New Guidelines & the Latest in Research for TPN in ICU/Surgical

Patients - practical implications

Prof. Hon. Mette M. BergerLausanne University Hospital

Switzerland

Disclosures - Mette M BergerGrants: Baxter, Fresenius Kabi

Lecturer: Baxter, BBraun, DSM, Fresenius Kabi, Nestlé, Nutricia

Advisory board: Baxter, Fresenius Kabi

Bonds ..: none

Member of ICU Guidelines working groups of ESPEN & ESICM

Guidelines for the Provision and Assessment of Nutrition Support Therapy in the Adult Critically Ill PatientSociety of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.)McClave – Taylor et al JPEN 2016

• Assess patients on admission to the intensive care unit (ICU) for nutrition risk, and calculate both energy and protein requirements to determine goals of nutrition therapy.

• Initiate enteral nutrition (EN) within 24−48 hours following the onset of critical illness and admission to the ICU, and increase to goals over the first week of ICU stay.

• Take steps as needed to reduce risk of aspiration or improve tolerance to gastric feeding (use prokinetic agent, continuous infusion, chlorhexidine mouthwash, elevate the head of bed, and divert level of feeding in the gastrointestinal tract).

• Implement enteral feeding protocols with institution‐specific strategies to promote delivery of EN.

• Do not use gastric residual volumes as part of routine care to monitor ICU patients receiving EN.

• Start parenteral nutrition early when EN is not feasible or sufficient in high‐risk or poorly nourished patients.

Table 2. Bundle Statements

1 - ASSESSMENTGLOBAL STATUS – NRSINTESTINAL TRACT

NRS nutritional risk screeningKondrup et al ClNu 2003

Points

A. BMI kg/m2

A. % Eating

A. Weightloss 3 m

B.Severity

C.Age

Total

0 > 20 Normal >75%

<5% No disease <70

1 18.5-20 50-75 % 5-10% Hip # >702 <18.5

(<20 if >70y)25-50 % >10% Major surgery

BPN3 <25 % ICU

APACHE>10

ICU cut-off: > 5 points

« Worst A » + B +C

Metabolic and Nutritional Characteristics of 150 Long-StayCritically Ill PatientsViana et al, J Clin Med 2019; 8, 985

Surv

ival

pro

babi

lity

Days after ICU admission

//

NRS 3-4___

NRS 5-6-7- - -

Kaplan–Meier analysis comparing elevated and low NRS scores (p=0.012). NRS: Nutrition Risk Screening score

Global Mortality by D9035.3%

25.7%

43.8%

2 - TIMINGMETABOLIC & INTESTINAL ASPECTS

Singer et al, Clin Nutr 2019.38:48;

Effects of isoenergetic glucose based or lipid based PN on Glucose metabolism, DNL and respiratory gas exchanges in critically ill patientsTappy et al CCM 1998; 26:860 Substrate oxidation in critically ill patients after a 3-day starvation

Resting metabolic rate 1824 kcal/ day 116% of predicted

Glycemia 7.3 mmol/LEndogenous glucose production 310 g/ day – 3.1 mg/kg/min

1230 kcal/dayNet glucose oxidation 8% (512 kcal/ day)Net fat oxidation 46% (840 kcal /day)Net protein oxidation 26% (470 kcal/ dayNet protein balance ‐117 g/ day

N=16, age 40 yrs, 69.3 kg, predominantly trauma patients

0

50

100

150

200

250

300

350

Day 1 Day 2 Day 3 Day 4 Day 9

EGP

(g/d

ay)

Starved *

Partially fed **

Fed **

Endogenous glucose production over timeBerger, JPEN 2020

//

≅190 g/d

≅190 g/d

StarvationHealthy

EARLY FULL feeding

Ener

gy Overfeeding

1 Days6 72 3

Oshima et al Clin Nutr 2017

Nutrition to immediate full target overfeeding

Total energy expenditure

Endogenous energy production

How to cover energy?

• Assess Energy Expenditure using indirect calorimetry or VCO2 x 8.2

• Administer about isocaloric nutrition rather than hypocaloric nutrition to be progressively implemented (70%) in the early phase of acute illness.

• To be followed by 80-100% in the stable phase• Using EEN if possible.• If not, start PN from day 3 (earlier in depleted patients)

Singer et al, ClNu 2019

Cutoff before underfeeding complications Concept of cumulated energy deficit

Cut off Complications -10’000 kcalcertain: -130 kcal/kg

Critical level: -8’000 kcal-100 kcal/kg

problem start -4’000 kcal- 50 kcal/kg

Berger & Pichard, Nutrition 2019Based on data from Villet et al ClNu 2005, Dvir et al ClNu 2006

Cumulated Energy Deficit

0 4 8 10 kcal

100%

6000

3 - ROUTEDOES THE ROUTE MATTER?

