THE PEPaNIC PAPERSReviewing a hot topic in critical care nutrition

Heather Erzen, MS, RD, CNSC

Objectives

• Describe the pathophysiology of critical illness

• Cite at least 2 findings from a large, multi-center RCT

studying early versus late initiation of parenteral

nutrition support

• Identify at least 3 best practices in pediatric critical

care nutrition

Critical Illness

• Broadly, anything requiring intensive care admission

• Infection, sepsis, trauma, surgery, pancreatitis, burns,

hemmorhage, ischemia triggers inflammatory response

Sharma, 2019

The inflammatory response

• Initial focus at the site of infection or injury– Activation of macrophages, monocytes, neutrophils

• Then the compliment system which leads to vasodilation and increased capillary permeability– More macrophages, which further enhances phagocytic activity

• Release of tumor necrosis factor (TNF), interleukin (IL)-1, IL-2, IL-6 and other proinflammatory cytokines– Once high concentration at local site, then systemic circulation

• Systemic inflammatory response syndrome (SIRS)

• EG, sepsis is life threatening organ dysfunction caused by dysregulated host response to infection

Sharma, 2019

The ebb phase

• Immediately after injury, infection

• Hemodynamic instability, low cardiac output, low body

temperature, elevated glucagon, catecholamines and

free fatty acids, lower metabolic rate

• Duration varies, 24-48 hours or longer

Sharma, 2019

The flow phase

• Higher cardiac output, higher metabolic rate and oxidation of all fuel sources

• Balance of pro-inflammatory and anti-inflammatory responses

• Anti-inflammatory cytokines (IL-4, IL-10) versus pro-inflammatory cytokines (TNF-alpha, IL-2)

• Role of nutrition: modulating inflammatory response, maintaining immune function, mitigating catabolism of lean tissue, maintaining gut and lung mucosal barrier when generally patients are unable to eat by mouth

Sharma, 2019

Simple starvation

• Hypometabolism

• Glucose preserved for brain and RBCs

• Mobilizing glycogen stores, gluconeogenesis from amino

acids, glycerol, lactate

• CNS ketoadaptation

• Spares muscle and liver glycogen and prevents

significant muscle wasting

Sharma, 2019

Fasting in critical illness

• Carbohydrate metabolism:

• Hyperglycemia + insulin resistance

• Pro-inflammatory cytokines signal release of catabolic

hormones glucagon, catecholamines, cortisol which

potentiate glycogenoloysis and gluconeogenesis

• CNS and inflammatory cells require glucose

• Glycogen stores are gone in hours

Sharma, 2019

Critical illness metabolism

• Protein metabolism:

• Main energy source during the acute phase

• Skeletal muscle, connective tissue, gastrointestinal

tract

• Used for gluconeogenesis but also acute phase protein

synthesis (haptoglobin, CRP)

Sharma, 2019

Critical illness metabolism

• Fat metabolism:

• Stress hormones stimulate lipase

• Releases triglycerides (glycerol +3 fatty acids)

• FFA get stuck in cytosol

• In order to convert to fat to ATP, we need oxygen and

fully functioning mitochondria, both often impaired

Sharma, 2019

Let’s pause here for a moment.

Goals of nutrition support in critical care

• Provide substrate to minimize catabolism of lean tissue

• Especially important in individuals without reserve

– Malnutrition

– Neonates

• If unable to provide EN, when do we start PN?

Mehta, 2017

EPaNIC - the context

• European guidelines historically -

• Early initiation of PN within 48 hrs in adults

• US/Canada practicing starting on hospital day 8

• EPaNIC trial comparing practice difference

• N = 4640, multicenter RCT

• Similar mortality and survival rates

• Early PN had higher rates of infection, increased days on

vent, increased costs, increase in renal replacement therapy

Caesar, 2011

PEPaNIC – part 1

• Multi-center RCT included Belgium, the Netherlands, Canada

• 1440 critically ill children

• Term infants, up to 17 years old

• Eligible if in ICU > 24 hrs

• STRONGkids risk is > 2

• Randomized to receive: – Early PN, supplemental PN in first 24 hrs if EN < 80% goal

– Late PN, no PN for first 7 days of ICU admission

Fivez, 2016

PEPaNIC – part 1

• Late PN given D5 or D10 if hypoglycemic

• Both groups received trace elements, vitamins, minerals

• Both groups received early EN

• All centers used protocolized feeding

• Outcomes adjusted for diagnostic group, age group,

severity of illness, risk of malnutrition and treatment

center

Fivez, 2016

PEPaNIC – part 1

• Late PN associated with fewer new infections– Blood stream and airway (p < 0.05)

– Adjusted odds ratio 0.48

• Late PN associated with shorter LOS in ICU by 2.7 days

• Hypoglycemia in late PN group 9.1%

• Late PN associated with fewer days on vent 6.4 vs 4.4 days

• Late PN associated with shorter hospital stay

• Total direct medical costs considerably lower with late PN– Greatest savings thought to be r/t new infection

• Higher CRP in late PN group

Fivez, 2016

Ready for a practice change?

