More Glucose Science

Jamie Egan

What happens to a preterm baby if you starve it of glucose and water?

In the case of Baby A, we know that he was a twin born by emergency Caesarean section at 8.30 pm on June 7th 2015. He has birth Asphyxia, which was treated with CPAP (for a short time). Then, there was a delay until 02.41 June 8th, when he was admitted into the neonatal unit. A nurse noted that his peripheral vein had "tissued." at 4 pm the following day.

Letby's defence failed to establish the following critical facts: Who put up the peripheral line? What time did it go up? What were the serum electrolytes and lactates at the time? What fluids were attached to this line? Why did they not establish a more secure central line? What was the training designation of the junior doctor who failed to establish the central line the following day? Had this doctor sufficient experience to establish a central line? Why did the consultants refuse to help the junior when they were informed midday that he could not access a central line on an asphyxiated newborn less than 24 hours old? Did the consultants check before they left to see if someone had accessed a central line on Baby A? Why did the registrar waste his time on a "handover" and not immediately attend to Baby A? Was the registrar aware of the dangers of leaving a preterm neonate on mechanical ventilation without a central line? What was the electrolyte status of Baby A before the decision to use Dextrose 10%? What was the mass of the baby before fluids started?

Many physiological factors are missing from an equation needed to save the baby's life:

A preterm neonate is about 90% water. A loss of mass from the birth weight is a reasonable proxy for the loss of water by sensible and insensible means. From a knowledge of the surface area and the resting oxygen consumption of a baby, it is possible to estimate the total water loss from a baby's skin and the proportion of the baby's resting heat production that this evaporative heat loss represents Thus, a term, 3 5 kg baby, one-day-old, nursed naked in an incubator loses about 30 ml water from the skin each day (8 ml/kg per day). In terms of heat loss, this is equivalent to about 10% of the resting heat production. Water loss from the skin of a term baby is not of significant importance once the skin has dried after delivery. This, however, is not so for meagre birth weight, immature babies with a relatively high surface area about body weight. A baby <30 weeks gestation, weighing 0 9 kg, one day old, nursed naked in an incubator loses about 75 ml water from the skin daily (about 85 ml/kg daily). In terms of evaporative heat loss, this exceeds his resting heat production. Hence, even if radiant and convective heat losses are eliminated, the baby can only maintain his body temperature by increasing heat production. If the capacity to do this is limited, his body temperature will fall. This explains a clinical paradox. A tiny, immature baby nursed naked in an incubator frequently has a low rectal temperature. If radiant heat losses are eliminated using a Perspex radiant heat shield and convective heat losses are abolished by raising the incubator air temperature to that of the baby's skin, the baby may remain cold. This is because his high evaporative heat loss is more significant than his maximum rate of heat production.

We are missing the following information, which the defence failed to exploit:

Fluid Balance and Serum Sodium: Serum sodium concentration reflects the total body water and sodium content. Changes in serum sodium levels can indicate disturbances in fluid balance. Still, they do not provide a complete picture of the hydration status, including serum sodium, blood urea nitrogen (BUN), creatinine, urine specific gravity, renal function, and intravenous fluid administration. The presence of underlying medical conditions, such as patent ductus arteriosus (PDA) ( hole in the heart), will influence fluid balance and serum sodium levels. Therefore, the interpretation of serum sodium must consider the overall clinical context.

There are two water spaces in a human: intracellular and extracellular. The osmotic pressure and electrical charge must stay roughly the same in each compartment. The osmotic pressure is determined by how much stuff (molecules) of electrolytes and other solutes are in solution. The main positively charged solute in the extracellular compartment is sodium (salt), and inside the cell, Potassium. If we cannot maintain this balance, vital cellular and enzyme functions will fail. If the extracellular water volume falls without replacement ( certainly the case for Baby A), water must shift from inside cells to make up the difference. Otherwise, the blood volume will fall. If the blood volume falls, so does the cardiac output. In adults, a fall in cardiac output due to volume loss causes a rise in heart rate to compensate. This does not happen in the preterm neonates.

It is safe to assume that Baby A had significant dehydration and electrolyte imbalance by the time the central line fluids started at 8.06 pm.

We arrive now at glucose depletion in Baby A.