Not as much as previously claimed more balanced PN composition

When should nutrition therapy be initiated ?Which route should be used?

Recommendation 5• If oral intake is not possible, early EN (within 48 hours) shall be performed/initiated in critically ill adult patients rather than early PN

•Grade of recommendation: A – strong consensus (100 % agreement)

Singer et al, Madrid 2018

Recommendations 1 + 21. We suggest using EEN in critically ill adult

patients (Grade 2C).1a. We suggest using EEN rather than early PN (Grade 2C).1b. We suggest using EEN rather than delaying EN (Grade 2C).

Reintam et al, Intensive Care Med (2017) 43:380–398

2. We suggest using Early EN in patients with shock receiving vasopressors or inotropes when shock is controlled with fluids and named medications (Grade 2D).Comment: EN should not be started if shock is uncontrolled and haemodynamic and tissue perfusion goals are not reached

N=24 international authors

Advantages of Enteral• Maintains mucosal structure & integrity• Maintains GI motility if early• Maintains GI immunity (IgA)• Feeds the microbiome• Limits exacerbation of inflammation• ⇓ bacterial proliferation• ⇓ Translocation (bacteria / toxins)• ⇓ line sepsis• ⇓ metabolic complications -hyperglycemia• ⇓ Feeding solutions are cheaper

But to benefit EN, you need a feeding protocol SOP …. and great nurses

GIdisordersin the ICU Stomach

Pylorus

Small bowel

Colon

Splanchnic ischemia- shock of any origin- vascular disease- Ischemia/reperfusion- cardiopulmonary bypass- compartment syndrome

↓ gastric motility & Pyloric closure :- catecholamines- mechanical ventilation-↑ intracranial pressure- sedatives, opiates

Paralytic ileus- opiates, sedatives, clonidine- excessive fluid resuscitation- retroperitoneal bleeding- severe abdominal sepsis

↓ motilityOgilvie syndrome

Diarrhea

Esop

hagu

s

Antiperistaltism

We suggest DELAYING EN

General recommendations – to delay EN• uncontrolled shock• uncontrolled hypoxemia and acidosis• uncontrolled upper GI bleeding• bowel obstruction

expert opinion = Grade 2D

15. Overt bowel ischaemia16. High-output fistula without distal feeding access18.b. Abdominal compartment syndrome21. Gastric aspirate > 500 ml/6 h

Early enteral nutrition in critically ill patients: ESICM clinical practice guidelines. Reintam et al, ICM 2017

• Recommendation 6In case of contraindications to oral and EN, PN should be implemented within 3-7 days.Grade of recommendation: B –consensus (89 % agreement)

• Recommendation 7Early and progressive PN can be provided instead of no nutrition in case of contraindications for EN in severely malnourished patients. Grade of Recommendation: 0 –strong consensus (95 % agreement)

Singer et al, Madrid 2018

Always assess/consider GI tract first

Which route?

SupplementalPN

ParenteralNutrition

ENTERALDuodenal/

Jejunal Tube

N Engl J Med. 2014 Oct 30;371(18):1673-84

Septic shock patientsN= 2410EN: greater risk of digestive severe complications

more vomiting (34 vs 20% p<0·0001)more diarrhoea (36 vs 33% p=0·009)

bowel ischaemia (2% vs <1% p=0·007), acute colonic pseudo-obstruction (1% vs <1% p=0·04)

CALORIESMechanically ventilated patientsN=2400PN: less hypoglycemia (3.7% vs.

6.2%, P = 0.006) less vomiting (8.4% vs16.2% P<0.001)

4 - COMPOSITION AMINO ACIDS LIPIDS GLUCOSE

Evolution of PNBerger, Clin Nutr 2014

1930

.//.

1960

1970

1980

1990

2000

2010

2020

0,5 1,0 1,5 2,0 2,5 3,0

ASPEN/SCCM 2009BMI < 30

BMI > 30

SFAR/SRLF BMI

> 40

American Burn Association

Protein intake according to the guidelines

ESICM1998

2001

2009

2014

g/kg/d

Healthy

ASPEN/SCMM2016

2019 ESPEN

ESPEN

Ishibashi et al, CCM 1998;26:1529-35

Change in Total Body ProteinIn trauma & sepsis

Courtesy J Wernerman

Optimal protein requirement during the first 2 weeks after the onset of critical illness.

