HYPOGLYCAEMIA - keywords

Neonatal Hypoglycaemia

Causes

Classification of neonatal hypoglycaemia

In term and near term newborn infants who do not have any underlying disorders and are otherwise healthy, hypoglycaemia is classified as transitional, representing a delay in the adaptation from fetal life. About 40% of infants with transitional hypoglycaemia have severe or recurrent episodes. Secondary causes of hypoglycaemia include acute illness, such as sepsis and hypoxic-ischaemic encephalopathy, and moderate or very preterm birth. The primary causes include congenital malformations that affect endocrine function, and genetic disorders of glucose or intermediary metabolism. Transitional neonatal hypoglycaemia often resolves within 48 hours, but occasionally persists beyond 72 hours and is termed prolonged transitional hypoglycaemia, resolving within weeks to a few months. Primary causes should be considered, particularly in the presence of: acidosis or alkalosis; bradycardia or arrhythmia; conjugated hyperbilirubinaemia; micropenis, microcephaly, or cleft palate; a family history of infant hypoglycaemia; persistently absent ketones; very high insulin concentrations; or a normal insulin:glucose ratio during hypoglycaemia (≤1.0 mU/mmol). The rate of prolonged transitional hypoglycaemia is reported to be about six per 10 000 births. The primary inherited causes are rare, usually requiring ongoing treatment and monitoring throughout infancy, and are sometimes referred to as persistent hypoglycaemia of infancy.

At risk

- preterm
- IUGR (SGA < p10)
- maternal diabetes mellitus
- macrosome
- hypothermia
- hematocrit above 70 %
- maternal alcohol, medication (like beta-lytics, …)

The diagnostic criteria for hyperinsulinism

Glucose requirements > 6–8 mg/kg/min to maintain blood glucose above 2.6–3 mmol/L
Laboratory blood glucose < 2.6 mmol/L
Detectable insulin at the point of hypoglycaemia with raised C peptide
Inappropriately low blood free fatty acid and ketone body concentrations at the time of hypoglycaemia
Glycaemic response, during hypoglycaemia, after the administration of glucagon
Absence of ketonuria

Severe and persistent or otherwise unexplained hypoglycaemia should be investigated for an underlying metabolic or endocrine cause, where deficiency in energy production or utilization results from a defect in the liver, myocardium, muscle or brain. Recurrent, unpredictable postprandial hypoglycaemia is observed in hyperinsulinism or growth hormone deficiency and related disorders. Organic acidemias or defects of gluconeogenesis (glycogen storage disease type I or fructose 1,6-bisphosphatase deficiency) usually present with associated ketoacidosis. The presence of non-glucose reducing substances in urine is characteristic of classic galactosemia and hereditary fructose intolerance. Both diseases are generally associated with other prominent clinical problems such as liver failure. Hyperinsulinism and fatty acid oxidation disorders are the most frequent causes of hypoketotic hypoglycemia. - Hyperinsulinism is rarely part of genetic syndromes Beckwith-Wiedemann syndrome, Perlman syndrome, Sotos syndrome, and Kabuki syndrome (Kapoor et al. 2009). Congenital anomalies and dysmorphic features associated with hyperinsulinism raise suspicion for these conditions. - Congenital hyperinsulinism may also be a feature of a mutation in a metabolic enzyme such as hyperinsulinism/hyperammonemia syndrome due to autosomal dominant mutations in the glutamate dehydrogenase (GDH) gene (Stanley et al. 1998) and defects of the β-oxidation enzyme 3-hydroxyacyl-CoA dehydrogenase (HADH) (Flanagan et al. 2013; Clayton et al. 2001). In hyperinsulinism/hyperammonemia syndrome, the hypoglycemia occurs with fasting but can also be triggered by protein feeding (Hsu et al. 2001). In contrast to urea cycle disorders, the hyperammonemia is mild and without fluctuations related to fasting or protein feeding. - The capacity to derive energy from mitochondrial fatty acid oxidation is critically important especially during stress and starvation. Therefore, inherited disorders of fatty acid oxidation are an important and treatable cause of neonatal hypoglycemia. Congenital lactic acidaemias (deficiencies of pyruvate carboxylase, pyruvate dehydrogenase, Krebs cycle and mitochondrial respiratory chain disorders) also present with hypoglycaemia. Symptoms common to this group include failure to thrive, severe hypoglycaemia, hyperlactacidaemia, severe generalized hypotonia, myopathy, cardiomyopathy, cardiac failure, arrhythmias, conduction defects, circulatory collapse, sudden infant death, dysmorphia and malformations. Most of the disorders presenting with hypoglycaemia are at least partly amenable to treatment while congenital lactic acidaemias are in general not treatable.