Preterm and small-for-gestational-age infants have diminished glycogen reserves that may be rapidly depleted within twelve hours after birth. This rapid depletion is due to their limited glycogen stores at birth, which is common among preterm infants, especially those with very low birth weights and infants who are small for gestational age because of placental insufficiency.

Typically, fatty acid oxidation (FAO) starts when glycogen reserves are depleted, in conjunction with increased gluconeogenesis. However, gluconeogenesis is not active immediately after birth. The liver's capacity to produce glucose through gluconeogenesis increases to adult levels by 24 hours of life. In the first 2 hours of life, plasma glucose values can drop precipitously. This indicates a critical period immediately after birth during which preterm neonates are at a high risk of hypoglycemia due to the depletion of their glycogen stores and the gradual initiation of gluconeogenesis.

Phosphoenolpyruvate carboxykinase (PEPCK) plays a crucial role in the metabolic processes of preterm neonates, particularly in gluconeogenesis, the metabolic pathway that generates glucose from non-carbohydrate substrates. PEPCK is a critical enzyme in gluconeogenesis, facilitating the conversion of oxaloacetate to phosphoenolpyruvate (PEP), a critical step in the formation of glucose. In preterm neonates, the activity and expression of PEPCK are developmentally regulated. The enzyme's activity is not immediately apparent after birth but increases to adult levels within the first few days of life, contributing significantly to the neonate's ability to produce glucose. Novel variants in the PEPCK gene (PCK1) have been identified, which can affect the enzyme's function and contribute to metabolic diseases, especially during stress. In the context of metabolic stress, such as illness or fasting, the proper functioning of PEPCK is crucial for energy production through gluconeogenesis.

Therefore, we can reasonably assume that Baby A was critically short of glucose and could not resupply himself.

We have only one route to correct water, electrolyte, and glucose depletion, which are three separate problems. We cannot replace water without affecting electrolytes, and we cannot supply glucose without affecting electrolytes.

So what can happen when we choose to correct only the glucose? And did we make this choice knowing what the rest of the blood chemistry showed? Sadly, Myers didn't find out.

At the point of administration, Dextrose 10% is a hypertonic solution, which means it is more concentrated than the plasma receiving it. The homeostatic response is to rebalance by releasing intracellular fluid to dilute the dextrose. However, the dextrose does not last long in the plasma. Cells, especially brain cells, will absorb it very rapidly.

The recommended rate of infusion for D10 (10% dextrose solution) in neonates varies depending on the infant's specific needs, such as their weight, age, and clinical condition. Myers failed to interrogate anyone about this.

A minimum GIR (glucose infiltration rate) of 4-8 mg/kg/min is recommended to meet neonates' basal (basic) glucose requirements and prevent hypoglycemia. This GIR is particularly important for the brain. In neonates, recommendations for initiating fluid therapy suggest starting at 60-80 ml/kg/day with D10W for infants >26 weeks gestation. For infants ≤26 weeks, the initial fluid volume may be higher, ranging from 80-150 ml/kg/day. The infusion rate may be adjusted based on the neonate's age and weight. For example, preterm infants may require a higher GIR of 6-8 mg/kg/min due to their increased risk of hypoglycemia and higher metabolic demands.

Because Myers didn't find out, we can assume that the GIR was at least 6mg/kg/minute and water was at least 80 ml per Kg per day. The infusion ran for (about) 25 minutes until the baby was arrested. That's 6 x 1.6 kg ( Baby A's birth weight) x 25 = 240 mg ( minimum) of glucose.

If we do a little boring maths, 240mg of glucose, measured in moles, is approximately 30.59 mg of sodium or 52mg of Potassium. That's a lot of salt to move around in such a tiny body.

In chemistry, a mole is a fundamental unit that measures the amount of substance. It expresses the number of particles (such as atoms, molecules, ions, or electrons) in a sample. The mole is defined as the amount of substance that contains the same number of elementary entities as there are atoms in exactly 12 grams of carbon-12 (12C). Twelve grams of carbon is a reference called Avogadro's number of particles, which is 6.022×10 (to the power) 23.

The mole allows chemists to convert between a substance's mass and the number of particles it contains. This is particularly useful because chemical reactions often involve vast numbers of atoms or molecules, and it is more practical to use the mole as a counting unit rather than directly dealing with such large numbers.

