pharmacologie nutritionnelle en réanimation nutritionnelle en réanimation u 1073 nutriment (s)...

48
18 mars Académie Nationale de Pharmacie P. Déchelotte CHU Rouen, INSERM UMR 1073, Normandie Université Pharmacologie nutritionnelle en réanimation U 1073

Upload: truongkien

Post on 28-May-2018

217 views

Category:

Documents


0 download

TRANSCRIPT

18 mars – Académie Nationale de Pharmacie

P. Déchelotte

CHU Rouen, INSERM UMR 1073, Normandie Université

Pharmacologie nutritionnelle

en réanimation

U 1073

nutriment (s)

pharmaconutriment(s)

énergie protéines

cible cible

+--

Nutrition clinique : concept de pharmaconutrition

Substrats et cibles en pharmaconutrition

muscle intestin immunité

glutamine IV

3

nucléotides

pré-probio

3

Entérale

Parentérale

glutamine, arginine

citrulline

Vit, trace

Domaines d’application de la pharmaconutrition

périopératoire, chirurgie majeure du cancer

traumatologie, brûlé

réanimation médicale, chirurgie compliquée

inflammation intestinale

cachexie, chimiothérapie, escarres, sujet âgé…

Pharmaconutrition entérale

dans la chirurgie pour cancer

Immunonutrition périopératoire : patients dénutris

Braga et al, Arch Surg 2002

pré + post : la meilleure stratégie

- préop Impact° pré-op Impact°

+ Std EN + Std EN péri-op

(50) (50) (50)

infections 21 14 9*

DSH (d) 15.3* 13.2* 12.0*#

Immunonutrition pré-opératoire chez des patients

cancéreux non ou peu dénutris

Gianotti et al, Gastro 2002

5 j pré-op per os

Impact° Impact° pas

pré-op pré + post-op de NA

(102) (101) (102)

infections 14* 16* 31

DSH (j) 11.6* 12.2 14.0

Immunonutrition : méta-analyses

Beale 1997, Heys 1999, Heyland 2001,

Waitzberg 2006…

chirurgie pour cancer digestif: réduction

significative de la durée de séjour et de

l’incidence des complications infectieuses

recommandations canadiennes, italiennes,

espagnoles, française (SFC), européennes

(ESPEN, grade A); remboursement

Immunonutrition : aspect médico-économique

moins de complications / produit plus coûteux ?

économie

/patient

Senkal 1997 Impact° 170

Senkal 1999 Impact° 1133

Braga 2001 Impact° 1733

Gianotti 2003 Impact° 3260

c

Pharmaconutrition entérale : en résumé

• périopératoire, chirurgie majeure programmée (cancer) avec arg, n-3, nucléotides : A

• chirurgie cardiaque: évidence faible• polytrauma: glutamine A• brûlé grave: glutamine A, vit & trace A• réanimation médicale : risque ? (arg, omega-3)• chimiothérapie, escarres, sujet âgé, inflammation

intestinale, cachexie : en devenir…

Pharmaconutrition parentérale :

• Glutamine IV (dipeptide)

• Emulsions lipidiques enrichies en omega-3

• Eléments trace : Se, Zn

Pharmaconutrition parentérale :

Bénéfices de la glutamine IV (sous forme d’alanyl-glutamine)

quand le patient nécessite une NP

• Périopératoire - chirurgie majeure programmée pour cancer

• Pancréatites aigüe sévères

• Réanimation médicale et chirurgicale

Critical illness is associated with low plasma levels

of glutamine in most patients (not all…)

• Novak 2002, Wang et al, 2010 , Chao Yue 2013 :

meta-analysis of RCTs

significant reduction of length of hospital stay

(p<0.001)

significant reduction of infectious complications

(p=0.02)

Benefits of Gln-dipeptide supplemented PN in

surgical patients

(0.2-0.35 g/kg bw/day dipeptide)

Cancer patients undergoing major

surgery

Severe pancreatitis

Complicated surgery, ICU patients

IV Glutamine-TPN: patients groups

Glutamine-TPN in acute pancreatitis :

(0.2-0.35 g/kg bw/day dipeptide)

Ockenga et al, Clin Nutr 2002

• reduced acute-phase response and better lymphocyte

proliferation

• reduced length of hospital stay (21 vs 25 days)

(11 vs 16 days)

De Beaux, Nutrition 1998

Hadju et al, Mag Seb 2012

• less infections and reinterventions

• less patients with complications

• lower incidence of complications, prevention of

pancreatic infections

metanalysis: reduced infections, LOS, mortality

risk

Glutamine-TPN in acute pancreatitis :