Normal Glucose Levels

1 mmol/L = 25 mg/dL

Centiles of plasma and interstitial concentrations of glucose over the first five days in healthy term newborns. The 10th centile, in the period from two to 48 hours after birth, is about 2.6 mmol/L. (Harris et al. 2020)

Management

encourage early (within the hour after birth) breast feeding
strict follow-up of breast feeding the first 24 hours The level of blood glucose (BG) that leads to injury and adverse neurodevelopmental outcome is unknown. Because of this uncertainty, an 'operational threshold' approach to the management of neonates with hypoglycaemia has been proposed, which defines 'the concentration of plasma or whole blood glucose at which clinicians should consider intervention based on evidence currently available in the literature.' In this context, infants at risk are identified, and interventions to raise the BG are recommended at specified thresholds, with the caveat that acute neurological dysfunction in association with low BG at any level should prompt urgent investigation and treatment (Cornblath et al. 2000). A review supports the previous consensus that BG levels below 1.0 mmol/l that are persistent beyond 2-3 hours (or are recurrent) and associated with acute neurological dysfunction present the greatest risk for permanent damage, and that brief episodes of hypoglycaemia, in the absence of acute symptoms and of an associated disorder, are unlikely to lead to poor outcome (Rozance et al. 2006). The spectrum of cerebral lesions associated with hypoglycaemia includes: white matter injury, cortical neuronal injury, and sometimes injury to the basal ganglia, mainly globus pallidus (Anderson et al. 1967, Spar et al. 1994, Aslan et al. 1997, Barkovich et al. 1998, Murakami et al. 1999, Alkali et al. 2005, Filan et al. 2006). There is a vulnerability of white matter and cortex of posterior parietal and occipital lobes, well reported in human imaging studies, but the site of injury is more widespread in pathological and experimental studies of neonatal hypoglycaemia. In a large series of neonates with isolated symptomatic hypoglycaemia, although a predominantly posterior pattern of injury was seen in one-third of the cohort, a more extensive distribution of lesions was common (Burns et al. 2008).

Clinical Presentation

Signs may be non-specific but include altered consciousness, lethargy, irritability, high-pitched cry and tremor, sweating, poor feeding after initially feeding well, hypotonia, apnoea, and hypothermia. There can be rapid progression to seizures and coma. Electroencephalography (EEG)(and aEEG) is useful for detecting encephalopathy and seizures. Specific EEG measures may be sensitive to changes in BG. aEEG should be initiated as soon as neurological dysfunction is diagnosed. A full montage EEG should be considered if any aspect of the neurological examination remains abnormal 5-7 days after the hypoglycaemic event or if seizures persist.

Treatment

The key principles of emergency treatment are: (i) identify high risk groups based on expected inability to use or mobilize alternative cerebral fuels from glycogen and fat in the presence of low BG concentration, and the likelihood of having impaired or immature counter-regulatory mechanisms;
(ii) promote early and frequent feeds;
(iii) monitor BG in high risk infants using an accurate measurement system;
(iv) ensure energy provision to keep BG ≥ 2.0 mmol/L (3.5 mmol/L in hyperinsulinism);
(v) prompt treatment if BG < 2.0 mmol/L on two consecutive pre-feed measurements or ≤1 mmol/l at any time or any infant with low BG and signs of acute neurological dysfunction.

Outcome

Although the effect of mild transient asymptomatic hypoglycemia on brain development remains unclear, a correlation between severe and prolonged hypoglycemia and cerebral damage has been proven. There is increasing evidence that sequelae follow severe neonatal hypoglycaemia, usually not in the form of severe CP, but with some motor problems, visual, learning and behaviour difficulties, poor head growth and later seizures. Longer term neurodevelopment follow-up is needed to detect these problems (Murakami et al. 1999, De Leon et al. 2007, Burns et al. 2008, Montassir et al. 2010, De Angelis et al. 2021). Outcome may depend on strict and swift use of diagnostic and therapeutic algorithms, e.g. for management of hyperinsulinism.

Imaging

When hypoglycemia occurs in combination with hypoxic-ischaemic encephalopathy (HIE), it appears to exacerbate injury severity and is associated with watershed or focal-multifocal injury patterns (Basu et al. 2018). Unlike in adults, neonatal hypoglycemia can lead to infarction with cavitation, a lesion type specific to newborns and young infants (Barkovich et al., 1998; Gataullina et al., 2015).

Typical Imaging

Two patterns are supported by these MRI reports (Liu et al. 2013).
One is the occurrence of bilateral, rather symmetrical, injury of occipital and posterior parietal cortex and underlying white matter. The cortical ribbon may be lost on T2 and infarction can occur (cavitation). The extension is beyond the area covered by the posterior cerebral artery and is too extensive to be classified as watershed, but the imaging behaviour is similar.
A second paradigm seems to be unilateral complete hemispheric neocortical necrosis (Yager et al. 2002). Pallidal damage reported in one case by Barkovich et al. 1998, still needs confirmation in other reports.

