CritCareNut2022.pdf

GLBL/MG17/20-0019 04/2020 © 2020 Baxter Healthcare Corporation
Nutrition and Metabolic Needs
in Critical Care and COVID-19
Twitter: @Paul_Wischmeyer
Paul Wischmeyer M.D., E.D.I.C., FASPEN, FCCM
Professor of Anesthesiology and Surgery
Associate Vice Chair, Clinical Research
Director, Nutrition Support Service
Duke University School of Medicine
Instagram: @Paul_WischmeyerMD

NIH Funding (Past/Pres)
NIA, NIDDK, NIGMS,
NHLBI, NICHD
CIHR Funding
RE-ENERGIZE Trial
Mentee Research Grants
ASPEN, IARS, FAER, SCCM
Dept of Defense:
SendHOME Trial
RE-ENERGIZE Trial
Cardiac Surgery Care
Industry Financial Relationships:
Consultant/Grant Support: Abbott,
Baxter, Cosmed, Fresenius,
Musclesound, Nestle, Nutricia,
Takeda, DSM
Paul Wischmeyer “Alignment” of Interests

We Must Take
Responsibility For Not
Just Outcomes in ICU...
But…What
Happens After
ICU as Well!

Courtesy :Arthur Van Zanten MD
CRRT
Paralyzed
Norepinephrine
Prone Position
Often Obese
How to give
Nutrition?
Often Male
Mechanical
Ventilation
(Prolonged)
Physical Therapy?

Pharmacological treatments
during acute COVID-19
Antiretroviral 102 (71.3)
Hydroxychloroquine 104 (72.7)
Azithromycin 59 (41.3)
Anti–IL-6 drugs (tocilizumab) 44 (30.8)
Length of hospital stay, mean (SD), d 13.5 (9.7)
Post–acute COVID-19 follow-up
characteristics
Days since symptoms onset, mean (SD) 60.3 (13.6)
Days since discharge, mean (SD) 36.1 (12.9)
Persistent symptoms, No. (%)
None 18 (12.6)
1 or 2 46 (32.2)
≥3 79 (55.2)
Worsened quality of life, No. (%)b
63 (44.1)
Only 5% in ICU
Fatigue - 53% of post-
COVID pts at 60 days..

Mortality Related to Severe Sepsis and Septic Shock Among
Critically Ill Patients in Australia and New Zealand, 2000-2012
Kirsi-Maija Kaukonen, MD, PhD, EDIC; Michael Bailey, PhD; Satoshi Suzuki, MD; David Pilcher, FCICM;
Rinaldo Bellomo, MD, PhD
IMPORTANCE Severe sepsis and septic shock are major causes of mortality in intensive care
unit (ICU) patients. It is unknown whether progress has been made in decreasing their
mortality rate.
OBJECTIVE To describe changes in mortality for severe sepsis with and without shock in ICU
patients.
DESIGN, SETTING, AND PARTICIPANTS Retrospective, observational study from 2000 to 2012
including 101 064 patients with severe sepsis from 171 ICUs with various patient case mix in
Australia and New Zealand.
MAIN OUTCOMES AND MEASURES Hospital outcome (mortality and discharge to home, to
other hospital, or to rehabilitation).
RESULTS Absolute mortality in severe sepsis decreased from 35.0% (95% CI, 33.2%-36.8%;
949/2708) to 18.4% (95% CI, 17.8%-19.0%; 2300/12 512; P < .001), representing an overall
decrease of 16.7% (95% CI, 14.8%-18.6%), an annual rate of absolute decrease of 1.3%, and a
relative risk reduction of 47.5% (95% CI, 44.1%-50.8%). After adjusted analysis, mortality
decreased throughout the study period with an odds ratio (OR) of 0.49 (95% CI, 0.46-0.52)
in 2012, using the year 2000 as the reference (P < .001). The annual decline in mortality did
Editorial
Supplemental content at
jama.com
mortality rate.
patients.
in 2012, using the year 2000 as the reference (P < .001). The annual decline in mortality did
not differ significantly between patients with severe sepsis and those with all other diagnoses
(OR, 0.94 [95% CI, 0.94-0.95] vs 0.94 [95% CI, 0.94-0.94]; P = .37). The annual increase in
Editorial
jama.com
JAMA, 2014.
ICU Mortality
Decreasing
...over last 10 years!

Will We Win
Some Battles?
But…Lose
the War!!
In Critical Care…Especially in COVID-19

Sometimes, success leads to tragedy
PYRRHIC VICTORY

JAMA, Online March 18, 2014
Although Sepsis Deaths Fall By Half…

…Many More Patients to Rehab!

Improved Hospital Survival..But...
How many survive
even a year?

> 40%
of Mortality at
12 Month Follow-up
Occurs
Post-ICU Discharge
Shiell AM, Griffiths RD et al Clinical Intensive Care 1990;1 (6): 256-262

mortality rate.
patients.
Editorial
jama.com
Original Investigation | CARING FOR THE CRITICALLY ILL PATIENT
mortality rate.
patients.
Editorial
jama.com
JAMA, Online March 18, 2014.
“Given low ICU mortality…
Quality of Life
…will become focus of future
trials”

“Are we creating survivors...
or Victims?”
GLBL/MG17/20-0019 04/2020 © Baxter Healthcare Corporation

• 50% pts
• Not Back At Work At 1 yr
•
• 33% pts
• Never Return To Work
(including young pts)
Post-Hospital Weakness In ICU
Survivors....or VICTIMS??
G

Latronico Lancet Neurol 2011; 10: 931
60-80%
Functionally
Impaired
Courtesy: Wes Ely M.D.

This is an
EPIDEMIC...
COVID-19 Will
Make Worse!

Average time on ventilator
in COVID-19:
8-21 days
The Challenge is…

Why Are We Losing the Quality of
Life War?

ICU & Major Surgery Patients Can Lose
Up to 1 kg of Lean Body Mass Daily!
Hypermetabolism & Catabolism Can Persist for Months - 2 Years!
Wischmeyer PE, San-Millan I. Crit Care. 2015;19(suppl 3):S6.
May Be Worse
in COVID-19!

CRRT
Paralyzed
Norepinephrine
Prone Position
Often Obese
How to give
Nutrition?
Often Male
Mechanical
Ventilation
(Prolonged)

Right Nutrition Dose…
In Right Patient…
At Right Time…
Personalized ICU Nutrition Stratagy
We Must Measure!

Current Opinion in Critical Care: Online, May, 2021

How Do We Put This
Data Into Practice?
What do new
ASPEN/SCCM/ESPEN
Guidelines say?
And…Can We Learn From
Worldwide Experience...

Elijah W. - 49 y.o. African-
American (AA) male
(Science Professor) with
cough, fever x 7 days
Wife and Brother both
COVID (+)…

Admitted to hospital
on 3L Nasal Cannula
Oxygen...
History of recent
surgery for
diverticulitis…

Within 6 h of admit…Rapid Respiratory
Decompensation, RR-45, Sat 78% on 8 L FM
Elijah W. - 49 y.o. Found to be COVID (+)

Paralysis
Started…
In ICU…
Tachypnea
Dyssynchrony
With Ventilator
PaO2- 52
FiO2 100%

In ICU- Paralyzed and Prone- Day 1
-Blood pressure: 100/60 on
0.07 ug/kg/min levophed
-On Ventilator…Peep 10, Fio2
60%
-CVP 12
-MV O2 sat- 77%, Lactate 1.2

Nutrition Therapy in the Patient with COVID-19 Disease
Requiring ICU Care
Updated April 1, 2020
Robert Martindale, PhD, MD –Professor of Surgery, Department of Surgery, Oregon Health and
Science University, Portland Oregon
Jayshil J. Patel MD– Associate Professor of Medicine, Division of Pulmonary & Critical Care
Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin
Beth Taylor DCN, RD-AP- Research Scientist/Nutrition Support Dietitian, Barnes-Jewish
Hospital, St. Louis, Missouri
Malissa Warren, RD - Advanced Practice Nutrition Support Dietitian, Oregon Health and
Science University and Portland VA Health Care Center, Portland Oregon
Stephen A McClave MD - Professor of Medicine, Division of Gastroenterology Hepatology and
Nutrition, University of Louisville, School of Medicine, Louisville Kentucky
Reviewed and Approved by the Society of Critical Care Medicine and the American
Recommendation 2: Timing of Nutrition Delivery
-Early EN Within 24-36 h of ICU admission and 12 h
of intubation
- Use NG Tube- avoid post-pyloric typically
Martindale et al. SCCM/ ASPEN Guidelines Apr 2020
SCCM/ASPEN COVID-19
Nutrition Guidelines