Protein RequirementsFerrie et al, JPEN 2016

119 ICU patientsPN solutions with AA at 0.8 g/kg or 1.2 g/kgThe higher level of amino acids was associated with small improvements in a number of different measures, supporting guideline recommendations for ICU patient

Glutamine – “Conditional Deficiency”

Newsholme P., J. Nutr. 131: 2515S–2522S, 2001

Glutamine improves glucose homeostasis

Romanian multicenter trial

Spanish multicenter trial

French multicenter trial

Clin Nutr 2015;34:377

Difference between enteral and parenteral feeding solutions

Enteral (oral)

Maltodextrines Full blend of

polymeric proteins, incl. glutamine 8%

Mix of fatty acids with variable proportions of n-6, n-9 and n-3 fatty acids

TE + Vitamins in RDA dose

Parenteral Glucose Amino acids,

incomplete blend, in particular, NO glutamine

Triglycerides with various combinations of n-6, n-9 and n-3 fatty acids

NONE

Carbohydrates

Proteins

Lipids

Micronutrients

Amino acids: beware of unbalanced PN solutions

Fürst & Stehle New Horizons 1994

Stehle P et al., Clin Nutr ESPEN 17 (2017) 75-85

This meta-analysis clearly confirms that when critically ill patients are supplemented with parenteral GLN dipeptide according to clinical guidelines as part of a balanced nutrition regimen, it significantly reduces hospital mortality, infectious complication rates, and hospital LOS.

15 RCTs (16 publications) including 842 critically ill patients. None had renal and/or hepatic failure. Average study quality (Jadadscore) > predefined cut-off of 3.0 (3.8 points)

Intervention : parenteral GLN dipeptides in combination with supplemental or total PN for at least 3 days while the control treatment consisted of isoenergetic and iso-N supplements

CompositionCommercialPN

Should we use additional enteral / parenteral glutamine (GLN) in the ICU?

Recommendation 26• In patients with burns > 20% body surface area, additional

enteral doses of glutamine (0.3-0.5 g/kg/d) should be administered for 10-15 days as soon as EN is commenced.

• Grade : B – strong consensus (95 % agreement)Recommendation 28• In ICU patients except burn and trauma patients, additional

enteral glutamine should not be administered.• Grade : B – strong consensus (92.31 % agreement)Recommendation 29• In unstable and complex ICU patients, particularly in those

suffering from liver and renal failure, parenteral glutamine-dipeptide shall not be administered.

• Grade : A – strong consensus (92.31 % agreement)

ICU length of stay

infectious complications

duration of mechanical ventilation

Stehle P et al., Clin Nutr ESPEN 17 (2017) 75-85

P=0.02

P=0.001

P=0.04

Length of stay in hospital

Hospital mortality

P=0.01

P=0.03

Stehle P et al., Clin Nutr ESPEN 17 (2017) 75-85

Essential Fatty Acid Requirements and Intravenous Lipid EmulsionsGramlich et al JPEN 2019

Fatty acid structures and biosynthetic pathways

Essential Fatty Acid Deficiency in Human Adults During PN

Hamilton et al NCP 2006

pivotal paper in 19753 case studies of patients receiving prolonged fat-

free PN at home skin lesions + abnormal plasma fatty acid profiles

The skin lesions and biochemical evidence of essential fatty acid deficiency (EFAD) resolved when Intralipid was administered. Until this time, EFAD was documented only in animals and infants but not in adults.

Essential fatty acid deficiency

Courtesy Stanley Dudrick & Stanislaw Klek

Essential Fatty Acid Requirements and Intravenous Lipid Emulsions

Gramlich et al JPEN 2019

Linoleic acid (LA) and α-linolenic acid (ALA) must be supplied to the human body and are therefore considered essential fatty acids. This narrative review discusses the signs, symptoms, diagnosis, prevention, and treatment of essential fatty acid deficiency (EFAD).