• 209 term neonates < 28 days

• Further divided < 1 day, < 1 week

• PICU infections showed a trend, but not significance in

multi-variate analysis

• Duration of PICU + duration mechanical support did

• More hypoglycemia (23%) in late PN group

• In the subset of infants who received no or very little

EN, hypoglycemia was 53%

PEPaNIC - neonates

Van Puffelen, 2018

• Higher average protein dose associated with poor

outcomes

• Less likely to have early discharge from PICU (HR 0.56-

0.71)

• Less likely to wean from vent by day 3 (HR 0.44-0.66)

• Higher lipid doses associated with improved outcomes

PEPaNIC - neonates

PEPaNIC - undernourished

• Cohort 20% malnourished

• Defined by weight-for-age z-score < -2 less than 1 year

or BMI z-score < -2 for those > 1 year

• Severe malnutrition defined < -3 z-score

• Overall, undernourished group had longer ICU- and

hospital LOS than nourished group

• Differences in baseline characteristics/diagnoses

Van Puffelen, 2018

PEPaNIC - undernourished

• Late PN associated with – Significant decrease in new infections

– Significant decrease in ICU and hospital LOS

• Weight deterioration was common – 58% in early PN, 48% in late PN (not significant)

• Weight deterioration showed worse outcomes

• Late PN did not alter weight- z-score deterioration during ICU stay

• Researches speculate that immunosuppression with malnutrition was exaggerated with early PN

Van Puffelen, 2018

Jacobs, 2019

Comparing Impact of late PN

0

0.5

1

1.5

2

2.5

3

New infection Fewer ICU days Fewer vent days

All

Neonates

< 1 week

< 1 day

Malnutrition

*

Odds

rati

o

Were there other unintended

consequences?

• Weight for age on admission and last day in PICU

• Less weight deterioration was associated with shorter

ICU LOS, fewer new infections

• No difference in weight deterioration between groups

• More than half participants were excluded due to

inadequate anthropometric data

PEPaNIC – weight deterioration

Van Puffelen, 2020

PEPaNIC - Weight deterioration

Van Puffelen, 2020

PEPaNIC – development

• Pre-planned 2-year follow up using caregiver reported executive functioning, general intelligence testing

• Children with severe intellectual disability excluded

– 68 in late PN

– 91 in early PN

• Compared to 405 controls

– Matched for age, sex, genetic, socioeconomic, environmental background, siblings and relatives were preferentially recruited

– Excluded if admitted to NICCU/ICU or hospitalized for > 7 days or had other other conditions which would require PN

• Growth, physical ability, neurologic and neurocognitive outcomes

Varstraete, 2019

PEPaNIC - development

• PEPaNIC participants were shorter, weighed less and had smaller HC

• Poorer health status, poorer clinically assessed neurologic exam

• Poorer caregiver reported executive functioning, emotional behavioral problems, clinical tests for intelligence, visual motor integration, alertness, memory

• Late PN showed a trend of being shorter, smaller HC but did not reach significance

• Effects of early PN were more pronounced in infants Varstraete, 2019

PEPaNIC - development

• Late PN associated with improvement in

neurodevelopmental outcomes

– Improved executive functioning (significant)

– Improved inhibitory control, working memory, meta-cognition

• Fewer externalizing behavioral problems

• Better visual-motor integration

Varstraete, 2019

PEPaNIC - development

• Frontal lobe particularly vulnerable to metabolic injury

with inflammation and neuronal damage

• Researchers surmise fasting induced responses in early

critical illness may be beneficial

• Increase in removal and prevention of damaged cells via

autophagy

• Potentially epigenetic changes

Varstraete, 2019

This wasn’t a perfect study.

Limitations of the study

• Did not use indirect calorimetry in 2 centers

• Did not receive standard PN

• Nutrition goals varied among centers

• Provided PN in populations that we would not

• Average length of ICU stay 4 days

• Variable BG control

• How many children received NO EN by hospital day 3-4?

So now what?