What About...
...Enteral Feeding On Pressors?
Key Words: critical care; enteral nutrition; gastrointestinal; gut;
intensive care unit; nutrition; parenteral nutrition; shock; trophic
feeding; vasopressor
period of starvation, lack of enteral nutrients and prebi
fiber delivery, and the presence of exogenous/endogen
vasopressorswilldrivedysbiosis(2,7).Recentdatashowsp
Enteral Nutrition Can Be Given to Patients on
Vasopressors
PaulE.Wischmeyer,MD,EDIC,FASPEN
Crit Care Med. 2020, 48(1): 122-125

feeding; vasopressor
T
he gut has long been felt to play a central role in the
progression and pathogenesis of critical illness. In fact,
seminal papers have described the gut as the “motor for
systemic inflammation and organ failure”(1). Perturbations of
intestinal epithelial homeostasis in critical illness can lead to
increased pro-inflammatory cytokine production, gut barrier
dysfunction, and cellular apoptosis which is felt to contribute
to multiple organ failure (1). This is felt to be driven by a range
of factors including rapid change in the microbiome, known as
dysbiosis (2), and intestinal permeability changes (1). Further,
inflammatory signaling changes via the vagus nerve (3) and
period of starvation, lack of enteral nutrients and prebiotic
fiber delivery, and the presence of exogenous/endogenous
vasopressors will drive dysbiosis (2, 7). Recent data shows pro-
vision of even 20% of nutrition via EN can prevent dysbiosis,
attenuate loss of gut barrier function, and innate immunity
(7). In addition, a body of experimental and human critical
care data demonstrates that EN can trigger activation of an-
ti-inflammatory vagal-cholinergic pathway via Cholecystoki-
nin-mediated receptor stimulation in shock states (3). Thus,
outside of the obvious need for protein/energy delivery to pro-
mote recovery, the mechanistic benefits of EN in critical care
settings are long established.
Specific to the effects of nutrition delivery on gut blood flow
duringshock,benefitsofENonsplanchnicischemiaduetoshock
have been long described in laboratory models of shock (8).
Human studies of cardiogenic shock reveal EN increases car-
diac index, splanchnic blood flow, and preserves bowel ab-
Enteral Nutrition Can Be Given to Patients on
Vasopressors
Paul E. Wischmeyer, MD, EDIC, FASPEN
Feeding On Vasopressors
May Not Only Be Safe in
Many Patients…
...But Also Saves
Lives!
Crit Care Med. Jan;48(1):122-125, 2020
Wischmeyer PE, Enteral Nutrition Can Be Given to Patients on Vasopressors. Crit
Care Med. 2020 Jan;48(1):122-125

Differences in effect of early enteral nutrition on mortality among
ventilated adults with shock requiring low-, medium-, and high-dose
noradrenaline: A propensity-matched analysis*
Hiroyuki Ohbe a, *
, Taisuke Jo b
, Hiroki Matsui a
, Kiyohide Fushimi c
, Hideo Yasunaga a
a
Department of Clinical Epidemiology and Health Economics, School of Public Health, The University of Tokyo, Tokyo, Japan
b
Department of Health Services Research, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
c
Department of Health Policy and Informatics, Tokyo Medical and Dental University Graduate School of Medicine, Tokyo, Japan
a r t i c l e i n f o
Article history:
Received 4 November 2018
Accepted 9 February 2019
Keywords:
Early enteral nutrition
Bowel ischemia
Shock
Vasopressors
Noradrenaline
s u m m a r y
Background & aims: Despite extensive research on early enteral nutrition (EEN), it remains unclear
whether EEN is effective for patients with shock requiring vasopressors. This study aimed to compare
outcomes between EEN and late enteral nutrition (LEN) in ventilated patients with shock requiring low-,
medium-, or high-dose noradrenaline.
Methods: Using a national inpatient database in Japan, we identified ventilated patients admitted to
intensive care units who had shock requiring catecholamines (noradrenaline or dobutamine) from July
2010 to March 2016. We defined patients who started enteral nutrition within 2 days after starting
mechanical ventilation as EEN group and the others as LEN group. Propensity score matching was
performed between patients undergoing EEN and LEN in each of the low- (<0.1 mg/kg/min), medium-
(0.1e0.3 mg/kg/min), and high-dose (!0.3 mg/kg/min) noradrenaline groups.
Results: We identified 52,563 eligible patients during the 69-month study period, including 38,488,
Original article
Hiroyuki Ohbe a, *
, Taisuke Jo b
, Hiroki Matsui a
, Hideo Yasunaga a
a
b
c
Article history:
Keywords:
Bowel ischemia
Shock
Vasopressors
Noradrenaline
s u m m a r y
11,042, and 3033 patients in the low-, medium-, and high-dose noradrenaline groups, respectively.
One-to-two propensity score matching created 5,969, 2,162, and 477 one-to-two matched pairs in
the low-, medium-, and high-dose noradrenaline groups, respectively. The 28-day mortality rate was
significantly lower in the EEN than LEN group in the low-dose noradrenaline group (risk
difference, "2.9%; 95% confidence interval [CI], "4.5% to "1.3%) and in the medium-dose noradren-
aline group (risk difference, "6.8%; 95% CI, "9.6% to "4.0%). In the high-dose noradrenaline group,
28-day mortality did not differ significantly between the EEN and LEN groups (absolute risk
difference, "1.4%; 95% CI, "7.4%e4.7%).
Conclusions: Although the size of the subgroup requiring high-dose noradrenaline may have been too
small to demonstrate a significant difference, the results suggest that EEN was associated with a
reduction in mortality in ventilated adults treated with low- or medium-dose noradrenaline but not in
2 groups:
-Patients started EN within 2 days- EEN group
-Pts started post 2 days - LEN group
52,563 patients identified & matched
Ohbe H1, Jo T2, Matsui H3, Fushimi K4, Yasunaga H3. Differences in effect of early enteral nutrition on mortality among ventilated adults with shock
requiring low-, medium-, and high-dose noradrenaline: A propensity-matched analysis. Clin Nutr. 2019 Feb 15. pii: S0261-5614(19)30074-3. doi:
10.1016/j.clnu.2019.02.020. [Epub ahead of print]
Clin Nutr 2019 Feb 15. [Epub]
Large Health Ouctome Study: National Inpatient Database
MV'd ICU patients with shock on norepinephrine or dobutamine

52,563 ICU patients with shock on vasopressors
Primary Outcomes:
28-d mortality rate significantly lower in EEN vs LEN in:
No difference observed between EEN & LEN
in High-Dose NE group (>0.3 mg/kg/min)
(OR 0.96; 95% CI, 0.81-1.14)
-Low-Dose Norepinephrine group (<0.1 mg/kg/min)
(OR 0.84; 95% CI, 0.77 - 0.93)
-Medium-Dose Norepinephrine group (0.1-0.3 mg/kg/min)
(OR 0.77; 95% CI, 0.68- 0.86)
Hiroyuki Ohbe a, *
, Taisuke Jo b
, Hiroki Matsui a
, Hideo Yasunaga a
a
b
c
Article history:
Keywords:
Bowel ischemia
Shock
Vasopressors
Noradrenaline
s u m m a r y
Original article
Hiroyuki Ohbe a, *
, Taisuke Jo b
, Hiroki Matsui a
, Hideo Yasunaga a
a
b
c
Article history:
Keywords:
Bowel ischemia
Shock
Vasopressors
Noradrenaline
s u m m a r y
difference, "1.4%; 95% CI, "7.4%e4.7%).

Authors Conclude:
“Results show EEN is associated with reduction in mortality
in ventilated adults treated with low- or medium-dose
norepinephrine but not high-dose norepinephrine”
Hiroyuki Ohbe a, *
, Taisuke Jo b
, Hiroki Matsui a
, Hideo Yasunaga a
a
b
c
Article history:
Keywords:
Bowel ischemia
Shock
Vasopressors
Noradrenaline
s u m m a r y
Original article
Hiroyuki Ohbe a, *
, Taisuke Jo b
, Hiroki Matsui a
, Hideo Yasunaga a
a
b
c
Article history:
Keywords:
Bowel ischemia
Shock
Vasopressors
Noradrenaline
s u m m a r y
difference, "1.4%; 95% CI, "7.4%e4.7%).

How to Feed Safely…
...Enteral Nutrition On Vasopressors
feeding;vasopressor
period of starvation, lack of enteral nutrients and prebiotic
fiber delivery, and the presence of exogenous/endogenous
vasopressorswilldrivedysbiosis(2,7).Recentdatashowspro-
EnteralNutritionCanBeGiventoPatientson
Vasopressors
PaulE.Wischmeyer,MD,EDIC,FASPEN
Crit Care Med. 2020, 48(1): 122-125
Care Med. 2020 Jan;48(1):122-125

Wischmeyer PE, Crit Care Med. 2020, 48(1): 122-125

How to Safely Give EN On Vasopressors...
Care Med. 2020 Jan;48(1):122-125
FEED STOMACH!
Not Small Bowel!
Best monitor for gut
perfusion and safety!
-Watch for residual >500 cc
or other intolerance signs

What about Bolus/
Intermittent
Feeding?

