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Composizione ottimale della nutrizione nel paziente in terapia intensiva Pietro Vecchiarelli U.O.C. Rianimazione Ospedale Belcolle – ASL VT Viterbo

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Composizione ottimale della nutrizione nel paziente in terapia intensiva

Pietro VecchiarelliU.O.C. Rianimazione

Ospedale Belcolle ASL VTViterbo

StressorSurgeryTrauma Infection




Weeks/ months

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 ventilation

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

Key question:

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


RelatoreNote di presentazioneOverfeeding lead to not only metabolic derangement but also muscle weakness



Control Autophagy

control Autophagy


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 ?


Cellular stress


ER stress

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

Ubiquitin stainining

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

delayed recovery

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)

X 100

X 100


Biological ValueBiological ValueBiological Value

Net Protein UtilizationNet Protein UtilizationNet Protein Utilization















Biological ValueNet Protein UtilizationPDCAAS










Control group

Intervention group

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


Preserve autophagy

Glycemic control

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

Avoid complications

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

Diapositiva numero 1Diapositiva numero 2Diapositiva numero 3Diapositiva numero 4Diapositiva numero 5Diapositiva numero 6Diapositiva numero 7Diapositiva numero 8Diapositiva numero 9Diapositiva numero 10Diapositiva numero 11Diapositiva numero 12Diapositiva numero 13Diapositiva numero 14Diapositiva numero 15Diapositiva numero 16Diapositiva numero 17Diapositiva numero 18Diapositiva numero 19Diapositiva numero 20Effect of early PN on muscle function: HypothesisDiapositiva numero 22Early PN (more aggressive feeding) does not prevent wasting of skeletal muscle over the first week and induces lipogenesisDiapositiva numero 24Diapositiva numero 25Diapositiva numero 26Diapositiva numero 27Diapositiva numero 28Cumulative protein/aminoacid dose rather than cumulative glucose dose, early during ICU stay, is associated with delayed recoveryDiapositiva numero 30Diapositiva numero 31Diapositiva numero 32Diapositiva numero 33Diapositiva numero 34Diapositiva numero 35Diapositiva numero 36Diapositiva numero 37Diapositiva numero 38Diapositiva numero 39Diapositiva numero 40Pratical conclusions: PRIMUM NON NOCERE!Diapositiva numero 42Diapositiva numero 43Diapositiva numero 44Diapositiva numero 45Diapositiva numero 46Goals of nutrition in ICU: classical teaching !!! Diapositiva numero 48Diapositiva numero 49Diapositiva numero 50Diapositiva numero 51Diapositiva numero 52Diapositiva numero 53