Critical Care Nutrition Goals - early EN

• Beyond macronutrient delivery

• Maintains the gut mucosal barrier

• Gut associated lymphoid tissue

• Mitigates gut/lung inflammation via gut/lung axis

• Modulates inflammation

• Outcomes in neonates who received late PN showed less benefit in those who were unable to be enterally fed; only duration of mechanical ventilation was significant in multivariate analysis (Van Puffelen 2018)

Mehta, 2018

• Definition varies

• Low-volume feeds < 25% goal within 6-48 hrs of admission to ICU

• Lower mortality for those with PICU stay > 96 hrs in one multi-center retrospective analysis (Mikhailov, 2014) and a single-center observational study (Bagci, 2018)

• Early EN corresponded with early reached target which was also associated with decreased PICU mortality (Bagci, 2018)

Critical Care Nutrition Goals - early EN

Critical Care Nutrition Goals -

protocolized feeding

• Associated with earlier feeding and more enteral

intakes (Mikhailov, 2014)

• Up to 2/3 nutrition goal associated with improved

outcomes in PICU (Mehta, 2018)

A focus on early full nutrition too soon?

• An active area of research in adult critical care

• Neutral benefit with more enteral feeding

• One RCT showing increased mortality with ARDS with

more enteral nutrition (Braushanewig, 2015)

• Role of suppressed autophagy?

Autophagy

Au

Van Dyke, 2018

Autophagy

Van Dyke, 2018

Autophagy

• Late PN associated with enhanced autophagy in muscle,

less muscle weakness and faster recovery of weakness

in EPaNIC trial (Caesar, 2011)

• Largely no benefit to early supplemental PN as reviewed

by Van Dyke, 2018, with several studies showing harm

• Current practices in critical care are based largely on

observation, expert opinion

• Early EN, protocolized feeding and individualized goals

are the current best practices

• Early, short-term, supplemental PN should be avoided

Closing thoughts

References

• Baǧci, Soyhan, et al. "Early initiated feeding versus early reached target enteral nutrition in critically ill children: An observational study in paediatric intensive care units in Turkey." Journal of Paediatrics and Child Health (2018).

• Braunschweig, Carol A., et al. "Intensive nutrition in acute lung injury: A clinical trial (INTACT)." Journal of Parenteral and Enteral Nutrition 39.1 (2015): 13-20.

• Casaer, Michael P., et al. "Early versus late parenteral nutrition in critically ill adults." New England Journal of Medicine 365.6 (2011): 506-517.

• Doig, Gordon S. and Fiona Simpson. "Early parenteral nutrition in critically ill patients with short-term relative contraindications to early enteral nutrition: A full economic analysis of a multicenter randomized controlled trial based on us costs." ClinicoEconomics and Outcomes Research 5.1 (2013): 369-379.

• Fivez, Tom, et al. "Early versus Late parenteral nutrition in critically ill children." New England Journal of Medicine 374.12 (2016): 1111-1122.

• Mehta, Nilesh M. "Guidelines for the Provision Assessment Nutrition Support ASPEN SCCM." n.d.

• Mikhailov, Theresa A., et al. "Early enteral nutrition is associated with lower mortality in critically ill children." Journal of Parenteral and Enteral Nutrition 38.4 (2014): 459-466.

• Sharma, K., Mogensen, K.M. and Robinson, M.K. (2019), Pathophysiology of Critical Illness and Role of Nutrition. Nutrition in Clinical Practice, 34: 12-22. doi:10.1002/ncp.10232

• Valla, Frédéric V., et al. "Nutritional Status Deterioration Occurs Frequently during Children's ICU Stay." Pediatric Critical Care Medicine (2019).

• Van Dyck, Lisa, Michaël P. Casaer and Jan Gunst. "Autophagy and Its Implications Against Early Full Nutrition Support in Critical Illness." Nutrition in Clinical Practice 33.3 (2018): 339-347.

• van Puffelen, E., et al. "Effect of late versus early initiation of parenteral nutrition on weight deterioration during PICU stay: Secondary analysis of the PEPaNIC randomised controlled trial." Clinical Nutrition 39.1 (2020): 104-109.

• van Puffelen, Esther, et al. "Early versus late parenteral nutrition in critically ill, term neonates: a preplanned secondary subgroup analysis of the PEPaNIC multicentre, randomised controlled trial." The Lancet Child and Adolescent Health 2.7 (2018): 505-515.

• —. "Outcomes of Delaying Parenteral Nutrition for 1 Week vs Initiation Within 24 Hours Among Undernourished Children in Pediatric Intensive Care: A Subanalysis of the PEPaNIC Randomized Clinical Trial." JAMA network open (2018).

• Verstraete, Sören, et al. "Long-term developmental effects of withholding parenteral nutrition for 1 week in the paediatric intensive care unit: a 2-year follow-up of the PEPaNIC international, randomised, controlled trial." 7 (2019).

References