CURRENT
OPINION Continuous or intermittent feeding: pros and cons
Danielle E. Beara,b,c,d,e,!
, Nicholas Hartc,d,e
, and Zudin Puthuchearye,f,g,!
Purpose of review
There has been a recent shift in the focus of providing nutrition support to critically ill adults towards
enhancing recovery and promoting survivorship. With this has come an evaluation of our current
approaches to nutrition support, which includes whether continuous feeding is optimal, particularly for
reducing muscle wasting, but also for managing blood glucose levels and feeding intolerance and at the
organizational level. This review will discuss the pros and cons of using intermittent and continuous feeding
relating to several aspects of the management of critically ill adults.
Recent findings
Few studies have investigated the effect of intermittent feeding over continuous feeding. Overall, intermittent
feeding has not been shown to increase glucose variability or gastrointestinal intolerance, two of the
reasons continuous feeding is the preferred method. A current study investigating the effect of intermittent
vs. continuous feeding is awaited to provide insight into the effect of muscle wasting.
Summary
Although there are limited studies investigating the safety and efficacy of an intermittent rather than
continuous feeding regimen in critically ill adults, there are several theoretical advantages. Further studies
should investigate these and in the meantime, feeding regimens should be devised based on individual
patient factors.
Keywords
er Health, Inc. All rights reserved.
Bridge Rd, London SE1 7EH, UK. Tel: +44 207 188 5642;
e-mail: Danielle.Bear@gstt.nhs.uk
!
Danielle E. Bear and Zudin Puthucheary have contributed equally to the
article.
Curr Opin Crit Care 2018, 24:256–261
DOI:10.1097/MCC.0000000000000513
Volume 24 " Number 4 " August 2018
CURRENT
OPINION Intermittent versus continuous feeding
in critically ill adults
Jayshil J. Patela
, Martin D. Rosenthalb
, and Daren K. Heylandc
Purpose of review
Early enteral nutrition is recommended in critically ill adult patients. The optimal method of administering
enteral nutrition remains unknown. Continuous enteral nutrition administration in critically ill patients
remains the most common practice worldwide; however, its practice has recently been called into question
in favor of intermittent enteral nutrition administration, where volume is infused multiple times per day. This
review will outline the key differences between continuous and intermittent enteral nutrition, describe the
metabolic responses to continuous and intermittent enteral nutrition administration and outline recent studies
comparing continuous with intermittent enteral nutrition administration on outcomes in critically ill adults.
Recent findings
In separate studies, healthy humans and critically ill patients receiving intermittent nutrition (infused over 3 h) had
improved whole body protein balance from negative to positive. These studies did not have an isonitrogenous
control group. A randomized controlled trial of intermittent bolus versus continuous enteral nutrition in healthy
REVIEW
lters Kluwer Health, Inc. All rights reserved.
ts of early
g gut integ-
d responses
2
&&
].
ne research
highlighted
e nutrition,
al nutrition
g, the effect
ing on out-
al nutrition
ntermittent)
nutrition expert panel identified the need for a
a
Division of Pulmonary and Critical Care Medicine, Medical College of
Wisconsin, Milwaukee, Wisconsin, b
Division of Acute Care Surgery,
University of Florida, Gainesville, Florida, USA and c
Division of Critical
Care Medicine, Queen’s University, Kingston, Ontario, Canada
Correspondence to Jayshil J. Patel, MD, Associate Professor of Medi-
cine, Division of Pulmonary and Critical Care Medicine, Medical College
of Wisconsin, 9200 West Wisconsin Avenue Suite E5200, Milwaukee,
WI 53226, USA. Tel: +1 414 955 7042; e-mail: jpatel2@mcw.edu
Curr Opin Clin Nutr Metab Care 2018, 21:116–120
DOI:10.1097/MCO.0000000000000447
Volume 21 ! Number 2 ! March 2018
REVIEW Open Access
Feeding critically ill patients the right ‘whey’:
thinking outside of the box. A personal view
Paul E Marik
Marik Annals of Intensive Care (2015) 5:11
DOI 10.1186/s13613-015-0051-2
DOI 10.1186/s13613-015-0051-2

Intermittent/bolus feeding in ICU-
• Is safe
• Is associated with similar levels of gastric
intolerance as for continuous feeding
• Intermittent/bolus feeding may be potential
tool for preventing muscle loss & functional
debility
Existing data indicates that bolus/Intermit feeding is:
See new data→
Effect of Intermittent or Continuous Feed
on Muscle Wasting in Critical Illness
A Phase 2 Clinical Trial
Angela S. McNelly, PhD; Danielle E. Bear, MRes; Bronwen A. Connolly, PhD; Gill Arbane, BSc; Lau
[ Critical Care Original Research ]
control group (standard continuous enteral feeding, n ¼ 59). The primary outcome was 10-
day loss of rectus femoris muscle cross-sectional area determined by ultrasound. Secondary
outcomes included nutritional target achievements, plasma amino acid concentrations, gly-
cemic control, and physical function milestones.
RESULTS: Muscle loss was similar between arms (–1.1% [95% CI, –6.1% to –4.0%]; P ¼ .676).
More intermittently fed patients received 80% or more oftarget protein (OR, 1.52 [1.16-1.99]; P <
.001) and energy (OR, 1.59 [1.21-2.08]; P ¼ .001). Plasma branched-chain amino acid concen-
trations before and after feeds were similar between arms on trial day 1 (71 mM [44-98 mM]; P ¼
.547) and trial day 10 (239 mM [33-444 mM]; P ¼ .178). During the 10-day intervention period the
coefﬁcient of variation for glucose concentrations was higher with intermittent feed (17.84 [18.6-
20.4]) vs continuous feed (12.98 [14.0-15.7]; P < .001). However, days with reported hypogly-
cemia and insulin usage were similar in both groups. Safety proﬁles, gastric intolerance, physical
function milestones, and discharge destinations did not differ between groups.
INTERPRETATION: Intermittent feeding in early critical illness is not shown to preserve muscle
mass in this trial despite resulting in a greater achievement of nutritional targets than
continuous feeding. However, it is feasible and safe.
TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT02358512; URL: www.clinicaltrials.gov
CHEST 2020; 158(1):183-194

Acknowledge
I acknowledge
to trial the inte
allowing us to
the best bedsid
Disclosure
Figure 1 and T
other sources.
Received: 3 M
References
Table 2 Intermittent feeding schedule
Time (h) Volume (ml) Duration of infusion (min)
0 100 20
4 150 20
8 150 20
12 200 30
16 200 30
20 250 40
24 Target
R E V I E W Open Access
Feeding critically ill patients the right ‘whey’:
thinking outside of the box. A personal view
Paul E Marik
Abstract
Atrophy of skeletal muscle mass is an almost universal problem in survivors of critical illness and is associated with
significant short- and long-term morbidity. Contrary to common practice, the provision of protein/amino acids as a
continuous infusion significantly limits protein synthesis whereas intermittent feeding maximally stimulates skeletal
muscle synthesis. Furthermore, whey-based protein (high in leucine) increases muscle synthesis compared to
soy or casein-based protein. In addition to its adverse effects on skeletal muscle synthesis, continuous feeding is
unphysiological and has adverse effects on glucose and lipid metabolism and gastrointestinal function. I propose
that critically ill patients’ be fed intermittently with a whey-based formula and that such an approach is likely to be
associated with better glycemic control, less hepatic steatosis and greater preservation of muscle mass. This paper
provides the scientific basis for my approach to intermittent feeding of critically ill patients.
Keywords: Nutrition; Whey; Muscle mass; Muscle atrophy; Intermittent feeding; Continuous feeding; Metabolic
function; Insulin; Incretin; MTOR; Autophagy; Ubiquitin–proteasome complex
Review
Survivors of critical illness suffer from marked muscle
wasting which may take years to recover. The loss of
muscle mass is associated with muscle weakness, pro-
longed mechanical ventilatory support, fatigue and de-
layed recovery [1–3]. This disorder is known as critical
illness myopathy (CIM) or intensive care unit-acquired
weakness (ICUAW) [1–3]. CIM is characterized by a
diffuse non-necrotizing myopathy accompanied by fiber
atrophy, fatty degeneration of muscle fibers and fibrosis
[4]. Multiple factors are likely to play a role in inducing
CIM including muscle inactivity, inflammation, cellular
energy stress, corticosteroids, hyperglycemia, neuro-
muscular blocking agents and inadequate nutritional
support [2, 4]. CIM is exceedingly common in ICU survi-
vors, being reported in up to 46 % of cases [5]. Herridge
et al. followed 109 survivors of ARDS for up to 5 years
after discharge from the ICU [6, 7]. All patients reported
poor functional status with proximal weakness and fatigue
at discharge. At 1 year, the distance walked in 6 minutes
Muscle breakdown during acute illness
In health, net muscle synthesis is stimulated in the post-
prandial state while net muscle breakdown occurs be-
tween meals with muscle mass being maintained through
balanced protein synthesis and breakdown [8]. Distinct
metabolic pathways are involved in the synthesis and
breakdown of muscle. Figure 1 provides an overview of
these pathways. Muscle protein synthesis and not break-
down is more responsive to anabolic stimuli [9]. In healthy
individuals, the anabolic effects of feeding occurs due to
an increase in the synthetic rate of muscle protein synthe-
sis of approximately 300 % with a concomitant 50 % de-
crease in the rate of protein breakdown [8, 10]. In healthy
young men following an oral bolus of essential amino
acids, there is a lag period of 45–90 min followed by an
increase in the muscle protein synthetic response which
continues for about 90 min then rapidly returns to base-
line [8, 10, 11]. The duration and degree of the muscle
protein synthetic response following protein ingestion is
influenced by exercise, age and the dose and type of pro-
REVIEW
Feeding criticall
thinking outside
Paul E Marik
Abstract
Atrophy of skeletal muscle mass is
DOI 10.1186/s13613-015-0051-2
Intermittent Feeding Strategy

Enteral Feeding in Proned Patients is Safe...
SCCM/ASPEN COVID-19 Guidelines
Recommendation 7: Nutrition for Patient in Prone Positioning
Retrospective/small prospective trials show EN in
prone pts not associated w/ increased risk of GI/
pulmonary complications, thus we recommend early EN
in prone pts
(JPEN J Parenter Enteral Nutr. 2016 Feb;40(2):250-5)
Most prone pts tolerate EN delivered to stomach. When
EN used in prone pts elevate HOB (reverse Trendelenburg)
to >10 -25 deg to decrease aspiration risk
Martindale et al.. SCCM/ ASPEN
Guidelines Apr 2020

