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Composizione ottimale della nutrizione nel paziente in terapia intensiva
Pietro VecchiarelliU.O.C. Rianimazione
Ospedale Belcolle ASL VTViterbo
Sympathetic nervous systemAdrenergic receptorsAdrenal meduclla
Hypothalamic-pituitary axisACTH,THS,GH,FSH,LHAdiponectines (leptine, resistine, adipokine)Entero-endocrine hormons (peptide YY,CCK, ghreline )
InflammationImmune systemCytokines, mediatorsOxidative stress
Legacy of critical illness:Persistent weakness and sarcopeniaLoss of bone mass & increased risk of fracturePsychiatric/neurocognitive problems
Risposta metabolica allo stress: fisiopatologia
modified with permission from J.C. Preiser et al. BJA, 2014
RelatoreNote di presentazioneAcute life-threating injuries cause an intensive stress reaction starting few seconds or minutes after the insult and lasting weeks or months leading to the legacy of critical illness When a stressor is detected and signalled to the central nervous system, within seconds or minutes will be triggered a complex response that last for weeks and months with persistent weakness and sarcopenia, loss of bone mas etc. In this response are involved sympatthetic nervous system in involved followed by the activation of hypothalamic.pituitary axes. Recent data has shown that even adiponectine and entero-endocrine hormons play an important role.
Preiser JC et al BJA, 2014Modified with permission
Metabolic changes during stress
RelatoreNote di presentazioneThe liver produce large amounts of glucose for the non insuline depended tissus using lactate from hypoxic tissus, glycerol from fat tissue and aminoacids from muscle .Il fegato diventa il motore produttore di glucosio dalla glicogenolisi e dalla neoglucogenesi. Il glucosio prodotto viene utilizzato dai tessuti insulinoindipendenti, mentre quelli insulinodipendenti vanno incontro ad una lisi. Lipolisi e proteolisi. Dalla lipolisi si liberano gli acidi grassi liberi estrememente suscettinbili alla perossidazione da parte dei ROS liberati dai mitocondri disfunzionali, ed il glicerolo che viene riutilizzato dal fegato per produrre glucosio. Dalla proteolisi si liberano gli aminoacidi che sono riciclati ina parte in glucosio, glutamina ed alanina ) ed in parte degradati in urea ed ammonio. Anche l acido lattico rilasciato dalle zone ipossiche viene riutilizzato per produrre energia con il ciclo di Cori
Puthucheary Z.A. et al
20% loss in RF CSA with > 2 organ failure after 10 days
26% loss in RF CSA with >4 organ failure after 10 days
RelatoreNote di presentazioneMany criticall ill patients devlop muscle wasting during the first 7 10 days of the ICU stay
Massanet P.L. et al JPEN 2015
Muscle wasting contributes to ICU- Acquired Weakness
Schefold J.C. et al J. Cachexia Sarcopenia Muscle, 2010
Prolonged ICU stay
Prolonged Hospital stay
Higher 1 year mortality
RelatoreNote di presentazioneand muscle weakness which has been associated with prolonged ventilation, prolonged ICU stay and higher 1 year mortality
Can artificial nutrition, administered early duringcritical illness, counteract the catabolic state? And can it prevent loss of lean body mass and improve the clinical outcome?
Macronutrient intake and outcomes in five RCT
Casaer M.P. et Van den Berghe G., NEJM 2014
There are no benefits with respect to mortality or ICU stay with enhanced EN or
PN early in a critical illness!
Dashed curves: PN Solid curves: no PN
RelatoreNote di presentazione in the recent years 5 RCT have been published about this topic. In those trials Patients received different macronutrient intake by enteral, parenteral or both in the first 7 days of there ICU stay . In two of this trials indirect calorimetry was udes to guide the caloric intake: in the titacos study from the beginning and only parenteral and in SPN on day 4 if enteral itake was less than 60 % of the targetthere are no benefit with respect of survival or ICU stay with enhanced Enteral nutrion or parenteral nutricion in the fistr 7 days of there ICU stay
- No difference in outcome( Marik PE and Hooper MH)
- No association of caloric intake with mortality.
