Optimal glucose in critically Ill children.

Background: Glucose is an important energy source in humans. Glucose is utilised by
all cells and serves as metabolic fuel for muscle, liver, heart, kidney and gut and
as the obligate energy source for brain, medulla and erythrocytes. Hyperglycemia and
insulin resistance are universal findings in critically ill adult patients. In the
acute stress state this metabolic response can be regarded as an adaptive response.
However more prolonged hyperglycemia has been associated with adverse outcome in
adults. Adult studies show reduced mortality when blood glucose levels are strictly
controlled by insulin (1). Intensive insulin therapy also will prevent complications
such as nosocomial infections, acute renal failure, liver dysfunction, critical
illness polyneuropathy, muscle weakness and anaemia and thus will reduce the length
of stay on the intensive care (1).
In many children during critical illness blood glucose concentration rises due to
the disruption of normal glucoregulation. Recent studies in critically ill children
show that hyperglycaemia is associated with worsening of outcome and even an
increase in mortality (2-6). The overall hypothesis is that critically ill children
will benefit as well from strict glucose control via exogenous insulin. Recently,
two studies in a small group of children with severe burns treated with insulin,
reported beneficial effects on survival, infection rates and the inflammatory
response (7, 8). The mechanism by which euglycemia reduces mortality is not yet
understood. Probably, insulin acts by metabolic pathways (improved whole body
protein balance and reduction of dyslipidemia) and non-metabolic pathways (reducing
oxidative stress and endothelial dysfunction and control of inflammatory processes).
It is also increasingly evident that lowering the blood glucose level and not the
insulin infus
ion perse, plays the critical role. The blood glucose concentration is controlled
by regulatory factors governing both uptake from endogenous production and
exogenous sources (enteral or parenteral nutrition). There are two components of
endogenous glucose production: glycogenolysis and gluconeogenesis. The majority of
studies to measure endogenous glucose production have been performed in neonates,
using stable isotopic tracers and indirect calorimetry, while only very few studies
are available for infants and children (9, 10). Recently, it was shown that in long
stay ICU adult patients without glycemic control, the ICU and hospital mortality
was independently related to the mean amount of infused glucose (11). Normal
values for glucose intake in healthy children in the Netherlands are extrapolated
from the study from Kalhan in 1999 (9). No data are available concerning the
endogenous glucose production in critically ill children in relation with the
amount of administered
glucose. Additionally, it is also not known whether decreasing the exogenous
glucose administration would affect whole body protein balance in post-surgical
children by decreasing the energy supply and thus increase protein oxidation as an
energy source.



Aims: The present proposal is designed to define the optimal glucose intake in
critically ill children.



Hypothesis:

1. In normoglycaemic critically ill children exogenous glucose administration
diminishes endogenous glucose production;

2. Elevated blood glucose levels in critically ill children are caused by the sum of
an increased endogenous glucose production rate and exogenous glucose
administration;

3. Optimal glucose intake will vary with body weight;

4. The decrease in exogenous glucose administration will not affect whole body
protein balance (synthesis ¨C breakdown).



Study design and methods:
This is a prospective, randomized, crossover study, which will enrol 48 patients in
the PICU divided in two study groups:

1. Critically ill pediatric patients after elective surgery (cardiac, craniofacial
or scoliosis surgery);

2. Critically ill pediatric patients with various medical diseases and >1 organ
failure.

The groups will be subdivided in subgroups as described below:

1a. After elective cardiac surgery, weight ¡Ü30 kg (n=8) and >30 kg (n=8);

1b. After elective craniofacial or scoliosis surgery, weight ¡Ü30 kg
(n=8) and >30kg (n=8);

2. With medical diseases and >1 organ failure, weight ¡Ü30 kg (n=8)
and >30 kg (n=8) .

Endogenous glucose kinetics will be qualified with stable isotope assays and the
predominant fuel source will be determined by indirect calorimetry.


Data analysis: Differences between study groups will be assessed using student¡¯s
t-test, Mann-Whitney test and ANOVA.


Relevance:
This study will lead to a better understanding of the causes of hyperglycemia in
critically ill children and will help to develop new guidelines on parenteral and
enteral glucose intake. Optimal glucose intake and treatment of hyperglycaemia with
insulin will change metabolism of the critically ill child towards early reversal of
catabolism. This is essential for reduction of morbidity of intensive care treatment
and reduction of PICU and hospital stay. On the longer term this will also influence
growth and development of the child.

1. In normoglycaemic critically ill children exogenous glucose administration diminishes endogenous glucose production;

2. Elevated blood glucose levels in critically ill children are caused by the sum of an increased endogenous glucose production rate and exogenous glucose administration;

3. Optimal glucose intake will vary with body weight;

4. The decrease in exogenous glucose administration will not affect whole body protein balance (synthesis – breakdown).

One day study, of which 8 hrs will be with a continuous tracer infusion.

Two levels of glucose infusion in a randomized cross-over fashion on the first day post-surgery. During the study a 8 hr primed, continuous stable isotope tracer infusion will be administered.