Cottrell and Patel’s NEUROANESTHESIA

Brain metabolism involves both the production and the utilization of energy; catabolism is
the breakdown and anabolism is the synthesis of components and molecules in the cells. For energy
formation the main catabolic process is the breakdown of glucose with the ultimate formation of
high-energy phosphate in the form of adenosine triphosphate (ATP). Other catabolic processes
break down structural and enzymatic proteins, lipids, and carbohydrates; these processes are
necessary to replace damaged and nonfunctional molecules. These molecules are resynthesized by
anabolic processes that renew the cells and maintain optimal function. Cellular function also
requires the maintenance of ionic homeostasis, which for neurons requires a large amount of
energy. The pathophysiologic mechanisms of brain injury are incompletely understood but
ultimately represent a failure of anabolic processes to maintain normal cell function. In this chapter
we explore the putative mechanisms of brain injury. The causes of neuronal damage are
multifaceted, and one pathway alone cannot explain how the injury occurs. Some pathophysiologic
mechanisms are common to damage caused by ischemic, epileptogenic, and traumatic injury,
whereas others are discrete for each of these processes. This review focuses on some common
triggers of neuronal damage, such as altered ionic gradients, and explores how they in turn lead to
long-term damage. We also discuss pharmacologic agents and clinical procedures that may lead
to a reduction in long-term brain damage.

BRAIN METABOLISM

The main substance used for energy production in the brain is glucose. Because glucose is
not freely permeable across the blood–brain barrier, it requires a transporter to enter the brain. This
transporter does not require energy and can move glucose only down its concentration gradient,
from a higher to a lower concentration. Normally the blood levels of glucose are well regulated so
glucose concentrations in the brain are adequate; however, if blood levels of glucose fall the supply
of glucose cannot meet the energy requirements of the brain. Thus adequate blood glucose levels
are critical for normal brain activity. During insulin shock or other conditions that cause a reduction
in blood glucose, unconsciousness can result from insufficient energy due to low brain glucose
levels. When glucose and oxygen levels are sufficient, glucose is metabolized to pyruvate in the
glycolytic pathway (Fig. 1.1). This biochemical process generates ATP from adenosine
diphosphate (ADP) and inorganic phosphate and produces nicotinamide adenine dinucleotide
reduced (NADH) from nicotinamide adenine dinucleotide (NAD+). Pyruvate from this reaction
then enters . The mitochondriathe citric acid cycle which, with regard to energy production,
primarily generates NADH from NAD+ use oxygen to couple the conversion of NADH back to
NAD+ with the production of ATP from ADP and inorganic phosphate. This process, called
oxidative phosphorylation, forms three ATP molecules for each NADH converted and yieldsa
maximum of 38 ATP molecules for each glucose molecule metabolized.1 Because numerous parts
of this pathway supplyother metabolic requirements, such as amino acid synthesis and the
formation of reducing equivalents for other synthetic pathways, the normal yield of this energy
pathway is approximately 30 to 35 ATP molecules for each glucose molecule. This pathway
requires oxygen; if oxygen is not present the mitochondria can neither make ATP nor regenerate
NAD+ from NADH. The metabolism of glucose requires NAD+ as a cofactor and is blocked in
its absence. Thus, in the absence of oxygen, glycolysis proceeds by a modified pathway termed
“anaerobic glycolysis”; this modification involves the conversion of pyruvate to lactate,
regenerating NAD+. This process produces hydrogen ion, which may accentuate neuronal damage
if the intracellular pH falls. A major problem with anaerobic glycolysis, in addition to lowering
pH, is that only two molecules of ATP are formed for each molecule of glucose metabolized. This
level of ATP production is insufficient to meet the brain’s energy needs. In addition, ischemia
curtails the supply of glucose so even anaerobic glycolysis is blocked. When the oxygen supply to
a neuron is reduced, mechanisms that reduce and/or slow the fall in ATP levels include the
following: (1) the utilization of phosphocreatine stores (a high-energy phosphate that can donate
its energy to maintain ATP levels), (2) the production of ATP at low levels by anaerobic glycolysis,
and (3) a rapid cessation of spontaneous electrophysiologic activity.

Morgan, G Edward, S Mikhail. Clinical Anesthesiology. 6th edition. New York: MC Graw
Hill; 2018.