Reports of imaging in brain injury due to severe neonatal hypoglycaemia
Study	Details / Findings
Spar et al. 1994	infant with seizures and hypoglycaemia for 15 hours; MRI at 19 days — neocortical injury: posterior parietal and occipital, bilateral
Traill et al. 1998	two term infants with seizures for 2 days; one MRI at 6 days the other at 7 years — bilateral neocortical injury: posterior parietal and occipital cortical and subcortical necrosis, later atrophy
Barkovich et al. 1998	neonates with seizures — neocortical injury: posterior parietal and occipital cortical and subcortical necrosis, bilateral pallidum in 1 (with also involvement of posterior frontal cortex); cortical ribbon disappeared in all, cavitation in some; in acute stage hyperintense (sub)cortex on T1 and T2
Murakami et al. 1999	follow-up scans at 9 months to 9 years of 8 children with neonatal hypoglycaemia, 7 with later epilepsy, 1 only with CP — neocortical injury: gliosis and atrophy in posterior parietal and occipital cortex, bilateral
Kinnala et al. 1999	symptomatic term infants, none with seizures, one with later hemiplegia — neocortical injury: in 3 posterior parietal and occipital cortical and subcortical necrosis, later atrophy, bilateral thalamus affected in 1; no specific sonographic changes
Yager et al. 2002	term infant, CT on days 5 and 12 — neocortical injury: unilateral cortical and white matter injury; ipsilateral thalamus affected
Alkalay et al. 2005	term infant, MRI on day 11 — neocortical injury: bilateral occipital and posterior parietal cortex and white matter injury; deep grey nuclei unaffected
Filan et al. 2006	term infants, three with seizures, all first week MRI, 3 with hyperinsulinism — neocortical injury: involvement of occipital cortex plus white matter, splenium plus optic radiation, parietal cortex in some (ADC values low); atrophy on follow-up MRI in affected occipital areas; sparing of PLIC and deep grey nuclei
Burns et al. 2008	35 term infants; white matter injury not confined to the posterior regions; haemorrhage, MCA stroke and basal ganglia/thalamic abnormalities also seen; cortical involvement common
Wong et al. 2013	selective edema in the posterior white matter, pulvinar, and anterior medial thalamic nuclei—structures that appear particularly vulnerable to hypoglycemia
Personal observations	three infants with seizures necessitating ventilation — neocortical injury: bilateral posterior parietal and occipital cortical and subcortical necrosis; hyperechoic post-atrial white matter, no cavitation

Limited Changes

Cranial ultrasound can assess associated structural malformations, such as septo-optic dysplasia spectrum, and detect parenchymal or deep grey matter echodensities in the neonatal period. However, detecting the posterior injury characteristic of hypoglycaemia can be challenging, and a normal scan via the anterior fontanel may not exclude this possibility. Imaging white matter and cortex through the posterior fontanelle can be yielding in such context. MRI characterises extent and nature of injury, explain neurological findings, differentiate from acute hypoxia-ischaemia or arterial stroke, detect structural abnormalities like septo-optic dysplasia or pituitary abnormality, predict outcome and counsel parents, and inform medico-legal proceedings. The imaging protocol should include T1 and T2 weighted axial sections, T1 weighted sagittal images, diffusion tensor/ADC imaging, and a sinus venogram. The optimal timing for image acquisition is 5-10 days from the hypoglycaemic insult to allow assessment of subtle white matter injury. Apparent diffusion coefficient values can be useful if the scans are performed within the first 7 days. MRI findings include a low signal on T1-WI and high signal on T2-WI (infarctions in the cortex or basal ganglia). The cause of changes in the MR signal arising from damaged cortex is most likely the same as in hypoxic-ischaemic injury, including calcification, petechial haemorrhage and myelin degradation. MR proton spectroscopy should be considered if underlying metabolic problems are suspected: it shows a low N-acetyl aspartate (NAA) in the pathological areas.

Term infant with seizures and hypoglycaemia not due to hyperinsulinism. Hyperechoic change in the parietal area was the only finding on ultrasound. Notice partial disappearance of the cortical ribbon in the occipital lobes (left > right) on T2 MRI, and low white matter signal occipitally on T1, high on T2.

Term infant with seizures due to hypoglycaemia. Notice hyperechoic aspect of mesial occipital cortex insonated from the posterior fontanel, and conspicuous changes on ADC map. (courtesy L de Vries, Utrecht)

Hypoglycaemia and Brain Histopathology

The most frequently observed neonatal injury pattern involves bilateral, relatively symmetrical damage to the occipital and posterior parietal cortex and the underlying white matter (selective vulnerability of second and third layers of the cerebral cortex, the dentate gyrus, the subiculum, the CA1 regions in the hippocampus). This was documented in a postmortem study of three patients (Anderson et al. 1967) and has since been confirmed in numerous in vivo studies (Burns et al. 2008). "In many cells the nucleus had broken up into numerous small uniform fragments which were scattered in the cytoplasm; in others the chromatin had formed a beaded pyknotic mass. In large nerve cells the nuclei were shrunken, opaque and finely stippled and there was chromatolysis. Many of the motor neurones of the cranial nerve nuclei and of the spinal cord were disrupted by large vacuoles. The nuclei of the glial cells both in the grey and white matter were pyknotic. These cytological reactions in nerve cells are not peculiar to hypoglycaemia for we have seen them in infants dying with severe hypoxia. The classical 'ischaemic nerve cell change', in which the cytoplasm is eosinophilic and the nucleus irregular and pyknotic, occurs only rarely in neonatal hypoglycaemia."

H&E staining, rat: normal neuron. (https://ntp.niehs.nih.gov/atlas/nnl/nervous-system/brain/Neuron-Necrosis)

H&E staining, rat: loss of Nissl substance, eosinophilia with early necrosis (day 1) — nuclear pyknosis

H&E staining, rat: basophilia and ferrugination near the cell membrane — nuclear karyorhexis