How Much to
Feed in Acute
Phase of
Critical Illness?
n

Nutrition Therapy in the Patient with COVID-19 Disease
Requiring ICU Care
Updated April 1, 2020
Robert Martindale, PhD, MD –Professor of Surgery, Department of Surgery, Oregon Health and
Science University, Portland Oregon
Jayshil J. Patel MD– Associate Professor of Medicine, Division of Pulmonary & Critical Care
Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin
Beth Taylor DCN, RD-AP- Research Scientist/Nutrition Support Dietitian, Barnes-Jewish
Hospital, St. Louis, Missouri
Malissa Warren, RD - Advanced Practice Nutrition Support Dietitian, Oregon Health and
Science University and Portland VA Health Care Center, Portland Oregon
Stephen A McClave MD - Professor of Medicine, Division of Gastroenterology Hepatology and
Nutrition, University of Louisville, School of Medicine, Louisville Kentucky
Reviewed and Approved by the Society of Critical Care Medicine and the American
Recommendation 4: Nutrition Dose
Start low dose EN (hypocaloric /trophic)
advancing to full EN slow over first ICU
week to meet energy goal of 15-20 kcal/kg
actual body weight (ABW)/d (70-80% of
caloric requirements) & protein goal of
1.2-2.0 gm/kg ABW/d
Martindale et al. SCCM/ ASPEN Guidelines Apr 2020
SCCM/ASPEN COVID-19
Nutrition Guidelines

Catabolic Response to Stress and Injury
Body Can Generate 50-75% of Pts Glucose Requirements!
Exogenous
Glucose Kcal
Delivery?
Text
Adapted from: Anesthesiology 2015; 123:1455-72

Catabolic Response to Critical Illness and Trauma
Exogenous
Glucose Kcal
Delivery?
Text

Resting energy expenditure, calorie and
protein consumption in critically ill patients:
a retrospective cohort study
Oren Zusman1*
, Miriam Theilla2,3
, Jonathan Cohen2,4
, Ilya Kagan2
, Itai Bendavid2
and Pierre Singer2,4
Abstract
Background: Intense debate exists regarding the optimal energy and protein intake for intensive care unit (ICU)
patients. However, most studies use predictive equations, demonstrated to be inaccurate to target energy intake. We
sought to examine the outcome of a large cohort of ICU patients in relation to the percent of administered calories
divided by resting energy expenditure (% AdCal/REE) obtained by indirect calorimetry (IC) and to protein intake.
Methods: Included patients were hospitalized from 2003 to 2015 at a 16-bed ICU at a university affiliated, tertiary care
hospital, and had IC measurement to assess caloric targets. Data were drawn from a computerized system and
included the % AdCal/REE and protein intake and other variables. A Cox proportional hazards model for 60-day
mortality was used, with the % AdCal/REE modeled to accommodate non-linearity. Length of stay (LOS) and length of
ventilation (LOV) were also assessed.
Results: A total of 1171 patients were included. The % AdCal/REE had a significant non-linear (p < 0.01) association
with mortality after adjusting for other variables (p < 0.01). Increasing the percentage from zero to 70 % resulted in a
hazard ratio (HR) of 0.98 (CI 0.97–0.99) pointing to reduced mortality, while increases above 70 % suggested an
increase in mortality with a HR of 1.01 (CI 1.01–1.02). Increasing protein intake was also associated with decreased
mortality (HR 0.99, CI 0.98–0.99, p = 0.02). An AdCal/REE >70 % was associated with an increased LOS and LOV.
Conclusions: The findings of this study suggest that both underfeeding and overfeeding appear to be harmful to
critically ill patients, such that achieving an Adcal/REE of 70 % had a survival advantage. A higher caloric intake may
also be associated with harm in the form of increased LOS and LOV. The optimal way to define caloric goals therefore
requires an exact estimate, which is ideally performed using indirect calorimetry. These findings may provide a basis for
future randomized controlled trials comparing specific nutritional regimens based on indirect calorimetry measurements.
Keywords: Indirect calorimetry, Nutrition, Protein, Resting energy expenditure, Calorie consumption
Background
The provision of nutritional support for critically ill pa-
tients continues to be the subject of intense debate, with
described [6, 7]. Importantly, for many reasons either by
design or default, many critically ill patients do not re-
ceive their full energy requirements and the proportion
1171 patients
Zusman et al. Critical Care (2016) 20:367
RESEARCH
Resting energy expenditure, c
protein consumption in critica
Zusman et al. Critical Care (2016)20:367
DOI 10.1186/s13054-016-1538-4
1171 pts in ICU > 96 h & Measured Energy Expenditure.
Lowest Mortality ~70% of REE Delivered

We Need Actual Data on Measured
Energy Needs in COVID-19!...
...This is A New
Pandemic Disease!

ICU Nutrition Guidelines
If available, energy expenditure
should be measured by indirect
calorimetry
Singer et al. Clin Nutr 2019; 38: 48-79

IC in ESPEN COVID-19 Updates
62
ESPEN expert statements and practical guidance for nutritional management of individuals with SARS-CoV-2 infection. March, 2020
Indirect Calorimetry Can Be Done Safely in COVID-19 With Precautions!
ESPEN expert statements and practical guidance for nutritional
management of individuals with SARS-CoV-2 infection
March 24, 2020
2.2. Statement 2
… Energy needs can be assessed using indirect calorimetry if
safely available with ensured sterility of the measurement
system…

Energy delivery guided by indirect
calorimetry in critically ill patients: a systematic
review and meta-analysis
Jing-Yi Duan1
, Wen-He Zheng2
, Hua Zhou1
, Yuan Xu1
and Hui-Bin Huang1*
Abstract
Background: The use of indirect calorimetry (IC) is increasing due to its precision in resting energy expenditure
(REE) measurement in critically ill patients. Thus, we aimed to evaluate the clinical outcomes of an IC-guided nutrition
therapy compared to predictive equations strategy in such a patient population.
Methods: We searched PubMed, EMBASE, and Cochrane library databases up to October 25, 2020. Randomized
controlled trials (RCTs) were included if they focused on energy delivery guided by either IC or predictive equations
in critically ill adults. We used the Cochrane risk-of-bias tool to assess the quality of the included studies. Short-term
mortality was the primary outcome. The meta-analysis was performed with the fixed-effect model or random-effect
model according to the heterogeneity.
Results: Eight RCTs with 991 adults met the inclusion criteria. The overall quality of the included studies was moder-
ate. Significantly higher mean energy delivered per day was observed in the IC group, as well as percent delivered
energy over REE targets, than the control group. IC-guided energy delivery significantly reduced short-term mortality
compared with the control group (risk ratio=0.77; 95% CI 0.60 to 0.98; I2
=3%, P=0.03). IC-guided strategy did not
significantly prolong the duration of mechanical ventilation (mean difference [MD]=0.61 days; 95% CI − 1.08 to 2.29;
P=0.48), length of stay in ICU (MD=0.32 days; 95% CI − 2.51 to 3.16; P=0.82) and hospital (MD=0.30 days; 95% CI
− 3.23 to 3.83; P=0.87). Additionally, adverse events were similar between the two groups.
Conclusions: This meta-analysis indicates that IC-guided energy delivery significantly reduces short-term mortality in
critically ill patients. This finding encourages the use of IC-guided energy delivery during critical nutrition support. But
more high-quality studies are still needed to confirm these findings.
Duan et al. Crit Care (2021) 25:88
https://doi.org/10.1186/s13054-021-03
RESEARCH
Energy delive
Page 8 of 10
Duan et al. Crit Care (2021) 25:88
Fig. 2 Forest plot showing the effects of energy delivery guided by indirect calorimetry on short-term mortality rate in critically ill patients
Eight RCTs with 991 adults in ICU
23%
⬇ICU Mortality with IC Use
IC Guided “Isocaloric Feeding” Improves Mortality

Original article
The clinical evaluation of the new indirect calorimeter developed by
the ICALIC project
Taku Oshima a
, Marta Delsoglio b
, Yves M. Dupertuis b
, Pierre Singer c
,
Elisabeth De Waele d, e, f
, Cecilia Veraar g
, Claudia-Paula Heidegger h
, Jan Wernermann i
,
Paul E. Wischmeyer j
, Mette M. Berger k
, Claude Pichard b, *
a
Department of Emergency and Critical Care Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana Chuou-ku, Chiba City, Chiba, 260-
8677, Japan
b
Nutrition Unit, Geneva University Hospital, Rue Gabrielle-Perret-Gentil 4, 1211, Geneva, Switzerland
c
Critical Care Medicine, Institute for Nutrition Research, Rabin Medical Center, Beilison Hospital, Petah Tikva, 49100, Israel
d
Department of Intensive Care, Vrije Universiteit Brussel, Brussels, Belgium
e
Department of Intensive Care, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium
f
Department of Nutrition, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium
g
Division of Cardiac Thoracic Vascular Anesthesia and Intensive Care Medicine, University Hospital of Vienna, Waehrihger Guertel 18-20, 1090 Vienna,
Austria
h
Department of Acute Medicine, Division of Intensive Care, Geneva University Hospital, Rue Gabrielle-Perret-Gentil 4, 1211 Geneva, Switzerland
i
Department of Anesthesiology and Intensive Care Medicine, Karolinska University Hospital Huddinge, Sweden
j
Department of Anesthesiology, Duke University, Durham, NC, USA
k
Service of Adult Intensive Care, Lausanne University Hospital, 1011 Lausanne, Switzerland
Contents lists available at ScienceDirect
Clinical Nutrition
journal homepage: http://www.elsevier.com/locate/clnu

Q-NRG+ Calorimeter : Innovations
Accurate
• < 3%
Rapid measurements
• No warm-up
• Monthly calibration
Easy to use
• Touchscreen operation
• Easy disinfection
Compact, easy handling
• Battery operation
• 4 kg
Affordable
COSMED Q-NRG Metabolic Monitor User Manual 2018.