Although rare, EFAD is diagnosed by an elevated triene:tetraene (T:T) ratio, which reflects increased metabolism of oleic acid to Mead acid in the absence of adequate LA and ALA

Fats - any side-effects?• Altered pulmonary hemodynamics (PHT) and

oxygenation• Hepatobiliary disorders associated with PN -

PNALD: steatosis, cholestasis, gallbladder sludge/stones …

• Fat Overload Syndrome in infants (> 3 g/kg/d)• Hypertriglyceridemia & pancreatitis• Decreased insulin sensitivity• Administration of IV fat resistance to

anticoagulation in patients on anti-vit K (warfarin)• Immune effects & risk of infection• Microbial growth in IV fat emulsions

Biological and Clinical Aspects of an Olive Oil-Based Lipid Emulsion-A Review

Cai, Calder et al, Nutrients 2018; 10: 776

Olive oil-based ILE appears to support the innate immune system, is associated withfewer infections, induces less lipid peroxidation, and is not associated with increased hepatobiliary or lipid disturbances. These data would suggest that olive oil-based ILE is a valuable option in various PN-requiring patient populations.

Infection rates in adult surgical patients (N = 458)Jia et al Nutr. J. 2015, 14, 119

Adhesion of LPS-induced leukocytes in a rat model. Demirer et al 2016

Infla

mm

atio

n

Hyper

Hypo

HYPERINFLAMMATION

Excess inflammatory eicosanoids,

cytokines, ROS, adhesion molecules;

NFkB activation

IMMUNOSUPPRESSIONExcess anti-inflammatory Cytokines;Suppressed HLA expression & antigen presentation;Suppressed T cell function

INSULT

POOROUTCOME

ω-3 PUFAs

0

1 2 3 4 5 6

SIRSCARS

eico

sano

ids

HLA

-DR

TNF,

IL-1

, 6 e

tc.

phys

iolo

gic

rang

e of

infla

mm

atio

nov

erw

helm

ing

infla

mm

atio

nim

mun

e-pa

raly

sis

IL-4, 10, 13, etc.

self destructiontissue injury

breakdownof host defense

shock

ω-6 fatty acids

ω-3 PUFAs

Influence of n-3 PUFAs enriched lipid emulsions on nosocomial infections and clinical outcome in critically ill patients: ICU lipids studyGrau-Carmona et al, CCM 2015; 43: 31.

Time free of infection for patients givenparenteral nutrition with different lipid emulsions

Inlcusion: 159 medical and surgical ICU patientsMain results: The number of patients with nosocomial infections was significantly reduced in the fish oil-receiving group (21.0% vs 37.2%, p = 0.035) and the predicted time free of infection was prolonged (21 ± 2 vs 16 ± 2 d, p = 0.03). No significant differences were detected for ICU, hospital, and 6-month mortality.

Should we use enteral / parenteral EPA/DHA? Recommendation 30• High doses of omega-3-enriched EN formula

should not be given by bolus administration. • Grade : B – strong consensus (91 % agreement)Recommendation 31• EN enriched with omega-3 fatty acids within

nutritional doses can (should) be administered. • Grade : 0 – strong consensus (95 % agreement)Recommendation 32• High dose omega-3-enriched enteral formulas

should not be given on a routine basis. • Grade : B – consensus (90 % agreement)

Singer et al, Clin Nutr 2019;38:48-79

ICU2019

Choosing the lipid: A key consideration in PNIndustry proposes AIO with different levels of SFAs, PUFAs, and MUFAs

Wanten GJA, Calder PC. Am J Clin Nutr. 2007;85(5):1171-1184. Driscoll DF. Nutr Clin Pract. 2006;21(4):381-386.

Intralipid®

20%

Lipofundin®

MCT/LCT 20%

Structolipid®

20%

Omegaven®

10%

ClinOleic®

20%

Lipoplus®

20%

SMOFlipid®

20%Oil source

% FA

100% soy 50% coconut 50% soy

36% coconut 64% soy

100% fish 80% olive 20% soy

50% coconut40% soy10% fish

30% soy30% coconut

25% olive15% fish

SFA 15.0 59.4 46.3 21.2 14.5 49.0 36.9

MUFA 24.0 11.0 14.0 24.3 63.7 14.1 32.7

PUFA 61.1 33.8 40.0 42.3 22.0 36.9 30.3

ω-3 8.0 4.5 5.0 35.2 2.8 10.5 8.3ω-6 53.1 29.3 35.0 7.1 19.2 26.5 22.0ω-9 24.0 11.0 14.0 15.1 62.3 13.9 31.2

Intravenous Fish Oil in Critically Ill and Surgical Patients - Historical Remarks and Critical Appraisal

Kreymann et al, Clin Nutr 2018;37:1075

Effect of different fish oil admixtures or fish oil-supplemented emulsions on infection rates in critically ill patients

Effect of different fish oil admixtures or fish oil-supplemented emulsions on infection rates in surgical patients with malignancies

Intravenous Fish Oil in Critically Ill and Surgical Patients - Historical Remarks and Critical Appraisal

Kreymann et al, Clin Nutr 2018, 37(3):1075

ω-3 Fatty-Acid Enriched PN in Hospitalized Patients: Systematic Review With Meta-Analysis & Trial Sequential Analysis

Pradelli et al JPEN 2019

Provision of ω-3-enriched lipid emulsions should be preferred over standard lipid emulsions in patients with an indication for PN.