For neonatal hypoglycaemia to induce macroscopically (i.e. with imaging) visible brain damage it has to be correlated with hypoglycaemia-induced seizures. Whether or not seizures are due to hypoglycaemia or subsequent excitotoxic cell necrosis is difficult to ascertain, but their presence in an episode of very low blood glucose entrains a vicious circle with increasing energy deficit. Reduction of pyruvate production increases release of glutamate. Typical of hypoglycaemia is the absence of ischaemia, on the contrary there is reactive hyperperfusion, and absence of high lactate levels due to low status of glycolysis. There is energy deficit, relatively controlled by the use of ketones and lactate for ATP production. Tissue is not acidotic, but alkalotic. In adults hypoglycaemia can cause disseminated neuronal death in neocortex, in hippocampus (dentate - resistant to ischaemic injury - and CA1) and caudate nucleus (Kalimo and Olsson 1980, Auer et al. 1989). Thalamus, pallidum and cerebellum seem to be relatively resistant to hypoglycaemia. In adults neocortex is preferentially hit in temporo-insular regions, a predilection for the posterior brain parts is not typically documented. Contrary to ischaemia, cell changes are not the typical eosinophilic kind seen with necrosis, and in neocortex the outer layers are most damaged (Banker 1967, Anderson et al. 1967). GABAergic neurons, vulnerable in ischaemia, are not affected so much by hypoglycaemia. Occipital (and insular) predilection was documented in a postmortem study of 3 patients with severe neonatal hypoglycaemia and seizures (Anderson et al. 1967). This report showed necrosis of cerebellar Purkinje and internal granule cells, in brainstem nuclei and in spinal motoneurons, contrary to the adult findings. Germinal matrix seems to resist hypoglycaemia in the newborn, thalamus and striatal cells do not. The picture is thus different between newborns and adults with hypoglycaemia severe enough to induce seizures. Infarction, not a feature in adults, has been reported in the newborn (Barkovich et al. 1998). Microcephaly, visual disturbances, and occipital epilepsy have been reported in children surviving severe neonatal hypoglycemia (Caraballo et al. 2004). The specific occipital nature of neonatal hypoglycaemic injury is not understood from the neonatal pattern of glucose metabolism as demonstrated with deoxy-glucose PET (Chugani 1998): glucose is most metabolised in sensorimotor cortex, cingulate cortex, thalamus, basal ganglia, brainstem, medial temporal region and vermis. The peculiarity of the relation between glucose homeostasis and occipital subcortex is further stated by a description of severe prolonged iatrogenic hyperglycaemia in a term infant of 4 weeks with dehydration: lesions were bilateral occipital, but involved parts of thalamus and striatum as well (Efron et al. 2003). The lesion pattern resembled PCA stroke on both sides, with pial infarction only on the left. The neonatal selective vulnerability of these regions may be related to their high metabolic demand and active synaptogenesis (De Angelis et al. 2021). Hypoglycemia-induced excitotoxicity and impaired glucose transport mechanisms are contributors to injury (De Angelis et al. 2021). But other factors may be the difference in innervation by sympathetic nerves and the different origin of pericytes in the carotid versus the vertebrobasilar system.

Brain Glucose Transporters

Glucose is the principle energy source for mammalian brain. Delivery of glucose from the blood to the brain requires its transport across the endothelial cells of the blood-brain barrier and across the plasma membranes of neurons and glia, which is mediated by facilitative glucose transporter proteins (Vannucci et al. 1998, Kyrtata et al. 2021). GLUT1 is the primary transporter in the blood-brain barrier, choroid plexus, ependyma, and glia; GLUT3 is the neuronal glucose transporter. The levels of expression of both are regulated in concert with metabolic demand and regional rates of cerebral glucose utilization. Glucose enters cytosolic glycolysis to produce ATP and pyruvate, the latter enters the mitochondrion for the Krebs cycle. The metabolic rate of glucose shows clear regional heterogeneity (Kennedy et al. 1978). Grey matter clearly uses more glucose than white matter.

Glucose Uptake in the (Rat) Brain

Glucose transport into the brain is carrier-mediated (Siegel et al. 1994). The carrier GLUT 1 at the BBB is rate limiting, more than the neuronal carrier GLUT3. With PET using deoxy-glucose, it is shown that glucose transport is enhanced during hypoglycaemia. Some use of ketones can replace glucose in conditions like starvation, and newborns also utilise a limited amount of ketones for brain energy. But a drastic fall in glycaemia inevitably leads to neuronal injury, at thresholds around 1.5 mmol/L. Ischaemia shuts down the energy cycle in seconds, hypoglycaemia in minutes (there is a limited glucose reserve stored in glycogen). Of all oxygen consumed in the body at least 20% goes to the brain, cerebral blood flow takes 15% of the total blood flow in adults, 20% in neonates (compare with relative weight of brain to body for adults 2%, for neonates 10%). In an experiment conducted on rats, the comparison between glucose influx and regional blood flow revealed that the influx to the cerebellum was significantly higher (approximately double) compared to the cerebral cortex, despite a lower blood perfusion (LaManna and Harik 1985). This observation may provide an explanation for the resistance exhibited by adult humans to cerebellar injury during severe hypoglycaemia. The absence of this substantial glucose uptake in the hippocampus may, in part, contribute to its vulnerability to a lack of glucose.

Representation of unidirectional fluxes involved in glucose transport at steady state, described by the reversible Michaelis–Menten kinetics. G plasma (µmol/g) denotes the plasma glucose, GT the glucose transporter at the cell membrane, and G brain (µmol/g) the brain glucose. Transmembrane glucose is assumed to influence influx.

