Sepsis is a major but potentially preventable cause of death in children worldwide, with
a mortality rate of 29%. It also causes 28% of mild disability and 17% of severe
disability in Europe. It is important to note that most studies only look at septic shock
in adults, but the populations most affected by septic shock are young children and the
elderly. An obvious difficulty in the diagnosis of septic shock in paediatrics is related
to the variability of physiological values according to age and the specific
pathophysiological features of this pathology in children. Septic shock should be
suspected when the child presents with a change in mental status associated with
infection and signs of tissue hypoperfusion. Unlike in adults, where septic shock is
classically biphasic with an early phase of vasoplegia followed by a phase of low cardiac
output, a specific haemodynamic profile is observed in children. It is characterised by
severe hypovolemia requiring vascular filling with very heterogeneous responses, low
cardiac output and high systemic arterial resistance. In children, septic shock is a
dynamic process with heterogeneous haemodynamic phases that change during the course of
the shock. The therapeutic agents used and their doses must therefore be adjusted at all
times to maintain vascular perfusion. Between 2005 and 2011, more than half of paediatric
deaths from septic shock occurred within the first 24 hours. Prompt treatment is a vital
factor in the prognosis, with each additional hour spent in shock doubling the risk of
death. Unlike in adults, low cardiac output, rather than increased systemic vascular
resistance, is associated with mortality. Due to a higher basal heart rate, the increase
in heart rate is more limited than in adults. Although the physiopathology of children is
different (lower cardiac reserve, lower basal arterial pressure), there are no specific
recommendations for children; those for adults are adapted to this population. On the
basis of these alarming data, there is a significant socio-economic interest in
identifying new treatments for the management of young patients.
Cardiac metabolism is an important area of research because it plays a central role in
maintaining cardiac function under stress. In recent years, O-N-acetyl-glucosaminylation,
more simply known as O-GlcNAcylation, a post-translational modification of proteins, has
attracted considerable interest because it plays a key role in regulating cellular
metabolism, but also in the ability to adapt to stress and cell survival. Particular
attention has been paid to this metabolic pathway in various pathologies (Alzheimer's
disease - patent US20200079766, diabetes, heart attack, etc.) but always in adults or the
elderly. The work that investigators have carried out shows that the levels of
O-GlcNAcylation of cardiac proteins vary during the early stages of life in rats. This
observation is crucial because it could explain some of the metabolic peculiarities of
the young heart (use of mainly glycolytic substrates during the first days of life, for
example) and the greater capacity of the hearts of newborn rats to withstand stress such
as ischaemia-reperfusion. O-GlcNAcylation is a ubiquitous, rapid and reversible
post-translational modification involving the addition of a monosaccharide:
ß-D-N-acetylglucosamine to the serine and threonine residues of proteins. In
physiological conditions, 2 to 3% of the glucose entering the cell is directed towards
the hexosamine biosynthesis pathway (VBH), which leads to the production of UDP-GlcNAc
used by O-GlcNAc transferase (OGT) to O-GlcNAcylate proteins. The reverse reaction is
catalysed by O-GlcNAcase (OGA). VBH is at the crossroads of several cellular metabolic
pathways (glucose, acetyl-CoA, glutamine, uridine and ATP) and O-GlcNAcylation is
considered to be a metabolic sensor. The number of O-GlcNAcylated targets (+8000
proteins) bears witness to the involvement of this modification in various cellular
functions. O-GlcNAc levels are finely modulated according to the cell's metabolic
environment, enabling it to adapt to stress. This last point is particularly important as
metabolism changes during development, and could have an impact on the hexosamine
biosynthesis pathway and therefore on O-GlcNAcylation. Stimulation of O-GlcNAcylation has
been shown to be beneficial in several acute pathologies and different animal models. It
could therefore be interesting to use this approach in children to limit the impact of
various pathologies that induce SIRS, such as extracorporeal circulation for major
surgery, septic shock and various traumas.