Publications after duplicates removed (n = 2992) Included in meta-analyses (n = 49)

Fig. 2. Infection ratesN= 2154Z = 5.26 P < 0.00001

ω-3 Fatty-Acid Enriched PN in Hospitalized Patients: Systematic Review With Meta-Analysis & Trial Sequential Analysis

Pradelli et al JPEN 2019

Fig.3. 30-day mortality Z = 1.44P = 0.15

Fig.4. LICUZ = 2.49 P = 0.01

Fig.5. LOSN= 2182Z = 5.35 P < 0.00001

ω-3 Fatty-Acid Enriched PN in Hospitalized Patients: Systematic Review With Meta-Analysis & Trial Sequential Analysis

Pradelli et al JPEN 2019

Fig.6. SepsisN=1141Z = 3.52P = 0.0004

Lipids in Parenteral Nutrition: Biological AspectsCalder et al, JPEN 2020

International summit “Lipids in Parenteral Nutrition” November 2–4, 2018 (Miami, FL, USA)Consensus statement

Summary of the Anti-Inflammatory Actions Attributed To Marine ω-3 PUFA

EPA and DHA are direct precursors of potent Specialized pro-resolving lipidmediators (SPMs): resolvins, protectins, and maresins

Lipids in Parenteral Nutrition: Biological AspectsCalder et al, JPEN 2020

TOTAL energy expenditure

Σ Endogenous production + exogenous supply

Endogenous production

1

Progressiveearly EN

Days72 3

Supplemental PN ?

Time (hrs) 24 48 72

Ener

gy

Indirect calorimetry

Proposed Feeding strategy in the ICU

Adapted from Oshima et al, Clin Nutr 2017;36:651

High+ protein High E + protein

43% of patients stay

> 72 hrs in SMIA

Goals 1st week: 20 kcal/kg + protein 1.2-1.3 g/kg

SPN - Combined EN +PN strategyHeidegger et al, Lancet 2013; 381: 385

OPTIMIZATION of ENERGY PROVISION WITH SPN IMPROVES the CLINICAL OUTCOME of CRITICALLY ILL PATIENTS: A RANDOMIZED

CONTROLLED CLINICAL TRIAL Heidegger et al,

Lancet 2013; 381: 385

Noso.infection in 41 [27%] /153 SPN versus58 [38%] / 152 EN patients during follow up

hazard ratio 0.65 [95%CI 0.43–0.97]Intervention Follow-upPr

opor

tion

witho

ut no

soco

mial

infec

tion

pg/m

L

E N S P N -D 1 00

5

1 0

1 5

2 0

P H A , d o s e 1 :1 , P o s t /P r e r e s p o n s e s , E N /S P N

nb o

f sub

ject

s

R

N R

Fisher's exact test 0.2138

r a t io p o s t /p re > 1 .2

TNF-α

(pg/m

L)

D 4 D 1 0 D 4 D 1 01 0

1 0 0

1 0 0 0

1 0 0 0 0

0.0923 0.0186

E N S P N

B

Supplemental Parenteral Nutrition 2Berger et al – Clin Nutr 2019

Supplemental parenteral nutrition in intensive care patients: A cost saving strategyPradelli et al Clin Nutr 2017

Tornado diagram depicting the results of the one-way deterministic sensitivity analysis

Swiss SPN Study (N = 305; ClinicalTrials.gov: NCT00802503 // Lancet 2013

The risk of nosocomial infection was by 10% for each 1000 kcal in cumulative energy deficit

Guidelines & Research in TPN Conclusions

• While enteral nutrition should remain the first option, ICU patients do no always tolerate it

• Malnutrition may result from prolonged failed EN attempts

• Parenteral nutrition is lifesaving• Main indication is GI failure, followed by low EN • The recent better balanced PN solutions

particularly regarding lipid emulsions improve outcome

• PN solutions still incomplete as to amino acids. • Modulation of inflammation, and ↓ infection is a

very important result of the addition of w-3 PUFA

Thank you!http://lavieestleplusgranddesguru.over-blog.com/2015/10/les-pensees-un-banc-de-poissons.html