When the (rat) brain glucose concentration approaches zero, glucose transport across the blood-brain barrier becomes rate limiting for metabolism during, for example, increased metabolic activity and hypoglycemia. Steady-state brain glucose concentrations in anesthetized rats were measured with magnetic resonance spectroscopy as a function of plasma glucose (Choi et al. 2001). The relation between brain and plasma glucose was linear at 4.5 to 30 mmol/L plasma glucose, which is consistent with the reversible Michaelis-Menten model. Glucose transport kinetics in humans and rats are similar. Extrapolation of the reversible Michaelis-Menten model to hypoglycaemia correctly predicted the plasma glucose concentration (2.1 +/- 0.6 mmol/L) at which brain glucose concentrations approached zero. At this point, CBF increased sharply by 57% +/- 22%, suggesting that brain glucose concentration is the signal that triggers defense mechanisms aimed at improving glucose delivery to the brain during hypoglycaemia.

Regional levels of GLUT3 and SNAP-25 protein (present in synapses) in brains of patients with Alzheimer disease. Western blots depicted for GLUT3, and corresponding Western blots for SNAP-25, were quantitated by phosphoimage analysis (mean values); the ratio of GLUT3/SNAP-25 was calculated. Significant decreases in GLUT3 in samples from Alzheimer's patients compared to controls; lower GLUT3 expression in occipital lobe.

Newborn pattern of cerebral glucose metabolism (Chugani 1998). At this stage of development, glucose metabolism is most apparent in the sensorimotor cortex, cingulate cortex, thalamus, basal ganglia, brainstem, medial temporal region, and cerebellar vermis. Metabolic activity is low in most of the frontal, parietal, temporal, and occipital cortex, as well as in the cerebellar cortex.

The needs of the brain for glucose increase rapidly after birth, peaking in early childhood, remaining high until about age 10 years, then gradually decreasing throughout adolescence and plateauing in early adulthood. When first diagnosed in infancy to early childhood, the predominant clinical findings of neuroglycopenia from Glut1 deficiency are paroxysmal eye-head movements, pharmacoresistant seizures of varying types, deceleration of head growth, and developmental delay (Wang et al. 2002, Falsaperla et al. 2025). Subsequently children develop complex movement disorders and intellectual disability ranging from mild to severe. Institution of ketogenic diet therapies (KDTs) helps with early neurologic growth and development and seizure control. Typically, the earlier the treatment the better the long-term clinical outcome. When first diagnosed in later childhood to adulthood (occasionally in a parent following the diagnosis of an affected child), the predominant clinical findings are usually complex paroxysmal movement disorders, spasticity, ataxia, dystonia, speech difficulty, and intellectual disability. Remarkable (> 10%) asymmetry of glucose uptake has been reported in preterms at term-equivalent age, with a pattern of right predominance that is common (Park et al. 2017).

Neurovascular Coupling and Glucose Use

In normal brain, metabolic rates rise when function increases and fall with drop in activity (Byrne et al. 2014). During activation of normal, normoxic subjects, most studies observed greater increases in blood flow and glucose utilization compared to oxygen consumption. Six O2 molecules are used for one glucose molecule to provide two pyruvates, and in the following metabolism 30 ATP molecules. This enormous production of energy is almost entirely for cell membrane activity and neurotransmission, some of it is for biosynthesis of proteins and long term memory organisation. The respiratory quotient is 1 (1 mol CO2 for 1 mol O2). The cerebral metabolic rate (CMR) of glucose (CMRglc) denotes the overall rate of glucose consumption by all pathways. Under normal steady-state conditions, the rate of any step in the glycolysis pathway equals glucose utilization, whereas the rate of the steps in the tricyclic acid cycle are twice those of glycolysis due to formation of 2 pyruvate per glucose. CMRO2 denotes the rate of oxygen consumption by all pathways. Most O2 is consumed via the electron transport chain to generate ATP in mitochondria, but there are other enzymes (e.g., monoamine oxidase, mixed-function oxidases) that utilize O2. Global rates of O2 consumption can be determined by measuring blood flow and arteriovenous differences for O2. Glycolysis is the metabolism of glucose or glycogen via the glycolytic pathway to pyruvate independent of O2 consumption. Glycolysis generates a net 2 ATP per glucose converted to 2 pyruvate. Glycolytic flux increases during hypoxia, with increased generation of lactate from pyruvate to regenerate NAD from NADH. Oxidative metabolism is the turn over of pyruvate, ketoacids, monocarboxylic acids, fatty acids, and amino acids via the tricarboxylic acid cycle. This is linked to the consumption of oxygen and generation of ATP via the electron transport chain. This energy can be used for de novo biosynthesis of amino acids from glucose, which also consumes O2 and generates ATP. Part of this energy is used for neurovascular coupling. "Coupling" of blood flow and metabolism occurs at a local level (Kaplan et al. 2020, Zhang et al. 2023). Rates of blood flow and glucose utilization in different areas in the brain are highly correlated and change in parallel during different physiological states, leading to the notion of coupling. Regulation of local rates of blood flow by cellular activity involves release of substances that regulate vascular diameter. The neurovascular unit consists of endothelium and smooth muscle cells, plus astrocytes and neurons. Direct regulation of muscle cell action can be by molecules released from astrocytes and neurons, via receptors on these cells. Indirect regulation (by glutamate and potassium) can be via neuronal effects on endothelial cells that propagate an action via connexins (gap junctions).