- A lower caloric intake was associatedwith a lower risk of bloodstreaminfections and incident renal replacementtherapy
( Al-Dorzi HM et al)
RelatoreNote di presentazioneIn the 2 recent meta-analysis comparing hypocaloric versus normocaloric feeding, and different intake of enteral nutrition
Adult critically ill patients
RelatoreNote di presentazioneIn our intensive care we are several type of criticall ill patients. Some of them are in the acute phase, some in chronic phase and some in recovery phase, moreover each patients has a different host response to insult, different trajectory of disesase progression, different severity of disease progression , different age, comorbidity , genetic
The things that complicate the question for each of these patients
What are the energy needs?
How are energy needs estimated?
Is energy expenditure the same as energy needs?
How to determine individual protein needs?
Timing and route af administration of nutritional support
RelatoreNote di presentazionewhat complicates the thing
Guidelines for ICU nutrition deliveryESPEN (2009), SCCM & ASPEN( 2016)
Energy requirement: indirect calorimetryor 25-30 Kcal/kg/die
Caloric target: to match caloric intake to 80-100 % of estimated or measured EE( normocaloric feeding )
Timing and route: early enteral nutrition
RelatoreNote di presentazioneCurrent guidelines recommend: energy requirement must be mesured by indirect calorimetry when available or the thumb rule 25-30 kg and to match the caloric intake to 80-100 % of mesured or estimated Energy Expenditure, what is called normocaloric feeding
Physiology is the only polar star we have!
Modified with permission Fraipont V, Preiser J.C. JPEN 2013
Endogenous production of calories
Endogenousproduction of calories,early in a critical illnessis = 50-75 % of EE, despiteenergy provisionby isoenergeticPN (glucose or lipid rich formula)(Tappy L 1998)
During the first days of critical illness energy needs are lower than Energy Expenditure
RelatoreNote di presentazioneIn the first days of critical illness the body is able to produce from 50 t0 75 % of energy expenditure and this production cannot be inhibited by esogenous administration of fedding, thereforeduring the first day of criticall illness energy need are lower than EE
Modified with permission Fraipont V, Preiser J.C. JPEN 2013
Endogenous production of calories
Even indirectcalorimetrydoesnt see
RelatoreNote di presentazioneIn the clinical practice is impossible to mesure this endogenous caloris
Daily caloric intake( Nutrition + non nutritional calories)
Daily endogenousnon- inhibitableproduction ofenergy
Fraipont V, Preiser J.C. JPEN 2013Modified with permission
During the early phase of critical illness inadvertentoverfeeding can occur every day
RelatoreNote di presentazioneIn the first days of critical illness overfeeding can occur every day especially with the use of early parenteral nutrition
Ziegler et al N Engl J Med. 2009;361:1088
ICU ACQUIRED MUSCLE WEAKNESSHermans 2013
RelatoreNote di presentazioneOverfeeding lead to not only metabolic derangement but also muscle weakness
Muscle atrophyLoss of force production
Morphological feature of myopathy
inhibition of autophagyexacerbates muscle
loss and degenerationin catabolic conditions
RelatoreNote di presentazioneIn an experiment animal model the inibition of phenotype of autophagy induced morphological feature or myopathy, loss of force production and musce atrophy more in female than in male animal
Activators of autophagy ?
Endurance and resistance exercice+lysosome
isolation autophagosome autolysosomemembrane
Courtesy of Greet Van den Berghe
Effect of early PN on muscle function: Hypothesis
Early PN via suppression of autophagy mayimpair clearance of damaged organelles and protein aggregates, thereby threating musclefunction and aggravating ICU-acquired muscleweakness.