Summary - New Indirect Calorimetry Device
• Accurate
• Easy to use
• Compact - portable
• Easy maintenance
• Easy disinfection
• Affordable
Rapid measurements

Longitudinal
Evaluation of Energy
Expenditure and
Metabolic
Pathophysiology of
COVID-19 (LEEP-COVID)
Whittle J…Wischmeyer PE for LEEP-COVID Group Crit Care. 24: 581, 2020
PMID: 32988390
ClinicalTrials.Gov: NCT04350073

Are COVID-19 ICU
Patients
Hypermetabolic in
Acute Phase?

This is an mid-50’s LTAC patient
COVID (+) (60 kg) early in care
(day 2):
- Spont breathing on vent (not
paralyzed)
- 15 kcal/kg is determined by
indirect calorimetry
-On Trophic Tube Feeds

49 yo COVID (+) patient early
in care (day 4):
-Being fed 1440 kcal/d-
based on 18 kcal/kg
- Proned and Paralyzed
when test was done on PEEP
of 12

What About Chronic
and Recovery
Phase?
Beyond Day 5-7…
G

-COVID (+) 49 yo pt (ICU Day 12)
-Being underfed 1440 kcal/d-
based on 20-25 kg/kg
-35 kg/kg/d by IC
-We changed feeding to 2400
kcal/d as patient weaned on vent
on pressure support
ICU Day 12

-Febrile at time of cart (> 70% of
day)
-44 kcal/kg via IC
-Changed feeding to 2400 kcal/d
w/ improved RQ & increased REE
as patient weaned on vent on
pressure support
ICU Day 15

(Now Afebrile-previous IC
measures pt febrile much of day)
-28 kcal/kg measured by IC
-We changed feeding to 2100
kcal/d to account for febrile &
non-febrile periods as pt weaned
on vent on pressure support
ICU Day 18

-Being fed < 50% of goal x 7 days
- RQ showing underfeeding and
continued protein breakdown
-34 kcal/kg measured by IC
-Feeding needs continue to be
156% of predicted and EN+SPN
being considered
ICU Day 23

Caloric Need Vs Predicted in COVID-19
40
60
80
100
120
140
160
180
200
0
-
2
3
-
5
6
-
8
9
-
11
12
-
14
15
-
17
18
-
20
21
-
23
24
-
26
27
-
30
>
30
RESTING ENERGY EXPENDITURE PREDICTED (%)
REE Expon. (REE)
DAYS
Whittle J…Wischmeyer PE for LEEP-COVID Group Crit Care. 24: 581, 2020 PMID: 32988390

- In first 3-7 days: COVID-19 patients are
NormoMETABOLIC (80-100% of predicted/
17-20 kcal/kg/d)
- After day 7: COVID-19 patients are
HYPERMETABOLIC - 120-200% of equation
predicted even paralyzed… (25->35+
kcal/kg/d)
Indirect Calorimetry Data in COVID-19
NCT:04350073
Initial LEEP-COVID Data
Whittle J…Wischmeyer PE for LEEP-COVID Group Crit Care. 24: 581, 2020 PMID: 32988390

How Well Do Existing
Predictive Equations
Perform Versus Measured
Energy Needs via
Indirect Calorimetry?
Hint…POORLY!
NEW
PUBLISHED
DATA!

Q-NRG Indirect Calorimeter (IC) longitudinal measures compared to Harris-Benedict
(HB), Mifflin St-Jeor (MSJ), & Penn State University (PSU) 2003b & PSU 2010
equations from ICU WEEK 1-7.
Methods:
Population: From LEEP-COVID Study- 38 Intubated COVID-19 patients in ICU
Prolonged progressive hypermetabolism during COVID-19
hospitalization undetected by common predictive energy equations
Laura E. Niederer a, b
, Hilary Miller a, b
, Krista L. Haines c
, Jeroen Molinger d
, John Whittle e
,
David B. MacLeod d
, Stephen A. McClave f
, Paul E. Wischmeyer d, *
a
Duke Ofﬁce of Clinical Research, Duke University School of Medicine, Durham, NC, USA
b
Duke Nutrition Services, Duke University Hospital, Durham, NC, USA
c
Department of Surgery, Division of Trauma Critical Care, and Acute Care Surgery, Duke University School of Medicine, Durham, NC, USA
d
Department of Anesthesiology, Duke University School of Medicine, Division of Critical Care, Durham, NC, USA
e
Centre for Perioperative Medicine, Division of Surgery & Interventional Science, University College London, London, UK
f
Department of Medicine, University of Louisville School of Medicine, Louisville, KY, USA
Article history:
Received 30 June 2021
Accepted 23 July 2021
Keywords:
Critical care
Intensive care unit
Nutrition status
Indirect calorimetry
SARS-CoV-2
Energy expenditure
s u m m a r y
Background & aims: Indirect calorimetry (IC) is the gold-standard for determining measured resting
energy expenditure (mREE) in critical illness. When IC is not available, predicted resting energy
expenditure (pREE) equations are commonly utilized, which often inaccurately predict metabolic de-
mands leading to over- or under-feeding. This study aims to longitudinally assess mREE via IC in critically
ill patients with SARS-CoV-2 (COVID-19) infection throughout the entirety of, often prolonged, intensive
care unit (ICU) stays and compare mREE to commonly utilized pREE equations.
Methods: This single-center prospective cohort study of 38 mechanically ventilated COVID-19 patients
from April 1, 2020 to February 1, 2021. The Q-NRG® Metabolic Monitor was used to obtain IC data. The
Harris-Benedict (HB), Mifﬂin St-Jeor (MSJ), Penn State University (PSU), and weight-based equations
from the American Society of Parenteral and Enteral Nutrition e Society of Critical Care Medicine
(ASPEN-SCCM) Clinical Guidelines were utilized to assess the accuracy of common pREE equations and
their ability to predict hypo/hypermetabolism in COVID-19 ICU patients.
Results: The IC measures collected revealed a relatively normometabolic or minimally hypermetabolic
Original article
, Jeroen Molinger d
, John Whittle e
,
David B. MacLeod d
a
b
c
d
e
f
Article history:
s u m m a r y
Clinical Nutrition ESPEN
journal homepage: http://www.clinicalnutritionespen.com
Published Online: Clinical Nutrition ESPEN, 8/2021

Comparison of Predictive Energy Expenditure Equations to Measured Energy
Expenditure Via IC in Critically Ill COVID-19 Patients
ICU= Intensive CareUnit, IC= Indirect Calorimetry,MSJ= Mifflin St. Jeor,HB= Harris Benedict,PSU= PennState University,SEM=StandardErrorof Mean
Indirect calorimetry REE in COVID-19 ICU patients by Intubation week
Week 1
(n=27)
Week 2
(n=16)
Week 3
(n=8)
Weeks 4-7
(n=8)
IC kcal/kg admit wt
(mean, SEM)
21.6 (1.1) 23.1 (2.4) 28.0 (1.9) 27.9 (2.1)
% of Harris
Benedict 113.1 (4.3) 122.3 (9.9) 142.1 (9.8) 147.2 (10.5)

15
20
25
30
MV Week 1 MV Week 2 MV Week 3 MV Weeks 4-7
IC mREE
ASPEN-SCCM
(Upper-End-
30 kcal/kg)
PSU
ASPEN-SCCM
Lower-End
(25 kcal/kg)
Harris-Benedict
MSJ
Kcal/Kg/Day Measured REE Via Indirect Calorimetry Versus Commonly Used
Predictive Equations in COVID-19 ICU Patients

Measured REE Via Indirect Calorimetry in OBESE vs.
NON-OBESE COVID-19 ICU Patients

“This study shows a previously unreported & unique pattern of a
prolonged hypermetabolic stress response to critical illness seen
only in patients infected by the SARS-CoV-2 virus & perhaps in
some severely burned patients”
Conclusions:
This prolonged hypermetabolic response
pattern appeared more significant in non-obese
verses obese patients.
, Jeroen Molinger d
, John Whittle e
,
David B. MacLeod d
a
b
c
d
e
f
Article history:
Keywords:
Critical care
Intensive care unit
Nutrition status
SARS-CoV-2
Energy expenditure
s u m m a r y
Original article
, Jeroen Molinger d
, John Whittle e
,
David B. MacLeod d
a
b
c
d
e
f
Article history:
s u m m a r y

“Indirect calorimetry is essential for nutritional targets in COVID-19 ICU
pts, preferably repeated measures longitudinally, as predictive energy
equations do not accurately predict actual mREE and/or account for
progressive hypermetabolism in COVID-19”
, Jeroen Molinger d
, John Whittle e
,
David B. MacLeod d
a
b
c
d
e
f
Article history:
Keywords:
Critical care
Intensive care unit
Nutrition status
SARS-CoV-2
Energy expenditure
s u m m a r y
Original article
, Jeroen Molinger d
, John Whittle e
,
David B. MacLeod d
a
b
c
d
e
f
Article history:
s u m m a r y
Conclusions:
If IC is unavailable, PSU 2003b & 2010 (2003b for
<60 y, and PSU 2010 for >60 y) should be used to
predict energy expenditure