Heterogeneous Regional Glucose Metabolism Rates (Monkey)

The [I4C]deoxyglucose method for quantitative determination of local cerebral glucose utilization was applied to the macaque monkey (Kennedy et al. 1978). The lumped constant for operation equation, measured in 7 normal conscious monkeys, was 0.344. With these essential constants evaluated, local cerebral glucose utilization was found to vary markedly throughout the brain but to fall within two distributions, a higher one in gray matter and a lower one in white matter. Marked heterogeneity was observed in a number of structures. In some the patterns were consistent with known cytoarchitecture; in others the patterns correlated with electrophysiological techniques. Many of the regions of the cerebral cortex showed columnar patterns of distribution of higher and lower rates of glucose utilization. Highest rates were in auditory cortex, inferior colliculus and medial geniculate. Low rates were in hippocampus, amygdala and pallidum. Visual cortex rate exceeded the rate in the motor cortex. Experiments were performed on 2 groups of baboons (Hamar et al. 1979). One group served as control and the other was premedicated with 5 mg/kg phenoxybenzamine (PBZ), an alpha-blocker. A 2-step hypovolemic shock model was used followed by retransfusion of the shed blood. Cerebral blood flow was measured by the 133Xe clearance method. The cerebral metabolic rates of oxygen, glucose, and lactate were calculated. In addition, the effect of CO2 inhalation was studied before shock was induced. PBZ produced no effect on either CBF or the flow response to CO2 prior to bleeding. PBZ pretreatment prevented the fall in cerebral blood flow and CMRO2, also prevented differences in response between different cortical areas. Lactic acid showed no evidence of change either in production or uptake by the brain during the experimental procedure. The cerebral metabolic pathway of glucose, however, seemed to be affected by PBZ both before and during shock.

Values in a baboon pretreated with PBZ.

Sequential changes in (regional) cerebral blood flow to the brain (brain stem, cerebellum, hypothalamus, white matter and grey matter) were measured in unanesthetized dogs subjected to gradual prolonged haemorrhage (Slater et al. 1975). Microspheres labeled with radioactive isotopes were injected into a left atrial catheter at five different times: control, early hypotension (immediately after hemorrhage), late hypotension, as well as one and eight hours after reinfusion of the shed blood. Immediately after haemorrhage, the total cerebral blood flow decreased slightly, but increased when calculated as a percent of the cardiac output. In the late hypotensive stage, there was decreased flow both as percentage of cardiac output and absolute. Immediately after reinfusion of the shed blood, there were further reductions of flow. Eight hours subsequently, flow rose to values slightly above control. The patterns of each region was almost identical to that of the total cerebral flow.

Autoregulation and Relation to Glucose Metabolism

Strictly defined autoregulation is the term that describes adaptation of the cerebral circulation to changes in systemic arterial pressure (usually MABP mean arterial blood pressure). Baroreceptors adapt to the systemic situation at the level of the large arteries. Autoregulation in adults and monkey models functions at the level of smaller arteries and arterioles (Edvinsson and Krause 2002). When systemic pressure falls, high sympathetic innervated other organs (not the brain) lose perfusion earlier than the brain because of this autoregulation. Between the low (around 60 mm Hg for adults) and high (around 140 mm Hg) mean arterial pressure thresholds, perfusion pressure is kept constant (the plateau phase where vasoreactivity is adequate). This plateau is individually smaller than the indicated thresholds. Autoregulation is size dependent: responses may differ between smaller arteries and arterioles versus larger arteries [during acute hypertensive crises (that lead to PRES for instance) larger arteries may constrict whereas smaller ones and arterioles dilate which leads to oedema; a similar event occurs during haemorrhagic hypotension (this pattern may occur with regional differences leading to patchy tissue ischaemia)]. Responses to high pressure mainly occur at the large arteries, whereas arterioles continue to dilate even when the pressure is below the autoregulatory threshold. The patterns of response to blood loss are similar for several brain regions (Slater et al. 1975) and can be prevented by alpha-blockers that seem to preserve cerebral perfusion (Hamar et al. 1979). Autoregulation may be impaired during various neonatal disease states including prematurity, hypoxic–ischemic encephalopathy (HIE), intraventricular hemorrhage, congenital cardiac disease, and during extracorporeal membrane oxygenation (ECMO)(Rhee et al. 2018). Because infants are exquisitely sensitive to changes in cerebral blood flow (CBF), both hypoperfusion and hyperperfusion can cause significant neurologic injury. Current clinical therapies have failed to fully prevent permanent brain injuries in neonates. Per maturational stage and dependent on the clinical condition, ideal mean blood pressures depend on the autoregulation plateau of every individual neonate. Bedside analysis of low frequency coherence (in the time or frequency domain or with wavelet coherence) between brain perfusion/oxygenation and MABP is possible with doppler and especially with NIRS.

Example of ideal mean arterial blood pressure in a newborn with slow wave trend analysis (hemoglobin volume index HVx) of brain blood volume (with NIRS) and MABP (Rhee et al. 2018).