Hermans G. et al. Lancet Resp Med, 2013
RelatoreNote di presentazioneTo explain the negative effect of early parenteral nutrition on muscle the authors hypothesized that early
Early PN (more aggressive feeding) suppresses autophagy and increases muscle weakness in humans
Hermans G. et al Lancet 2013
RelatoreNote di presentazioneThe patients who received early parenteral nutrition had higher markers of suppression of autophagy and more ubiquitin staining on the muscle
Early PN (more aggressive feeding) does not prevent wastingof skeletal muscle over the first week and induces lipogenesis
control Late PN Early PN
Casaer M.P & Langouche L et alCrit Care Med 2013
15 EPaNIC studyneurosurgical patients
RelatoreNote di presentazioneMoreover the use of early parenteral nutrition in this neurosurgical patients of the EPANIC study didnt prevent muscle waisting but Early enetarl feeding resulted in fat infiltration of the muscle
Hermans G. et al Lancet, 2013
ICU acquired muscle weakness in EPaNIC
ICU-AW 34% with late PN
versus43% with early PN (p 0.03))))
Late PN acceleratedrecovery from ICU-AW
RelatoreNote di presentazioneAnd the recovery from muscle weakness was slower in patients who had early parenteral nutrition
Not enough protein hypothesis!
Hoffer LJ and Bistrian BR. 2014Hoffer LJ and Bistrian BR. 2016
So many recent RCTs of nutrition support in the ICU have been disappointing
The amount of protein provided wasdrammatically less than what the best availableevidence suggest it ought to be
Protein not calories, is the crucial macronutrient in catabolic critical illness
RelatoreNote di presentazioneSome authors have argued that .
RelatoreNote di presentazioneIn all of this papers the amounts of protein were low compared to the raccomandations
Guidelines for ICU nutrition deliveryESPEN (2009), SCCM & ASPEN (2016)
Protein requirement: 1.2 -2.0 gr/Kg/die> 2 gr/ IBW/die (obese)1.5-3.0 gr/kg/die (severely burned)
They dont explain how to select an individualpatients dose within this wide range
Hoffer LJ and Bistrian BR, 2016
Increase Aminoacids intake?
Nephro-Protective trial : 474 patients
235 standard care versus 239 amino acid therapy
AA 0.75 gr/kg/day (1100 Kcal) versus AA 1.75 gr/kg/day (1300 Kcal)
A higher dose of AA1) did not lead to a clinically relevant benefit2) led to increased uragenesis3) with a trend towards more RRT4) no data on muscle weakness
RelatoreNote di presentazioneUntil now only this rct has studied the impact of administering supplementary amino acid in criticall ill patients. In the nephroprotective trial 474 patients were randomized to receive a daily intravenous supplementation of amino acids. 0.75 gr versus 1.75.
Casaer M et al. AJRCCM 2012
Cumulative protein/aminoacid dose rather than cumulative glucose dose, early during ICU stay, is associated with
RelatoreNote di presentazioneMorovear in the post hoc analysis of epanic study the cumulative dose of protein is associated with delayed recovery and in experimental animal with inibition of autophagy
Puthucheary Z.A. . et al
RelatoreNote di presentazioneEven in the patients of Puthucheary higher protein deliveryin the fisrt week was associated with greater musce waisting
Ebb Phase Aggression post aggression reconstitution
Catabolic Anabolic state
0 5-10-20 20-25 25-30 Kcal/kg7die0 5-10-20 20-25 25-30 Kcal/kg/d
Energy and protein
Hecker M et al, Anasthesist, 2012 ( modified)
Protein 0 ? ? ? 1.2-2.0 gr/Kg/die
the early administration of parenteralnutrition is not recommended
After the acute phase
A huge task of re-building in front of us!
What do we need after the acute phase?
