Continuous versus Intermittent Nutrition in Paediatric Intensive Care: a Proof-of-concept

We have recently shown in a large randomised study in paediatric ICIJ patients
that withholding Parenteral Nutrition during the first week of critical
illness, as compared with an early start (<48 hours), reduced length of
intensive care dependency and the number of nosocomial infections. The benefit
of this counterintuitive nutritional strategy, through which low macronutrient
intakes were accepted, is presumed to be caused by activation of autophagy due
to a fasting response. Autophagy is an intracellular recycling process crucial
for maintaining cellular integrity and function. lts protective role against
various forms of critical illness induced organ failure, including ICU acquired
muscle weakness, is strongly activated during periods of fasting. Currently,
artificial feeding is usually administered through continuous infusion,
although solid evidence supporting this practice is lacking. Intermittent, as
compared with continuous, (par) enteral nutrition may provide a more
physiological feeding/fasting pattern which activates autophagy, while
providing sufficient nutrition during critical illness. A physiological
feeding/fasting pattern could also sustain circadian rhythm. Thus, such
strategy could impact essential mechanisms such as immunology, metabolism,
neuropsychology, and pharmacodynamics, to improve recovery from critical
illness.

The main research objectives for the proof-of-concept study are to show the
feasibility and safety of a daily cycle of feeding and fasting in critically
ill children of different age-groups, that will trigger an adequate fasting
response while providing equal amounts of daily nutrients as with standard
continuous feeding. We hypothesize that in critically ill children intermittent
versus continuous feeding is feasible and safe, and will lead to a fasting
response, which could potentially activate autophagy while providing
sufficient nutrition. Ultimately we hypothesize that such strategy will lead to
accelerated recovery and reduced ICU dependency, which is to be tested in a
large multicenter RCT with clinically relevant outcome parameters in a
multicenter setting within the Rotterdam-Leuven consortium.

A randomized non-blinded proof-of-concept study to explore the feasibility and
safety of intermittent feeding in 140 critically ill children stratified over
three age groups; neonates (*28d), infants (<1yr) and children (*1yr) while
overall providing sufficient amounts of daily nutrients as with standard
continuous feeding. Based upon adult pilot data and from the PEPaNIC RCT
(n=1440, CCMO projectnr: NL38772.000.12 / MEC-2012-412 / EudraCT 2012-000811-10
/ S54127 / NCT01536275), a 12hrs fasting period in older children is expected
to be optimal. During health, fasting periods (overnight) are age-dependent and
therefore the fasting period are adjusted for infants to 10hrs and for neonates
to 8hrs. The study intervention will last a maximum of 14 days or PICU
discharge, or the ability for *oral nutrition*, whichever comes first. Methods
for evaluating the fasting response, autophagy and the circadian rhythm in the
planned subsequent RCT will be tested during this proof-of-concept study.

The *Continuous Nutrition* strategy will be the nutritional management
currently recommended and acting as *control*. Both enteral nutrition (EN) and
(after day 7) parenteral nutrition (PN) will be provided continuously 24
hrs/day. The *Intermittent Nutrition* strategy, acting as the *intervention*,
comprises a physiological *overnight fast* during which no artificial nutrition
(EN and/or PN) will be provided for a duration of 12 hours (infants 10 hrs,
neonates 8 hrs).
For both study arms, daily caloric targets are similar in both randomization
groups and increase during the first 2 weeks in the PICU. Isocaloric nutrition
between study arms will be achieved with higher intakes during the day and/or
with energy-dense formulas in the intermittent group. Enteral and/or parenteral
nutrition (timing and requirements) will be initiated and administered
according to the most recent nutritional guidelines for all patients; EN will
be started as early as possible (< 24 hrs) unless strictly contraindicated, and
increased in a step-wise manner. PN (glucose/amino acids/lipids) will be
started after day 7 if EN is still insufficient (<80% target intake).

The burden is expected to be minimal. Based on studies in the literature, there
is equipoise regarding feeding patterns. The risk in participating to the study
and being randomized to one of the nutritional strategies are minimal (based on
PEPaNIC data), and specifically compass an increased risk of developing
hypoglycemia in the fasting periods of the *Intermittent* nutrition. To prevent
hypoglycemia during the overnight fasting period, 1) age-dependent fasting
periods are applied, 2) frequent glucose controls are planned, 3) neonates and
infants will be provided with a guaranteed glucose intake ((±1 mg/kg/min
glucose and ±0.5 mg/kg/min glucose respectively), unless they develop
hyperglycemia with such regimen (at what time the glucose intake will be
tapered down and eventually stopped)or if glucose infusion is otherwise
contraindicated, and 4) insulin (if administered) will be stopped one hour
prior the fasting interval.
Another potential burden or risk in the intervention group (*Intermittent*)
might be gastro-intestinal intolerance to the administration of more
nutritional intake in a shorter time frame. However, safety measures
(standardized and regular checks; lactate / gastro-intestinal tolerance) will
be taken to further decrease these risks. Further risks are negligible, and
will only entail 1) additional blood draws, which will be taken from clinical
lines or in addition to pricks for clinical purpose, 2) neuro-monitoring /
sleep measurements, which will be performed non-invasively and 3) saliva swabs.
Clinical equipoise between Continuous and Intermittent nutrition is a specific
problem for critically ill patients in an ICU environment. A pilot study in
adults has shown that a 12hr fast in an ICU setting significantly increased
ketones as marker of a fasting response. A systematic review in adult ICU
patients was not able to show an impact of intermittent versus continuous
nutrition on clinical outcome, but moreover found no harm and possible benefit
of Intermittent feeding. However, although the results of this study have
provided essential information for the design of our study, this can NOT be
translated one-on-one to the pediatric patient, as critically ill children of
different age groups have different metabolic and nutritional characteristics.
The patient group of critically ill children (0 * 18 yrs), represents a
significant proportion of the worldwide ICU population. Therefore, the
feasibility and safety needs to be determined in our population of critically
ill children to allow the subsequent large RCT with clinically relevant outcome
measures.