Autoregulatory responses to vasopressors may vary by sex and age after brain injury. Common clinical situations with the potential physiologic changes outlined above include progressive intracranial hypertension with hydrocephalus, cerebral venous outflow impediments with cavo-pulmonary shunts for cardiac anomalies, high ventilator airway pressures, therapeutic hypothermia for HIE (which acutely lowers the lower threshold initially), extracorporeal membrane oxygenation (ECMO), and vasopressor and afterload reduction therapies. With large PDAs the diastolic perfusion of the brain may be so low that in this part of the cycle the blood flow stops because the pressure is below the critical closure pressure limit. An attractive alternative uses the relationship between heart rate changes (not systemic pressure) and cerebral oxygenation, the tissue oxygenation heart rate reactivity index (TOHRx)(Mitra et al. 2014). Higher TOHRx values were observed in sicker infants. In addition, increased passivity between TOI and HR was observed with arterial hypotension. In preterm infants, optimal MABP has been defined using TOHRx in a cohort of infants born at ≤ 32 weeks gestational age. Absolute deviations away from optimal blood pressure were higher in those infants who died. Infants who developed severe IVH had deviations away from optimal values greater than 4 mm Hg (da Costa et al. 2015). In the absence of other available autoregulation metrics for regional autoregulatory function, identifying optimal MABP for perfusion of the frontal lobe is a reasonable first approximation to guide haemodynamic management in critically ill neonates. But it is not certain that other brain regions behave just like the frontal cortex, and deep brain areas may also differ in autoregulation behaviour. Pressure autoregulation monitoring can define an individual patient's unique cerebral autoregulation and vasoreactivity physiology to determine the optimal arterial blood pressure with most-functional autoregulation in addition to the upper and lower limits of autoregulation (Vu et al. 2024, Surak et al. 2025). Term infants have functional autoregulation and vasoreactivity. In preterm infants autoregulatory function progressively improves between 24 and 34 weeks PMA (Rhee et al. 2018). At pressures below the lower threshold areas without abundant perfusion (deep white matter) may become ischaemic, at pressures above the upper threshold fragile vessels in germinal matrix or external cerebellar granular layer may rupture. Per gram tissue neonatal CBF is about one third of adult values, gradually increasing to peak at supra-adult values around 5 years of age. Suggested target thresholds for systemic blood pressure are widely applied (like keeping the MABP of a preterm in mm Hg at least at the number of its PMA in weeks) but their protective effect is not robustly proved and most likely individual assessment of autoregulation is the only method to do this. This matters because overtreatment to arrive at perfusions levels above the upper threshold may lead to haemorrhage. The ideal MABP will be in the centre of the individual's plateau of autoregulation.

Autoregulation Mechanisms

A myogenic response is initiated by vessel wall tension resulting in a negative feedback response leading to vasoconstriction. The mechanism involves membrane depolarisation, which activates voltage-gated calcium channels; the influx of calcium into the smooth muscle cell activates myosin light chain kinase which in turn phosphorylates myosin light chain and leads to vasoconstriction. Studies suggest that myogenic mechanisms of CBF autoregulation are not only complex, but also mediated by several types of potassium channels, chloride channels, stretch-activated cation channels, and transient receptor potential (TRP) channel homologs (TRPC6). Neurogenic mechanisms for CBF regulation refer to the processes by which neurones and glia regulate smooth muscle function via adrenergic and cholinergic fibres releasing various neurotransmitters. Neurogenic control of the cerebral vasculature is suggested to be an important factor in autoregulation, particularly in large vessels. An important role of neurogenic autoregulation is to buffer acute increases in perfusion pressure via sympathetic nervous system activity (preventing hyperperfusion). In animal models, parasympathetic stimulation is associated with an increase in CBF, and sympathetic stimulation or parasympathetic denervation results in decreased CBF and a shift of the LLA towards higher blood pressures. These neurogenic mechanisms contribute to fine-tuning of blood flow and play a key role in regional variability of CBF. Endothelial factors modulate vascular tone and thus autoregulation. The vasoconstrictors thromboxane A2 and endothelin-1 and the vasodilator nitric oxide are important regulators of CBF. Endothelial factors can be released by physical stimuli (shear stress or haemorrhage), neurotransmitters, or cytokines. Metabolic mechanisms of CBF regulation involve variations of metabolic activity that adjust blood flow. While the effects of PaCO2, PaO2, and pH are well described in altering CBF, the overall effects on autoregulation are complex and inconsistent. Each mm Hg increase in PaCO2 above normal corresponds with a 3-6% increase in CBF, while each mm Hg decrease in PaCO2 corresponds with a 1-3% reduction in CBF. Below a PaO2 of 50 mm Hg, CBF increases as a result of a reduction of vascular smooth muscle tone via increased activation of membrane potassium channels and inhibition of transmembrane calcium flux. With hypercapnia, the CBF response to hypoxemia is accentuated. Cerebral vascular smooth muscle cells constrict with increased pH and relax with decreased pH. There are numerous studies that have described the effects of volatile and intravenous anaesthetics on CBF. Volatile anaesthetics can influence CBF autoregulation and have been shown to shorten the autoregulatory plateau at concentrations ≥ 1 minimum alveolar concentration (MAC). The effects of temperature on autoregulation have been questioned and are particularly relevant during cardiac surgery when deep hypothermia is utilised. In a neonatal piglet model, the LLA is similar in normothermia and hypothermia. Prior clinical studies on this topic have likely been confounded because of the association with hypotension in states of deep hypothermia.