20
15
30
35
40
45
1.5
2.0
2.5
Kcal/kg/day Protein (g/kg/d)
25 0.5
Targeted Nutrition Delivery in Critical Illness
ICU
Intubations
Total Kcal
Delivery in Well
Nourished Pt
Activity/
Rehab
Increases
Severe Malnutrition
BMI < 25?
(0-5 d Post ICU-admit)
Acute phase Chronic phase
(5+ days Post ICU-admit)
Recovery Phase
(Post-ICU Discharge)
1.0
Wischmeyer PE. Crit Care Clin 34:107-125. 2018
“Traditional Patient
Proposed Kcal
Delivery”
“COVID-19 Patient
Proposed Kcal
Delivery”

NEW 2021 ASPEN ICU Nutrition Guidelines
There is no significant difference in clinical
outcomes between early EN or PN
(Strong Recommendation, Evidence Grade-High)
J Parenter Enteral Nutr. 46: 12– 41, 2022.
Because similar energy intake provided by PN or EN
led to no differences in risk/harm:
We recommend either PN or EN is acceptable
When similar energy is delivered by PN or EN early in
critical illness for relatively short periods of time,
clinical outcomes are similar.

Using Indirect Calorimetry in Clinical Practice
Wischmeyer PE et al, Indirect Calorimetry is Essential for Optimal Nutrition Therapy in the ICU, Accepted, Nutrition in Clinical Practice,2021

Carbohydrate Lipid
Electrolytes,
Trace
Elements
Protein
Nutrition must be the complete package...

Can’t build a house without bricks...
Protein
is Fundamental...

Energy Expenditure and Protein
Requirements 1.8-Fold Max Increase at Day 20
4-Fold Increase in Protein Loss Day 1
Fürst P, Protein and amino acid metabolism: Composition of stressed and nonstressed states, In Cresci G (ed), Nutrition
support for the critically ill patient, Taylor & Francis (CRC), Boca Raton, 2005 pg 29

Catabolic Response to Stress and Injury
Exogenous
Glucose Kcal
Delivery?
Text
Early
Protein Delivery
May be Essential
Due to
Catabolism!

Early Catabolic Response to Critical Illness and Trauma
Body Can Generate up to 50-75% of Glucose Requirements in Early Acute Phase !
Lower Early
Exogenous Non-
protein Kcal
Delivery?
Text
Early
Protein Delivery
May be Essential Due
to Catabolism!
(Start at 0.8 g/kg/d ->
1.2-2.0 g/kkg/d
Post ICU day 3)

Defining anabolic resista
Defining anabolic resistance: implications
for delivery of clinical care nutrition
Robert W. Mortona
, Daniel A. Traylora
, Peter J.M. Weijsb,c,d
,
and Stuart M. Phillipsa
Purpose of review
Skeletal muscle mass with aging, during critical care, and following critical care is a determinant of quality
of life and survival. In this review, we discuss the mechanisms that underpin skeletal muscle atrophy and
recommendations to offset skeletal muscle atrophy with aging and during, as well as following, critical care.
Recent findings
Anabolic resistance is responsible, in part, for skeletal muscle atrophy with aging, muscle disuse, and
during disease states. Anabolic resistance describes the reduced stimulation of muscle protein synthesis to a
given dose of protein/amino acids and contributes to declines in skeletal muscle mass. Physical inactivity
induces: anabolic resistance (that is likely exacerbated with aging), insulin resistance, systemic
inflammation, decreased satellite cell content, and decreased capillary density. Critical illness results in
rapid skeletal muscle atrophy that is a result of both anabolic resistance and enhanced skeletal muscle
breakdown.
Summary
Insofar as atrophic loss of skeletal muscle mass is concerned, anabolic resistance is a principal determinant
of age-induced losses and appears to be a contributor to critical illness-induced skeletal muscle atrophy.
Older individuals should perform exercise using both heavy and light loads three times per week, ingest at
least 1.2 g of protein/kg/day, evenly distribute their meals into protein boluses of 0.40 g/kg, and consume
g anabolic resistance: implications
very of clinical care nutrition
Robert W. Mortona
,
eview
e mass with aging, during critical care, and following critical care is a determinant of quality
vival. In this review, we discuss the mechanisms that underpin skeletal muscle atrophy and
ons to offset skeletal muscle atrophy with aging and during, as well as following, critical care.
ngs
stance is responsible, in part, for skeletal muscle atrophy with aging, muscle disuse, and
e states. Anabolic resistance describes the reduced stimulation of muscle protein synthesis to a
protein/amino acids and contributes to declines in skeletal muscle mass. Physical inactivity
bolic resistance (that is likely exacerbated with aging), insulin resistance, systemic
decreased satellite cell content, and decreased capillary density. Critical illness results in
muscle atrophy that is a result of both anabolic resistance and enhanced skeletal muscle
ophic loss of skeletal muscle mass is concerned, anabolic resistance is a principal determinant
d losses and appears to be a contributor to critical illness-induced skeletal muscle atrophy.
uals should perform exercise using both heavy and light loads three times per week, ingest at
protein/kg/day, evenly distribute their meals into protein boluses of 0.40 g/kg, and consume
2 h of retiring for sleep. During critical care, early, frequent, and multimodal physical
ombination with early, enteral, hypocaloric energy (!10–15 kcal/kg/day), and high-protein
day) provision is recommended.
utor of age-induced, a major contributor of disuse-
induced, and a secondary contributor to critical
DOI:10.1097/MCC.0000000000000488
1070-5295 Copyright ! 2018 Wolters Kluwer Health, Inc. All rights reserved. www.
Copyright © 2018 Wolters Kluwer Health, Inc. Unauthorized reproduction of this

Protein Intake to Optimize Muscle Gain
Frank
Zane
Age
70
Recommendations for maintaining skeletal muscle mass in healthy and cr
Protein Delivery
FIGURE 3. Recommendations for mainta
Strength Training
least 1.2 g of protein/kg/day, evenly distribute their meals into protein boluses of 0.40 g/kg, and cons
protein within 2 h of retiring for sleep. During critical care, early, frequent, and multimodal physical
therapies in combination with early, enteral, hypocaloric energy (!10–15 kcal/kg/day), and high-prot
(>1.2 g/kg/day) provision is recommended.
Keywords
amino acids, muscle, protein turnover
INTRODUCTION
Aging results in progressive and slow loss of skeletal
muscle (sarcopenia) [1]. In contrast, critical illness
results in rapid skeletal muscle atrophy [2,3]. Skeletal
muscle atrophy is a risk factor for all-cause morbidity
and mortality both as we age [4,5] and during critical
illness [6,7]. Skeletal muscle mass is determined by
the balance in muscle protein turnover [e.g. the
algebraic difference between muscle protein synthe-
sis (MPS) and muscle protein breakdown (MPB)].
Anabolic resistance is the inability of an anabolic
stimulus (e.g. protein provision, hormonal stimula-
tion, and/or muscle contraction) to stimulate MPS
and occurs with increasing age [8
&
,9,10
&
,11
&
,12], peri-
ods of inactivity [13,14], and during critical illness
[15,16,17
&&
,18,19]. This review aims to provide evi-
dence that anabolic resistance is a principal contrib-
illness-induced skeletal muscle atrophy. We di
how whole-body and muscle protein turnove
altered with age, inactivity, and critical illness b
elaborating on how insulin resistance, syst
inflammation, satellite cells, and alterations in
microvasculature contribute to anabolic resista
The latter portion of the review prescribes strat
a
Department of Kinesiology, McMaster University, Hamilton, C
b
Department of Nutrition and Dietetics, VU University, c
Departm
Intensive Care Medicine, VU Medical Center and d
Department o
tion and Dietetics, Amsterdam University of Applied Sciences, A
dam, The Netherlands
Correspondence to Professor Stuart M. Phillips, PhD, Departm
Kinesiology, McMaster University, 1280 Main Street West, Hamilt
L8S 4L8, Canada. Tel: +1 905 525 9140 x24465;
e-mail: phillis@mcmaster.ca
Adapted from:

Defining anabolic resista
Tx?:
HMB
Oxandrolone
Propranolol
Defining anabolic resistance: implications
for delivery of clinical care nutrition
Robert W. Mortona
,
Purpose of review
Skeletal muscle mass with aging, during critical care, and following critical care is a determinant of quality
of life and survival. In this review, we discuss the mechanisms that underpin skeletal muscle atrophy and
recommendations to offset skeletal muscle atrophy with aging and during, as well as following, critical care.
Recent findings
Anabolic resistance is responsible, in part, for skeletal muscle atrophy with aging, muscle disuse, and
during disease states. Anabolic resistance describes the reduced stimulation of muscle protein synthesis to a
given dose of protein/amino acids and contributes to declines in skeletal muscle mass. Physical inactivity
induces: anabolic resistance (that is likely exacerbated with aging), insulin resistance, systemic
inflammation, decreased satellite cell content, and decreased capillary density. Critical illness results in
rapid skeletal muscle atrophy that is a result of both anabolic resistance and enhanced skeletal muscle
breakdown.
Summary
Insofar as atrophic loss of skeletal muscle mass is concerned, anabolic resistance is a principal determinant
of age-induced losses and appears to be a contributor to critical illness-induced skeletal muscle atrophy.
Older individuals should perform exercise using both heavy and light loads three times per week, ingest at
least 1.2 g of protein/kg/day, evenly distribute their meals into protein boluses of 0.40 g/kg, and consume
g anabolic resistance: implications
very of clinical care nutrition
Robert W. Mortona
,
eview
e mass with aging, during critical care, and following critical care is a determinant of quality
vival. In this review, we discuss the mechanisms that underpin skeletal muscle atrophy and
ons to offset skeletal muscle atrophy with aging and during, as well as following, critical care.
ngs
stance is responsible, in part, for skeletal muscle atrophy with aging, muscle disuse, and
e states. Anabolic resistance describes the reduced stimulation of muscle protein synthesis to a
protein/amino acids and contributes to declines in skeletal muscle mass. Physical inactivity
bolic resistance (that is likely exacerbated with aging), insulin resistance, systemic
decreased satellite cell content, and decreased capillary density. Critical illness results in
muscle atrophy that is a result of both anabolic resistance and enhanced skeletal muscle
ophic loss of skeletal muscle mass is concerned, anabolic resistance is a principal determinant
d losses and appears to be a contributor to critical illness-induced skeletal muscle atrophy.
uals should perform exercise using both heavy and light loads three times per week, ingest at
protein/kg/day, evenly distribute their meals into protein boluses of 0.40 g/kg, and consume
2 h of retiring for sleep. During critical care, early, frequent, and multimodal physical
ombination with early, enteral, hypocaloric energy (!10–15 kcal/kg/day), and high-protein
day) provision is recommended.
induced, and a secondary contributor to critical
DOI:10.1097/MCC.0000000000000488
1070-5295 Copyright ! 2018 Wolters Kluwer Health, Inc. All rights reserved. www.
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Extra-Protein Reduces
Mortality!
Every additional
30 g/d protein
given...
Mortality decreased!
Alberda,C, Heyland D et al
Intensive Care Med.35:1728-37. 2009

Resting energy expenditure, calorie and
protein consumption in critically ill patients:
a retrospective cohort study
Oren Zusman1*
, Miriam Theilla2,3
, Jonathan Cohen2,4
, Ilya Kagan2
, Itai Bendavid2
and Pierre Singer2,4
Abstract
Background: Intense debate exists regarding the optimal energy and protein intake for intensive care unit (ICU)
patients. However, most studies use predictive equations, demonstrated to be inaccurate to target energy intake. We
sought to examine the outcome of a large cohort of ICU patients in relation to the percent of administered calories
divided by resting energy expenditure (% AdCal/REE) obtained by indirect calorimetry (IC) and to protein intake.
Methods: Included patients were hospitalized from 2003 to 2015 at a 16-bed ICU at a university affiliated, tertiary care
hospital, and had IC measurement to assess caloric targets. Data were drawn from a computerized system and
included the % AdCal/REE and protein intake and other variables. A Cox proportional hazards model for 60-day
mortality was used, with the % AdCal/REE modeled to accommodate non-linearity. Length of stay (LOS) and length of
ventilation (LOV) were also assessed.
Results: A total of 1171 patients were included. The % AdCal/REE had a significant non-linear (p < 0.01) association
with mortality after adjusting for other variables (p < 0.01). Increasing the percentage from zero to 70 % resulted in a
hazard ratio (HR) of 0.98 (CI 0.97–0.99) pointing to reduced mortality, while increases above 70 % suggested an
increase in mortality with a HR of 1.01 (CI 1.01–1.02). Increasing protein intake was also associated with decreased
mortality (HR 0.99, CI 0.98–0.99, p = 0.02). An AdCal/REE >70 % was associated with an increased LOS and LOV.
Conclusions: The findings of this study suggest that both underfeeding and overfeeding appear to be harmful to
critically ill patients, such that achieving an Adcal/REE of 70 % had a survival advantage. A higher caloric intake may
also be associated with harm in the form of increased LOS and LOV. The optimal way to define caloric goals therefore
requires an exact estimate, which is ideally performed using indirect calorimetry. These findings may provide a basis for
future randomized controlled trials comparing specific nutritional regimens based on indirect calorimetry measurements.
Keywords: Indirect calorimetry, Nutrition, Protein, Resting energy expenditure, Calorie consumption
Background
The provision of nutritional support for critically ill pa-
tients continues to be the subject of intense debate, with
described [6, 7]. Importantly, for many reasons either by
design or default, many critically ill patients do not re-
ceive their full energy requirements and the proportion
RESEARCH
Resting energy
protein consum
Zusman et al. Critical Care (2016) 20:367
DOI 10.1186/s13054-016-1538-4
1171 pts in ICU > 96 h & Measured Energy Expenditure.
Lowest Mortality- 1.3 g/kg/d Protein

20
15
30
35
40
45
1.5
2.0
2.5
Kcal/kg/day Protein (g/kg/d)
25 0.5
Nutrition Delivery Targets in COVID-19 from LEEP-COVID Data
ICU
Intubations
Activity/
Rehab
Increases
(Day 0-7 post-ICU admit)
Acute phase Chronic phase
(2nd-3rd ICU week)
Recovery Phase
(Post-ICU Discharge)
1.0
Adapted from Wischmeyer PE. Crit Care Clin 34:107-125. 2018
“Traditional ICU
Patient Proposed
Kcal Delivery”
“COVID-19 Patient
Proposed Kcal
Delivery”
Protein Delivery

International ICU Nutrition Survey

%
receive/prescribed
0
10
20
30
40
50
60
70
80
90
100
Canada Aust/NZ USA Europe Latin America Asia Total
54.5
54.5
51.3
60.7
48.9
61.1
58.9
54.5
54.5
51.3
60.7
48.9
61.1
58.9
We Underfeed For 2 Weeks...
https://www.criticalcarenutrition.com

0.6 g/kg/d
for 2 weeks in ICU!
Average Protein
Delivery
Guideline Protein: 1.2 -2.0 g/kg/d

Improved Protein and Kcal Delivery in 1st
ICU Week Improves Survival in Hi-Risk Pts
Wei X, et al. Crit Care Med. 2015;43(8):1569-1579.
0-50% Kcals
N= 475 Pts on Ventilator > 8 Days
50 - < 80% Kcals
> 80% Kcals

Improved Protein and Kcal in First
Week in MICU Improves Quality of Life
N= 475 Pts on Ventilator > 8 Days
Subgroup Analysis of the Effect of Nutritional
Adequacy on SF-36 scores
! !
Nutritional Adequacy
a
per 25% increase
Medical Patients
SF-36 N
b
Adjusted Estimate
c,
d
(95% CI)
P
PF: 3-mo 128 10.9 (4.3, 17.6) 0.001
PF: 6-mo 144 6.7 (0.2, 13.2) 0.04
RP: 3-mo 127 13.1 (6.7, 19.6) <.001
RP: 6-mo 144 7.2 (0.9, 13.4) 0.03
PCS: 3-mo 125 3.5 (1.2, 5.8) 0.003
PCS: 6-mo 142 2.5 (0.2, 4.9) 0.03

How you feed in the 1st
week in ICU...
Changes Pts
QoL
Months Later!!

-On Trophic EN at 15 cc/h
- Stopped multiple times for proning, GRV
> 500
-Receiving < 25% of protein/kcal needs
In ICU- Paralyzed and Prone- Day 4
-BP: 100/60 on 0.04 ug/kg/min levophed
-MV O2 sat- 81%, Lactate 1.0

Achieving Goal EN in
COVID Patients is…
VERY DIFFICULT!
The Challenge is…
And…GI Tract Involvement
is Common in COVID-19

CRRT
Paralyzed
Norepinephrine
Prone Position
Often Obese
EN often
< 50% goal!

-GI symptoms occur in 20-70% of COVID-19 Pts
-Include: Diarrhea, Nausea/Vomiting, Abd Pain,
Liver Injury
- ~50% of pts have stool w/ +COVID19
- SARS-COV-2 viral receptor angiotensin
converting enzyme 2 highly expressed in GI
epithelial cells
REVIEW
Covid-19 and the digestive system
Sunny H Wong,*,†
Rashid NS Lui*,†
and Joseph JY Sung*,†
*Institute of Digestive Disease, and †
Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, Hong Kong
Key words
coronavirus, Covid-19, diarrhea, gastrointestinal
infection, pneumonia.
Accepted for publication 24 March 2020.
Correspondence
Professor Joseph JY Sung, Department of
Medicine and Therapeutics, The Chinese
University of Hong Kong, 9/F Lui Che Woo
Clinical Sciences Building, Prince of Wales
Hospital, Shatin, Hong Kong.
Email: jjysung@cuhk.edu.hk
Declaration of conflict of interest: The authors
declare no conﬂict of interest.
Abstract
The novel coronavirus disease is currently causing a major pandemic. It is caused by the
severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a member of the
Betacoronavirus genus that also includes the SARS-CoV and Middle East respiratory syn-
drome coronavirus. While patients typically present with fever and a respiratory illness,
some patients also report gastrointestinal symptoms such as diarrhea, vomiting, and ab-
dominal pain. Studies have identiﬁed the SARS-CoV-2 RNA in stool specimens of in-
fected patients, and its viral receptor angiotensin converting enzyme 2 was found to be
highly expressed in gastrointestinal epithelial cells. These suggest that SARS-CoV-2 can
actively infect and replicate in the gastrointestinal tract. This has important implications
to the disease management, transmission, and infection control. In this article, we review
the important gastrointestinal aspects of the disease.
Journal of Gastroenterology of Hepatology
Online: 3/2020: doi:10.1111/jgh.15047

Personalization of Early
Nutrition Delivery by
Disease Type?
COVID-19 specific...?
New Data!