Cerebral Physiology

CEREBRAL METABOLISM

The brain normally consumes 20% of total body oxygen. Most cerebral oxygen
consumption (60%) is used to generate adenosine triphosphate (ATP) to support neuronal
electrical activity (Figure 26–1). The cerebral metabolic rate (CMR) is usually expressed in terms
of oxygen consumption (CMRO2) and averages 3 to 3.8 mL/100 g/min (50 mL/min) in adults.
CMRO2 is greatest in the gray matter of the cerebral cortex and generally parallels cortical
electrical activity. Because of the rapid oxygen consumption and the absence of significant oxygen
reserves, interruption of cerebral perfusion usually results in unconsciousness within 10 s. If blood
flow is not reestablished within 3 to 8 min under most conditions, ATP

stores are depleted, and irreversible cellular injury occurs. The more rostral “higher” brain
regions (cortex, hippocampus) are more sensitive to hypoxic injury than the brainstem.FIGURE
26–1 Normal brain oxygen requirements. Neuronal cells normally utilize glucose as their primary
energy source. Brain

glucose consumption is approximately 5 mg/100 g/min, of which more than 90% is

metabolized aerobically. CMRO2 therefore normally parallels glucose consumption. This
relationship is not maintained during starvation, when ketone bodies (acetoacetate and β-
hydroxybutyrate) also become major energy substrates. Although the brain can also take up and
metabolize lactate, cerebral function is normally dependent on a continuous supply of glucose.
Acute sustained hypoglycemia is injurious to the brain. Paradoxically, hyperglycemia can
exacerbate global and focal hypoxic brain injury by accelerating cerebral acidosis and cellular
injury. Adequate control of perioperative blood glucose concentration is advocated in part to
prevent adverse effects of hyperglycemia during ischemia; however, overzealous blood glucose
control can likewise produce injury through iatrogenic hypoglycemia.

CEREBRAL BLOOD FLOW

Cerebral blood flow (CBF) varies with metabolic activity. There are a variety of methods
available to directly measure CBF, including positron emission tomography, xenon washout, and
computed tomography perfusion scans. Except in research environments, these methods do not
lend themselves to bedside monitoring of CBF. Regional CBF parallels metabolic activity and can
vary from 10 to 300 mL/100 g/min. For example, motor activity of a limb is associated with a
rapid increase in regional CBF of the corresponding motor cortex. Similarly, visual activity is
associated with an increase in regional CBF of the corresponding occipital visual cortex. Although
overall CBF averages 50 mL/100 g/min at a PaCO2 of 40 mmHg,flow in gray matter is roughly
80 mL/100 g/min, whereas that in white matter is 20 mL/100 g/min. Total CBF in adults averages
750 mL/min (15–20% of cardiac output). Flow rates below 20 to 25 mL/100 g/min are usually
associated with cerebral impairment, as evidenced by slowing on the electroencephalogram (EEG).
CBF rates below 20 mL/100 g/min typically produce a flat (isoelectric) EEG, whereas rates below
10 mL/100 g/min are usually associated with irreversible brain damage. Indirect measures are
often used to estimate the adequacy of CBF and brain

tissue oxygen delivery in clinical settings. These methods include: • The velocity of CBF
can be measured using transcranial Doppler (TCD); see Chapter 5 for a discussion of the Doppler
effect. An ultrasound probe (2 mHz, pulse wave Doppler) is placed in the temporal area above the
zygomatic arch, which allows insonation of the middle cerebral artery. Normal velocity in the
middle cerebral artery is approximately 55 cm/s. Velocities greater than 120 cm/s can indicate
cerebral artery vasospasm following subarachnoid hemorrhage or hyperemic blood flow.
Comparison between the velocities in the extracranial internal carotid artery and the middle
cerebral artery (the Lindegaard ratio) can distinguish between these conditions. Middle cerebral
artery velocity three times that of the velocity measured in the extracranial internal carotid artery
more likely reflects cerebral artery vasospasm.

• Near-infrared spectroscopy was discussed in Chapter 6. Decreased saturation is

associated with impaired cerebral oxygen delivery, although near-infrared spectroscopy primarily
reflects cerebral venous oxygen saturation.

• Brain tissue oximetry measures the oxygen tension in brain tissue through placement of
a bolt with a Clark electrode oxygen sensor. Brain tissue CO2 tension can also be measured using
a similarly placed infrared sensor. Normal brain tissue oxygen tension varies from 20 to 50 mm
Hg. Brain tissue oxygen tensions less than 20 mm Hg warrant interventions, and values less than
10 mm Hg are indicative of brain ischemia.