum.com/content/18/1/R8/figure/F2?highres=y


Route :

Enteral

Parentérale

Combinée


Dosing


Single-centre vs multiple centres

FROM MARTIN LUTHER KING BACK TO

HIPPOCRATES

Primum non nocere

Glutamine is THE

life-saving

pharmaconutrient

First check

its safety

Au nom du principe de

précaution…


Péri-opératoire




Ann Fr Anesth Réa 2014 Réanimation

Nut Clin Metab

0

50

100

150

200

250

RGV group No RGV group

At least onevomiting

No vomiting

Vomiting

27.0% 39.6%

N patients

1.86 [1.32; 2.61], p = 0.0030

Difference, 12.6%; 90% CI 5.4% to

19.9%

Proportions of patients who

vomited Vomiting episodes

Proportions of Patients Who Achieved

Their Calorie Target During the First

Week

OR, 4.13; 90% CI, 2.20-7.69; P<0.001

Control: with RGV

monitoring

Intervention: without RGV

monitoring

Proportion of patients with at least one

episode of VAP (primary outcome)

0

50

100

150

200

250

RGV No RGV

MVAP

No MVAP

15.8% 16.7%

Difference, 0.9%; 90% CI -4.8% to 6.7%

patients

Incidence of VAP

Total number of VAP

episodes

Cumulative incidence of

VAP

Ou

« Ce qui était considéré comme

Vrai hier n’est plus forcément

La Vérité aujourd’hui »

Ou

« Ce qui était considéré comme

Vrai hier n’est plus forcément

La Vérité aujourd’hui »

Mais

efforçons-nous de la regarder

en face, quelles que soient

nos convictions

Documents

IMPACT DE NOUVELLES ETUDES - Hôpital Erasme · IMPACT DE NOUVELLES ETUDES ... - Marins souffrant de scorbut - 2 mois de mer ... James Lind, 1747 . 10 29 avril 2015 ANALYSE OBJECTIVE