Early EN Improves Clinical Outcomes in COVID-19
- Retrospective cohort study on timing of EN initiation in patients undergoing MV
Methods:
Population:
- 851 patients from multiple U.S. hospitals with COVID-19 on MV
- Early EN (within 3 days of MV) vs. Late EN (after 3 days post-ICU)
- Premier Database- 75 U.S. Hospitals contributed COVID-19 data- 265,298 pts total
- Inverse-probability-of-treatment weighting (IPTW) to control confounding variables
- Multivariable logistic regression model
DukeCAPER
DukeCAPER
Krista Haines, Virginia Parker, Tetsu Ohnuma, Vijay Krishnamoorthy, Karthik Raghunathan,
Suela Sulo, Kirk W. Kerr, Beth Besecker, Bridget A. Cassady, Paul Wischmeyer
Submitted for Publication: Under Review

Covid-19 Patients Are Being STARVED in ICU!
Time to EN Start (N)
Mean EN
Start
Std Dev
Early EN < 3 d 513 2.4 0.8
Late EN > 3 d 348 9.9 8.4
> 40% of COVID-19 ICU Pts Not
Fed Any EN for > 3 d
Mean Time to EN Start in Late EN group
was ~10 days!

Early EN Improves Clinical Outcomes in
COVID-19
Early EN Reduces Mechanical Ventilation Days
(HR=1.25, 95% CI:1.01-1.54)
Early EN Reduces ICU LOS
(Hazard Ratio [HR] =1.39, 95% CI:1.15-1.68)
Early EN Reduces Hosp LOS
(HR=1.53, 95% CI:1.23-1.91)

Early EN Improves Clinical Outcomes in
COVID-19
No Difference in Mortality
Early EN Reduces Hospital Costs
(-$22,443, 95%CI:-$32,342 to -$12,534)

We Must Start EN and/or PN
Sooner in COVID-19 ICU
Patients to Optimize
Outcomes!

SCCM/ASPEN Recommend Early TPN in COVID!
“In contrast to other populations of
critically ill patients...
…a lower threshold for switching
to PN in the patient with COVID-19
disease needs to be utilized.”
Martindale et al.. SCCM/ ASPEN Guidelines Apr 2020

Does Parenteral
Nutrition (TPN) lead
to increased risk of
infection in ICU pts?
A. Yes
B. No

Four New Large Randomized
Trials Show....
TPN Does Not
Increase
Infection Risk
in 2022!
Doig et al. JAMA, 2013
Heidegger et al, Lancet, 2013
CALORIES Trial, NEJM, 2014
NUTRIREA-2, Lancet, 2017

TPN No Longer Related To
Infection in 2022!
- No Longer “Hyperalimentation”
- We Now Control Hyperglycemia
- Improved Protein Delivery
- Better Central Line Care
Improved Lipids?

Finally!....New IV Lipids in U.S!

Lipid Choice
Matters To
Outcome!

If Your Hospital is Still
Using Pure Soybean Oil
in TPN...
STOP!

If Your Hospital is Still
Using Pure Soybean Oil
in TPN...
Your Patients
Deserve Better!

Switch to Olive Oil or
Fish Oil PN Lipid Now!

Rapidly developing severe hypertriglyceridemia
in even low propofol does have been seen in
COVID pts
Monitor serum triglyceride levels in COVID-19 pts
receiving propofol and/or IV lipids (w/in 24 h)
post-initiation of lipids or propofol
COVID-19 Hypertriglyceridemia
SCCM/ASPEN COVID-19 Guidelines

New Oliguria...
Urine Output - 10-15 cc/h
Creatinine - 4.6 mg/dL
CRRT Initiated...

ICU Day 21…
Pt Develops
Pancytopenia
(Plts- 27, WBC-1.0)
All drug-related
etiologies ruled-out...

What CVVH related metabolic/
nutritional loss may be
causing pancytopenia?
Copper level < 10 umol/L
Copper Chloride- 4 mg/d IV given

Vitamin/Nutrient Losses in CRRT

2016 ASPEN/SCCM Guidelines
[Quality of Evidence: Very Low]
We recommend pts on CRRT or
freq. HD receive increased
protein, up to
2.5 g/kg/d
Protein should not be restricted in
AKI pts to avoid or delay initiating
dialysis therapy!

Malnutrition, CVVH and Complications
Wischmeyer PE. Nutrition in Sepsis
Crit Care Clin 34:107-125. 2018
Pancytopenia/Neutropenia: Copper, Vitamin B12, Folate, Vitamin B6
Lactic Acidois: Thiamine
Encephalopathy/Delerium:
Vit. B6 (50 mg IV q day), Thiamine, Vit. B12, Folate
Prolonged Weakness/Neuromuscular Dysfunction (Can Be Permanent!)
Carnitine, Copper

Incidence & Role of Severe Micronutrient
and Vitamin Deficiencies Caused by
Continuous Renal Replacement Therapy
(CRRT) in Critically Ill Patients
Investigator Initiated Trial:
Duke CAPER Health Outcomes
Group

89.6% of CRRT pts developed 1 deficiency in
trace/water-soluble vitamins
≥

Conclusions
A Majority of Patients on CRRT > 5-7 Days
Develop Significant Nutrient Deficiencies
Copper (71%), Vit B6 (71%)
Selenium (43%), Carnitine (38%)
is Most Common in CRRT
Zinc (50%), Vit B6(40%), & Selenium (29%)
Most Common in Nutritionally “At-Risk”

Conclusions
Carnitine & Selenium Deficiency Show
Signal for Increased Mortality in CRRT
Any Nutrient Deficiency in Any Patient
(CVVH or NOT) ↑ Mortality Risk 2.4-fold
Other Nutrient Deficiencies Show Initial
Trends for Increased Mortality in CRRT

Current Opinion in Critical Care: Online, May, 2021
CVVH and Malnutrition:
Must Check…& Continue to Replete!
Would also check Vitamin C, Folate, Vit B12, Vit D
Copper, Carnitine, Zinc, Thiamine, Selenium,
Vit. B6 Need Continuous Monitoring and
Repletion While on CVVH q weekly

Started on Oral Nutrition...
Will they eat enough on her own?
Recovering COVID-19 Patients…
Not Likely!!
Average Post-ICU
Intake: 700 kcal/d

Oral Nutrition
Supplements (ONS)
Only Way To Deliver
Post-ICU Nutrition
Needs!

ONS Reduces Hospital Mortality
OR 0.61 [95% CI 0.48–0.78], p < 0.001
Meta-analysis of 11 trials, n = 1965;
Control ONS
Stratton et al, 2003
Book: Disease-related malnutrition: an evidence-based approach to treatment

SECTION 5
ONS Reduces Hospital Complications
Stratton et al, 2003
Book: Disease-related malnutrition: an evidence-based approach to treatment
OR 0.31; 95% CI 0.17–0.56, p < 0.001
Meta-analysis of 7 trials, n = 384
Control ONS

Every $1 spent on ONS...
Saves
$52.63
in hospital costs
ONS Reduces Costs...
Philipson et al.
American Journal of Managed Care
19:121-128, 2013

HP-HMB ONS Reduces Death at 90 d
Post-Hospital Discharge
Deutz NE et al, Clinical Nutrition, 35:18-2, 2016
HP-HMB ONS
Placebo
78 Center, RCT,
n=652 pts

HP-HMB Associated with 50% Reduction in Mortality
Day 30 Day 60 Day 90
0%
5%
10%
15%
Mortality in all patients
Placebo
HP-HMB
P=0.049
P=0.020
P=0.018
The number
needed to treat
(NNT) to prevent
1 death was
20.3
Deutz NE, et al., Clinical Nutrition (2016) 2016;35(1):18-26

Conclusions
Use of ONS in
Post-ICU pts is essential!
Highly Effective
Intervention To Improve
Clinical Outcomes and
Reduce Costs

Is “Right”
Nutrition Enough
to Win the War?

SRM SRM+NS Partial SRM
Disease-related Malnutriion
60
70
80
90
100
1 2 3 4 5 6 7
Time
Lean
Body
Mass
(%)
Calorie Delivery Alone Won’t Stop LBM Loss!
Acute (ICU)
Malnutrition
Acute (ICU)
Malnutrition +
Nutrition Support
Chronic Dz
Malnutrition
Chronic Dz
Malnutrition + Nutrition Support
Jensen et al, JPEN, 34:156-159, 2010

“Survival of
the Fittest”
We Are NOT
Evolved For
This!
Hypermetabolism &
Catabolism Can Persist
for Months - > 2 Years!

Can We Learn From Elite
Athletes…
…To help our pts?

Take “Right”
Anabolic
Agents!?

Should NOT be given in
“acute phase or early ICU”
Post-acute phase
testosterone much more
promising!
Testosterone and
Analogs

Testosterone Levels in ICU:
Must Check…
Virtually All Testosterone Levels I Check Are:
Wischmeyer PE. Nutrition in Sepsis Crit Care Clin 34:107-125. 2018
Severely Deficient
After 3-5 days in ICU!
Wischmeyer PE et al Curr Opin Crit Care. Online 8/2020

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