Effects of sodium lactate infusion in patients with glucose transporter 1 deficiency syndrome (GLUT1DS)

In glucose transporter 1 deficiency syndrome (GLUT1DS) cerebral glucose uptake
from the systemic blood circulation is limited, because of deficient transport
of glucose across the blood-brain barrier by the transporter protein (GLUT1).
Classically patients present with developmental problems, movement disorders
and severe epilepsy. There is no curative treatment for GLUT1DS, and
anti-epileptic drugs usually have little to no effect. The ketogenic diet,
providing ketones as an alternative energy substrate for the brain is an
effective treatment option for the epilepsy and movement disorders in many
GLUT1DS patients. Unfortunately, not in all GLUT1DS patients the ketogenic diet
has a positive effect and other treatment options for these patients are very
limited.
Traditionally, lactate is seen as a waste product of glycolysis during
anaerobic conditions and a marker of ischemia. Interestingly, research has
shown the beneficial side of lactate as an energy source for the brain, besides
glucose and ketones. The aim of this study is to investigate whether lactate
can be an alternative energy source for the brain of children with GLUT1DS, and
as such can reduce seizures and epileptic discharges on EEG when intravenously
administered in these patients.

The purpose of this explorative study is to investigate whether treatment with
lactate has any positive effect on the symptoms of GLUT1DS, especially the
drug-resistant epilepsy.

Primary Objective:
- To assess changes in EEG during and shortly after the infusion of lactate.

Secondary Objective(s):
- To assess any changes in seizure frequency during and shortly after infusion
of lactate.
- To assess any change in laboratory parameters during and shortly after
infusion: lactate, pH, sodium, bicarbonate, chloride, potassium, glucose.

This is a single center, explorative, interventional, open-label proof of
principle study in an hospital setting. The study will be conducted at the
Radboudumc in Nijmegen and includes patients with GLUT1DS.
The duration of the study will be 4 months (1 month data collection, 3 months
analyzing the data and writing an article). Patient participation is 1 day per
patient.

Sodium lactate will be administrated intravenously and we will use a primed
(0,10 mmol/kg/min for 15 minutes) continuous (0,06 mmol/kg/min for 105 minutes)
infusion scheme, aiming at plasma lactate levels of 7,5-10 mmol/L. Dosage
modifications will be performed if plasma lactate levels fall below 7 mmol/L or
rise above 10.5 mmol/L.

Potential risks include hematomas and/or phlebitis following infusion, yet this
is self-limiting. To reduce the risk of phlebitis, we will flush the catheter
with 100 ml NaCl 0.9% after the lactate infusion. Some early studies have
described that sodium lactate can induce panic attacks in patients with panic
disorders, when a high dose of sodium lactate was rapidly infused, but
substantial methodological problems (i.e. lack of specificity and sensitivity,
disregard of baseline cofounders) render the evidence highly questionable. Such
adverse effects have not been reported in later studies involving healthy
volunteers and different patient groups
Based on all literature studied, (serious) adverse effects aren*t expected with
the use of sodium lactate intravenously. Studies have showed that lactate
concentration in blood can rise to more than 10 mmol/L during excersise,
without any serious adverse effects. Multiple other studies have infused sodium
lactate above physiologically rest values, without any (serious) side effects.
Only mild shifts in electrolyte balance in blood, mild increase of pH blood are
occasionally reported. No participants in earlier studies needed intervention
for these effects, and values returned quickly to normal after treatment.
A benefit of participation in this study is that they could have a temporarily
reduction of frequency of seizures and normalisation of their EEG. Most
importantly, participation contributes to evidence based developing of new
treatment options in the future, regarding the role of lactate in patients with
GLUT1DS.