So we know that a baby who is already dehydrated, likely suffering from electrolyte disturbance, and at the limit of its ability to create new energy must now move massive amounts of Sodium and Potassium back and forth across cell membranes. When Baby A receives glucose in his bloodstream, this will cause a rise in Insulin. Insulin affects potassium levels in cells by promoting the uptake of potassium into the cells, thereby decreasing the concentration of potassium in the bloodstream. This process is primarily mediated through the activation of sodium-potassium ATPases by insulin. Insulin enhances the permeability of body cells to not only glucose but also to other nutrients such as potassium, phosphate, and magnesium. When insulin binds to its receptors on the cell surface, it activates sodium-potassium ATPases, which pump potassium into the cells and sodium out, leading to an increase in the intracellular concentration of potassium.

And so we have insulin promoting the sudden and rapid movement of potassium into cells and dehydration pulling potassium out of cells. The homeostatic cascade necessary to sustain intracellular potassium at optimal levels is beyond the capability of a pre-term neonate forced into this state by poor medical care.

What can happen to the baby's heart and brain? It has neither the energy nor the enzymes to absorb this massive change.

Dysglycemia ( hyperglycemia, hypoglycemia, and glycemic variability (GV)) is associated with an increased risk of various cardiac arrhythmias. Hyperglycemia and GV, in particular, have been linked to ventricular arrhythmias and atrial fibrillation (AF). These conditions may contribute to arrhythmogenesis through oxidative stress, endothelial dysfunction, and alterations in ion channel function.

Ion channel functions, which means the flow of electricity across cellular membranes.

Potassium (K+) plays a pivotal role in the function of ion channels and, by extension, in numerous physiological processes across the body. Potassium ion channels are crucial for setting and maintaining the resting membrane potential of cells, the action Potentials in Neurons, muscle contraction, cardiac rhythm, cell volume regulation, enzyme secretions regulation, and neurotransmitter release.

We also know that Baby A had high serum lactates, meaning his blood was relatively acidic. Acidosis also affects the electrical activity of the heart, affecting cardiac rhythm and the contractile force of the heart. Acidosis can cause ventricular arrhythmias through several interconnected mechanisms that affect the electrical stability of the heart. During acidosis Hydrogen ions (H+) accumulate in the extracellular fluid, and to maintain electrochemical balance, potassium ions (K+) move out of the cells, leading to hyperkalemia. Elevated extracellular potassium levels can decrease the resting membrane potential of cardiac cells, bringing them closer to the threshold for depolarization. This can increase the excitability of the myocardium and predispose to arrhythmias. Acidosis can affect the function of ion channels, including those responsible for the conduction of electrical impulses in the heart. Changes in ion channel function can slow conduction velocity and promote the development of reentrant circuits, which are a common mechanism underlying arrhythmias. Reentrant circuits can cause premature ventricular contractions (PVCs) and more serious forms of ventricular tachycardia.

Acidosis can affect the repolarization phase of the cardiac action potential. Specifically, it can prolong the action potential duration by affecting the function of repolarizing potassium channels. Prolongation of the action potential can lead to early afterdepolarizations (EADs) and delayed afterdepolarizations (DADs), which are abnormal depolarizations that can trigger arrhythmias.

Acidosis often occurs in conjunction with other electrolyte imbalances, such as calcium and magnesium disturbances, which can further contribute to the development of ventricular arrhythmias. Hypocalcemia, which can accompany acidosis, can prolong the QT interval and increase the risk of torsades de pointes, a specific type of ventricular tachycardia. The QT interval is the total time of polarization, discharge and repolarisation of heart muscle. The smooth function of this process is also critical to life.

Is it possible that the sudden infusion of dextrose against a background of acidosis caused the death of Baby A by creating chaos in potassium channels? I think so. It is more than reasonable to suggest that the sudden and overwhelming chaos in potassium channels leads to ventricular fibrillation and death than to simply ignore these facts in favour of Letby's miraculous air syringe.

Why did Myers fail to grill the "expert" Doughy Evans on all of these possibilities?

Why did he not ask the doctors if they considered using dextrose gel?

Perhaps Myers was a little constipated on the ion front.

That, too, we'll never know.