Fuentes-Orozco et al, JPEN 2008

Sahin et al , Eur J Clin Nutr 2007

He et al , Clin Nutr Suppl 2004

Asrani et al, Pancreatology 2013

Jafari et al, Clin Nutr 2014

Cancer patients undergoing major

surgery

Severe pancreatitis

Complicated surgery, ICU patients

IV Glutamine-TPN: patients groups

The french Dipeptiven study

Studies with IV glutamine + TPN in ICU :

114 ICU patients

multiple trauma (38) complicated surgery (65)

others (11) with an indication for TPN over > 5 days

Prospective randomized double-blind controlled trial

isocaloric isonitrogenous TPN supplemented with

Statistics : intention to treat analysis

Alanyl-glutamine

(Dipeptiven°) :

0.5 g x kg-1 x day-1

N=58 N=56

Isonitrogenous control

(alanine + proline) :

0.7 g x kg-1 x day-1

Déchelotte, Crit Care Med 2006

Better clinical outcome (primary endpoint)

Dipeptide Control p

complicated outcome 24 34 0.04

(41.4%) (60.7%)

nosocomial infections 0.45 0.71 <0.05

per patient

wound alterations 1 1

death during study 2 2

Déchelotte, Crit Care Med 2006

Reduced infectious complications

Dipeptiven Control p

total number

of infectious episodes 26 40

pneumonia 10 19 <0.05

surgical wound infection 3 7

septic shock or sepsis 7 6

urine infection 0 4

IV catheter 1 2

others 5 2

Déchelotte, Crit Care Med 2006

Better metabolic tolerance

Dipeptiven Control p

total metabolic 38 56

disorders (40 %) (60 %)

hyperglycemia 20 30 <0.05

requiring insulin 9 18 <0.05

hypertriglyceridemia 7 11

liver disorders 24 34

total adverse events 116 159 <0.01

Déchelotte et al, Crit Care Med 2006

Fuentes-Orozco, Clin Nutr 2004

Reduced infectious complications :

Dipeptiven Control p

nosocomial infections / pt 1.5 2.1 0.20

pneumonia 22 31 0.02

UTI/1000 cath days 2.5 16.7 0.04

Reduced insulin dose and insulin resistance <0.001

Grau et al , Crit Care Med 2011

Spanish Dipeptiven study : reduced infections

Parenteral glutamine reduces insulin resistance

in trauma patients

Bakalar et al Crit Care Med 2006

The Rumanian Dipeptide study

82 multiple trauma patients

with an indication for TPN

Prospective controlled trial

isocaloric isonitrogenous TPN

+ Alanyl-glutamine:

0.5 g x kg-1 x day-1

N=41 N=41

+ control

Grintescu et al, Clin Nutr 2014

reduced incidence of hyperglycemia (p<0.05)

reduced insulin needs (p<0.05)

IV glutamine in ICU :

reduced mortality

Heyland et al. 2009

www.criticalcarenutrition.com

IV glutamine in ICU :

reduced infectious complications

Heyland et al. 2009

www.criticalcarenutrition.com

IV glutamine + PN in ICU : recommendations

« When PN is indicated in ICU patients, the AA solution

should contain 0.2-0.4 g/kg/day of L-glutamine (e.g. 0.3-0.6

g/kg/day of alanyl-glutamine dipeptide) » - grade A

Chambrier et al Ann Fr Anesth Réanim 2011; 30:381-389

French (SFNEP/ASFAR)

European (ESPEN)

Singer et al Clin Nutr 2009, 28:387-400

In case of major post-operative complications, it is

recommended to prescribe glutamine intravenously and

at high dosage (0.2 à 0.4 g/kg/day i.e. 0.3 à 0.6 g/kg/day of

dipeptide).

• 200 italian ICUs data base

• reduced mortality (24.6% ± 1.6% vs. 34.5% ± 2.1%),

infection rate (13.8% ± 2.9% vs. 18.8% ± 3.9%), and

hospital LOS (24.9 ± 0.3 vs. 26.0 ± 0.3 days)

• a lower total cost per patient (23,409 ± 3,345 vs.

24,161 ± 3,523 Euro).

• treatment cost more than offset by savings on ICU

and antibiotic costs cost-efficiency of IV glutamine

Pradelli et al.

Int J Technol Assess Health Care 2012; 28(1):22-8

Effectiveness and cost-effectiveness of supplemental

glutamine dipeptide in TPN for critically ill patients:

IV glutamine + TPN and demonstrated favourable

outcome in ICU patients: which patients?