Manpower/ bulldozer = EnergyBricks= Proteins
All proteins are not created ugual
Pennings B, 2011
Muscle synthesis and the role of leucine
Biological Value Net ProteinUtilization
Whey Casein Soy
Hoffman J, Favo M. J Sports Sci and Med 2004; 3:118-130
Biological value= N2 for tissue formationN2 absorbed from food
Net protein utilization= N2 for tissue formationN2 consumed/ingested
PDCAAS= Protein Digestibility Corrected AA score ( fecal digestibility of protein)
Biological ValueBiological ValueBiological Value
Net Protein UtilizationNet Protein UtilizationNet Protein Utilization
Biological ValueNet Protein UtilizationPDCAAS
Pratical conclusions: PRIMUM NON NOCERE! During the early phase of acute illness endogenous substrates
match 50-75 % of energy requirement.
Currently, there are no specific methods to mesure the proteinrequirement.
During the first week (?) in ICU: the dose of enteral nutrition ( administered via the normal gastric route) that is tolerated by the patient, but supplemented with micronutrients from admissiononward.
Early full parenteral nutrition , as a strategy to reduce musclecatabolism, may actually damage cellular function, by impairingautophagy. Protein appear more harmful than glucose.
After the acute phase caloric intake should match Energy Expenditure with supplementation of high quality protein in sufficient amount to stimulate anabolism.
Si quis febricitante cibumdet, convalescenti quidem, robur: aegrotanti ver, morbus fit.
Aph. VII.65Food given to those who are convalescent from fever, increases strength; but if there be still disease, increasesthe disease.
Hippocrates: The Aphorisms of Hippocrates. The Classic of Medicine Library, New York 1982
Energy: when, howmuch
protein: when, how much, which
Early mobilizationPhysical exercice
Light sedationIntermittent feeding?
Arabi, Y.M., Casaer, M.P., Chapman, M. et al. Intensive Care Med (2017).
Goals of nutrition in ICU: classical teaching !!!
Providing optimal amounts of energy and proteins:
Attenuate loss of Lean Body Mass
Improve clinical outcomes
RelatoreNote di presentazioneWe learned that we can attenuate loss of lean body mass, avoid complication adn improve the clinical outcome by providing an optimal amount of energy and proteins
Caloric target according indirect calorimetry
TICACOS trial ( N=130)
matching caloric intake to mesured REE compared with matching caloricintake to estimated requirements
Outcome: more feeding but no significant effect on mortality with increasedmorbidity
SPN trial ( N= 305)
patients in ICU from day 4-8 fed by EN with a median 60-100% target:
EN vs extra PN from day 4-8 both guided by REE
No effect on mortality, ICU stay, or hospital stay whereas less infectionsbetween day 9 and 28 but no difference in infections between day 4 and day 28
REE only 66 Kcal different from estimated caloric need.
RelatoreNote di presentazioneThe same if we are looking at the 2 only RCT in which caloric intake was guided by indirect calorimetry. No significant effect on mortality, but increas morbidity in ticacos study
Metabolic response to stress
J.C. Preiser et al. BJA ,2014Modified with permission
Anterior pituitary hormones
RelatoreNote di presentazioneThe final common pathway of this metabolic response is an uncontrolled catabolism and resistance to anabolic signals including insulin
Arabi, Y.M., Casaer, M.P., Chapman, M. et al. Intensive Care Med (2017).
Pennings B. et al Am J Clin Nutr, 2011
Whey protein stimulates postprandial muscle proteinaccretion more than do Casein and Casein hydrolysate
Each of these patients
Is in a different phase of critical illness
Has a different host response to injury
Has a different trajectory and severity of disease progression
Has a different genetic, age, comorbidity, drugs, body composition
Infusion of AA increases ureagenesis, urea/ creatinine ratio and nitrogen loss early in Early Parenteral Nutrition group and after 1 week in Late Parenteral nutrition group
RelatoreNote di presentazioneSimilar results where published 3 years ago on Patients of EPANIC study in which early parenteral nutrition increased plasma urea, urea/creatinine ratio and nitrogen excretion . Early in the eraly parenteral group and after one week in the late parenteral nutrition. This suggest that extranitrogen is not usefull, and can be harmful
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