Glucose, Lactate and Brain Function

Sugar for the brain: Mergenthaler et al. 2013, Zhang et al. 2023 Hexokinase uses ATP to phosphorylate glucose (Glc) to glucose-6-phosphate (Glc-6-P) in the first irreversible step of the glycolytic pathway. Glc-6-P regulates hexokinase activity by feedback inhibition, and it is a 'branch-point' metabolite that has alternative metabolic fates. Glc-6-P can continue down the glycolytic pathway to generate pyruvate that can then be used in mitochondria by oxidative metabolism via the tricarboxylic acid (TCA) cycle. It can also enter the pentose phosphate shunt pathway (PPP) to generate NADPH for management of oxidative stress and precursors for nucleic acid biosynthesis and, in astrocytes, Glc-6-P is a precursor for glycogen. Most of the glucose carbon derived from the PPP re-enters the glycolytic pathway downstream of Glc-6-P. The glycolytic pathway produces a net of 2 ATP per molecule of glucose and oxidation of pyruvate via acetyl coenzyme A (acetyl CoA) in the TCA cycle produces approximately 30 ATP for a total of approximately 32 ATP. Formation of pyruvate from glucose requires regeneration of NAD+ from NADH produced by the glyceraldehyde-3-phosphate dehydrogenase reaction by the malate-aspartate shuttle (MAS). NADH cannot cross the mitochondrial membrane, and the MAS transfers cytoplasmic NADH to the mitochondria, where it is oxidized via the electron transport chain (ETC). When glycolytic flux exceeds that of the MAS or the TCA cycle rate, or during hypoxic or anoxic conditions, NAD+ is regenerated by the lactate dehydrogenase (LDH) reaction that converts pyruvate to lactate. Because intracellular accumulation of lactate would cause reversal of the LDH reaction, lactate must be released from the cell by monocarboxylic acid transporters (MCT). Exit of lactate eliminates pyruvate as an oxidizable substrate for that cell and limits the ATP yield of glycolysis per molecule glucose to two. Three models for the fate of lactate generated in the brain from blood-borne glucose or astrocytic glycogen: (1) The astrocyte-to-neuron lactate shuttle (ANLS) was proposed on the basis of glutamate-evoked increases in glucose utilization and lactate release by cultured astrocytes. In brief, the model states that Na+-dependent uptake of the neurotransmitter glutamate from the synaptic cleft by astrocytes generates a demand for 2 ATP in astrocytes, one to extrude Na+ and one to convert glutamate into glutamine in the glutamate–glutamine (Glu–Gln) cycle. The model states that this ATP is generated by the glycolytic pathway and is associated with release of lactate from astrocytes and its uptake by nearby neurons, where it is oxidized. Thereby, astrocyte–neuron metabolic coupling is linked with the glutamate–glutamine cycle and excitatory neurotransmission. Thus, during brain activation, glycolytic upregulation is stated to occur in astrocytes, with astrocyte-derived lactate providing the major fuel for neurons. (2) The neuron-to-astrocyte lactate shuttle (NALS) is based on the kinetics of glucose uptake into brain cells in response to increased metabolic demand and different model assumptions compared with the ANLS. Here, glucose is predicted to be predominantly taken up into neurons due to their high energy demand and the higher transport rate of the neuronal glucose transporter 3, GLUT3, compared with the astrocytic glucose transporter 1, GLUT1. Lactate is posited to be generated by neurons and taken up by astrocytes. (3) The lactate release model is based on the observed mismatch between total glucose utilization and oxidative metabolism and measured lactate release from brain during brain activation in vivo. If lactate were produced and locally oxidized, total and oxidative metabolism would be similar in magnitude. However, the increase in oxidative metabolism varies with experimental condition and pathways stimulated, and it is much less than that of total glucose utilization. Astrocytes have a faster and greater capacity for lactate uptake from extracellular fluid, and for lactate dispersal among gap junction-coupled astrocytes compared with neuronal lactate uptake and shuttling of lactate to neurons. Astrocytic endfeet surround the vasculature, and can discharge lactate to perivascular fluid for efflux from brain.

In the PPP, G6P catalyzes ribulose-5-phosphate (R5P), converting nicotinamide adenine dinucleotide phosphate (NADP)+ to NADPH at the same time. Concurrently, R5P can also be converted to glyceraldehyde-3-phosphate and fructose-6-phosphate (F6P), the latter of which can isomerize back to G6P.

The astrocyte-neuron lactate shuttles provide energy for neuron activity. Lactate is transferred from astrocytes into neurons through monocarboxylic acid transporters (MCTs) and is converted to pyruvate to generate ATP in neuronal mitochondria. The neuron, during activity, generates a small circle of glutamate release around it where oxygen and glucose are actively consumed, surrounded by potassium and adenosine that reduce use of oxygen and glucose, itself surrounded by far dispersed lactate that induces a sink of glucose into the active zone (Barros 2013).

Glucose enters the parenchyma through the capillary endothelium and astrocytic end feet. Lactate is generated by glycolysis in astrocytes and shuttled into neurons either directly (synaptic regions) or via oligodendrocytes (myelinated axons). Approximately 5% of the glucose is metabolized by the pentose phosphate pathway. Astrocytes store glucose in the form of glycogen to be mobilized as lactate on demand. Gap junctions speed the exchange of glucose and lactate between glial cells. Neuronal mitochondria are fueled by pyruvate and perhaps by lactate, generating > 90% of the ATP. Transport of glucose and lactate across plasma membranes is mediated by glucose (GLUTs) and lactate transporters (MCTs), respectively. (Barros 2013)

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