• mixed populations of ICU patients

• surgical and medical patients, unable to be fed enterally

• some patients in shock, but TPN + IV gln were

introduced after resuscitation,

• severe liver or renal failure : always excluded

IV glutamine + TPN and favourable outcome

in ICU patients: which dose and nutrition?

• dipeptide dose adapted to patient’s weight

• 0.5 g/kg/day of alanyl-glutamine dipeptide

= > recommended dose in ICU

• Gln-dipeptide given along with TPN, continuous infusion

• patients adequately fed with full TPN

• SIGNET trial : fixed, low dose of glutamine (20

g/day x 5 d) or Se, EN and/or PN: no significant

difference on new infections and mortality, no harm

Andrews et al BMJ 2011

Debate : trials with IV glutamine in ICU using

different study design and dose:

• fixed and low dose of glutamine

• low nitrogen/protein supply

• heterogeneity of nutritional support : underpowered

both for EN and PN-treated patients

• 2x2 design : interactions??

not included in the 2014 meta-analysis

Limitations of the SIGNET trial :

• 40 RCTs, 3107 patients : surgery, critical illness, mixed

• reduction of mortality in critically ill group (p=0.024),

• reduction of infection risk (p=0.009) in global

population

• reduction of hospital length of stay (p=0.001, global)

• in studies with dose 0.3-0.5 g/kg bw/day dipeptide:

significant reduction of short term mortality, infections

and LOS.

• no evidence of harm or toxicity

Bollhalder et al Clin Nutr 2013

Global meta-analysis of RCTs of parenteral Gln

• REDOX Study

• very high Gln load : around 0.7 g/kg bw/d in total

• given both IV and enterally

• alone or combined with AOX,

• 2 x 2 design

• Gln supply separated from nutrition, started D1

• large, multicenter, heterogeneity+++

Heyland, NEJM 2013

Debate : trials with glutamine in ICU using

different study design and dose:

• primary outcome : 28 day mortality (ITT)

no significant difference (p=0.05 but the level of

significance is 0.044 because of 2 interim analyses); despite this, the

authors discuss a “trend”…

REDOX study: results…

and debate

Heyland, NEJM 2013

• post-hoc secondary outcome : “trend” for increased

hospital and 6-month mortality in combined groups with

gln vs no gln…

but :

• this combined “gln” group was not planned in the

statistical design post-hoc analysis

• in-hospital mortality was not a priori defined

• 6-month mortality only exploratory : massive loss in

the follow up, no adjustment for interim analysis

Buys et al, NEJM 2013

REDOX study: controversy on “toxicity”…

• very severe ICU patients :

inclusion criteria = 2 or more organ failures,

• high proportion with renal (32-38%) or hepatic failure

• high incidence of vasopressors use,

• most patients (93%) were in shock (cardiogenic,

septic) at the initiation of glutamine

• Unbalanced randomisation

Specificities of the REDOXS study:

Wernerman J Critical Care 2014, 18:214

Unbalanced randomization : sicker patients die more!

Specificities of the REDOXS study:

• high total dose of Gln, different from guidelines

•full Gln dose at D1 while feeding was minimal

• patients remained severely underfed (mostly enteral

nutrition, < 50% of nutritional goals at 1 week)

• inclusion of patients with renal failure and liver

failure

Specificities of the REDOXS study:

• post-hoc analysis to identify significant

predictors of mortality:

- renal dysfunction,

- fed <30% of caloric needs (p<0.03)

• “trends” for other predictors: GI diagnostic, use of

vasopressors, steroids, early supply of Gln

Heyland, JPEN 2014,

Specificities of the REDOXS study:

• early provision of high Gln dose in ICU patients

with shock, MOF and underfeeding brings no benefit

• gln remains to be avoided in ICU patients with

renal or hepatic failure

• some very sick ICU patients presenting with high

gln plasma levels at admission have a poor prognosis

indicative of Gln impaired metabolism rather

than toxicity

REDOXS study: so what?

*

* : referring to the updated metanalysis on

www.criticalcarenutrition.com

Parenteral glutamine supplementation in critical

illness: a systematic review : reduced hospital mortalityWischmeyer P 2014 Crit Care

Wischmeyer P 2014 Crit Care

Parenteral glutamine supplementation in critical

illness: a systematic review : reduced hospital length of stay

Cancer patients undergoing major

surgery needing TPN

Severe pancreatitis needing TPN

0.2-0.35 g dipeptide/kg bw/d

ICU patients needing TPN, without renal

or liver failure or severe MOF

0.5g dipeptide/kg bw/d

IV Glutamine for the right patients: