CPB & Effects on the Brain
Seoul National University Hospital
Department of Thoracic & Cardiovascular Surgery
Central Nervous System
Nervous regulation
The central nervous system (CNS) performs
three types of functions:
(1) Mental processes, such as thought or
emotion;
(2) Actions on the external environment,
such as
locomotion, or other actions requiring
skeletal
muscle work;
(3) Actions on the internal environment,
Central Nervous Systems
Functional anatomy
Spinal Cord
 Structure
• Structure of the spinal cord; The intermediolateral gray matter
is shown in color. This is the region in which sympathetic
preganglionic neurons are located.
Central Autonomic Control
Hierarchy
• Limbic cortex and amygdala
• Hypothalamus
• Brainstem ; The brainstem consists of
three
anatomically distinct regions: midbrain,
pons,
and medulla. They are linked at the core
by
reticular formation.
Limbic Cortex & Amygdala
Functions
• These very high centers function both as a brake on
automatic responses that may accompany emotional
states, such as fear, rage, embarrassment, or sexual
desire, and as direct activators of the system.
• The latter is seen prominently in two circumstances:
(1) in the responses of blood pressure, sweat glands,
or genitalia to dreams and fantasies and
(2) in the volitional control of resting autonomic
functions during states of deep meditation.
• In this state, metabolic rate, heart rate, arterial blood
pressure, and distribution of blood flow can all be
modified by application of conscious mental effort
Hypothalamus
Basic functions
• It is an interface between the autonomic nervous
system and higher nervous centers, on the one
hand, and the endocrine system,
• It coordinates whole-body autonomic responses
to behavioral drives (such as fear) or to input
from autonomic and environmental sensors.
• This coordination involves the following:
Integration to hunger, thirst, and sexual drives
Integration of thermoregulation
Integration of defence reactions
Control of several endocrine secretions,
Brainstem
Structures
• Midbrain. The midbrain acts as a conduit for ascending and
descending fibers. It also harbors nuclei that are associated
with
complex neurologic patterns
• Pons. The pons contains nuclei for several cranial nerves
as well as
reflex centers for cardiovascular and respiratory control.
• Medulla. This region contains many nuclei, among them
the nucleus ambiguous and dorsal motor nucleus, which are
the origins
of cranial nerves IX & X. It contains rostral ventrolateral
medulla, a major originating site for sympathetic outflow to
spinal cord.
• Reticular formation. This is a collection of both
ascending and
Spinal Cord
Function
• Spinal cord is a collection of nerve cell bodies &
axons
• Gray matter consists mostly of neuronal cell bodies and is
subdivided on each side into three regions: (1) the dorsal horn is
the region where sensory afferents synapse with spinal neurons,
(2) the ventral horn contains groupings of motor neurons that
supply skeletal muscle, and (3) the intermediate zone lies between
the other two and contains local afferent or efferent interneuron
linkages as well as cell bodies of autonomic preganglionic nerves.
• White matter of the spinal column is the nervous tissue that
surrounds the gray matter. It is composed chiefly of ascending and
descending axons, arranged into fascicles and columns: (1) the
dorsal column contains principally ascending fibers, (2) the ventral
column contains mainly descending fibers, and (3) the lateral
column contains a mixture of ascending and descending fibers.
Spinal Cord
Structure
• The intermediolateral gray matter is shown in color. This is the
region in which sympathetic preganglionic neurons are located.
DC = dorsal column; LC = lateral column; VC = ventral column.
Spinal Nerves
Structure
Spinal Nerves
Structure
• Pre- and postganglionic autonomic fibers synapse either in a
paravertebral ganglion or a peripheral ganglion.
Neurotransmitters
• Diversity of neurotransmitters and
function
Efferent Fibers
Characteristics of differences
• Preganglionic fibers ; Cell bodies of autonomic
efferent nerves are located in the brainstem or the
spinal cord.
Their location and the location of the associated
ganglion
form two of the criteria by which the system is
classified
into sympathetic or parasympathetic divisions
• Postganglionic fibers ; Postganglionic fibers
project
directly to the effector organ target cells where they
form
a synapse. In sympathetic postganglionic nerves,
this
Autonomic Nervous System
Autonomic Nervous System
Divisions
Two major divisions of the autonomic nervous system
are the sympathetic and parasympathetic nervous
systems.
They differ from each other in some anatomic features
and in their respective target organ neurotransmitters
• Adrenergic control mechanism
• Cholinergic control mechanism
• Nitroxidergic control mechanism
Adrenoreceptors
Cholinoreceptors
• A variety of insecticides are anticholinesterases and,
thereby, act to prolong the action of acetylcholine.
Cerebral Blood Flow
Dererminants
1. Threshold cerebral blood flow at normothermia
under 30ml/100g/min ; brain acidosis occurs
less than 20ml/100g/min ; loses electrical activity
less than 10ml/100g/min ; loses further cellular membrane integrity
2. Cerebral blood flow during deep hypothermia (20 C)
less than 7ml/100g/min ; results in reduction of cerebral O2 metabolism
9 ml/100g/min is necessary for aerobic metabolism (25-30% of normal)
3. Full-flow perfusion at hypothermia
Metabolic rates for oxygen lower than those with 40ml/kg/min perfusion
The ratio of the glucose to oxygen metabolic rates are also increased
this luxury perfusion ---- paradoxical harm of luxury perfusion
(cerebral vasoconstriction that would harm the microcirculation during
deep hypothermia due to downregulation of cerebral blood flow )
Paradoxical acidosis & brain embolism at extreme velocity
4. Brain averages 2% of total body weight, 14% of
cardiac output, 20 % of total O2 consumption
Cerebral Collateral Circulation
Collateral flow anatomy
1. Intracranial
Circle of Willis
2. Extracranial
Vertebral arteries
Internal thoracic arteries
Intercostal arteries
Congenital Heart Disease
Etiology of neurologic deficits
• Incompletely understood, & likely to be multifactorial
• Clinical evidence points to the combination of
hypoxemia and low cardiac output in the early
neonatal period as a risk factor for periventricular
leukomalacia
• This encompasses a spectrum of lesions characterized
by multiple areas of necrosis in the periventricular
white matter
• In infants with complex congenital heart defects,
preoperative cerebral blood flow (CBF) is often
diminished, and that lower levels of CBF are associated
with periventricular leukomalacia.
Open Heart Surgery
Neurologic injury
• Neurologic injury is the second most common reason
for death in open heart operations
• Significant neurologic injury was observed in 2% to
5% of patients, whereas mild cognitive dysfunction was
seen in 70% of patients in the early stage
• Extracorporeal circulation does not cause changes in
brain blood circulation, but hemodilution and decrease
in oncotic pressure lead to edema in the brain and in
other organs
• Cerebral ischemia due to microemboli or macroemboli,
systemic inflammatory response, and cerebral
hypoperfusion during cardiopulmonary bypass (CPB)
causes impairment in the blood brain barrier.
Brain Temperature
Determinants of changes
1. Cerebral blood flow
2. State of metabolic rate
3. Heat exchange with environment
Basic Effects of Hypothermia
Gas transport
• The solubility of gases in liquids is inversely related to
temperature, and therefore substantially more oxygen
and carbon dioxide will be carried in physical solution
in the blood under hypothermic conditions
• As temperature is lowered, oxyhemoglobin dissociation
curve shifts to left, so that for a given partial pressure
of oxygen in the tissues, less of the gas is unloaded from
the hemoglobin
• Decreasing temperatures increase the carrying power
of blood for carbon dioxide through an increased
activity of the blood buffers
Hypothermic Circulatory Arrest
Effects on CNS
• Hypothermia is the most efficient measure to prevent
or reduce ischemic damage to the central nervous
system when blood circulation is reduced
• The CNS system has a high metabolic rate and limited
energy stores, which make it extremely vulnerable to
ischemia
• The CNS is the most sensitive to ischemia, attention has
been mainly centered on neurologic outcome when
perfusion is reduced
Hypothermic Circulatory Arrest
Effects on brain
• Hypothermic circulatory arrest results in global brain
ischemia followed by ischemia-reperfusion injury
• This leads to loss of wall integrity in microvasculature
and fluid leakage; ie, fluid escaping the intravascular
space into the brain tissue
• The resulting brain edema and elevated intracranial
pressure further decrease brain tissue perfusion by
compressing and occluding small vessels.
• Adherent neutrophils and microvascular thrombosis
blocking the small cerebral vessels may also play a role
in the impairment of cerebral blood flow
Brain Protection
Hypertonic saline dextran
• Hypertonic saline dextran is used with encouraging
results in the treatment of elevated intracranial pressure
and head trauma with hypotension
• Its neuroprotective properties have been demonstrated in
animal models of brain ischemic injury
• Hypertonic saline dextran increases plasma osmolarity
has an inotropic effect on the heart, causes vasodilation,
is associated with better tissue perfusion and oxygenation,
and attenuates the ischemia-reperfusion injury
• Dextran may have its own beneficial immunomodulatory
effects that hydroxyethyl starch is lacking, possibly
making HSD superior
Brain Protection
Hypertonic saline
• Hypertonic saline, its rapid and powerful hemodynamic
effects, however, last only 30 to 60 minutes.
• Hypertonic saline was combined with a hyperoncotic
substance such as dextran (HSD) or hydroxyethyl starch,
yielding a more sustained effect which lasts up to 3 to 4
hours
• Hypertonic saline has a direct effect on the inflammatory
response, suppressing neutrophil activation and
decreasing susceptibility to sepsis after hypovolemic shock
• Indeed, hypertonic saline has been shown to downregulate the expressions of some key adhesion molecules
of neutrophils
Carbon Dioxide on Hypothermia
Roles in metabolism
• Carbon dioxide is the major end product of cellular
metabolism, continuously being produced by all cells.
• Increased solubility of carbon dioxide which is 20 times
more soluble than oxygen
• Decreased dissociation and reduction of hydrogen ion
activity
• Increased carrying power of blood for carbon dioxide
by blood through an increased ability of blood buffers
• Decrease in the base-binding capacity of protein by
decreased ionization process of protein and increase in
the amount of free base or hydrogen ion acceptor
Hypothermic Circulatory Arrest
Management strategies
•
•
•
•
•
•
Cerebral metabolic rate
Direct & secondary ischemic injury
Cerebral blood flow
Management of temperature
Neurologic injury after DHCA
Prevention of ischemic neurologic damage
Hypothermia on Brain
Effects
• Hypothermia reduces the metabolic rate of the CNS
and lengthens the period of the tolerated ischemia.
• The CNS almost exclusively extracts its energy through
the aerobic process of glycolysis
• The uptake of oxygen or glucose is consequently a
reliable parameter of the metabolic rate
• Reduction of metabolic rate in relation to temperature
espouses an exponential curve with a greater drop at
high temperatures (about 6 % for 1 C around 37 C)
• Clinically, electrocerebral silence is obtained at a mean
nasopharyngeal temperature of 17.5 C , but the
minimal nasopharyngeal temperature to obtain silence
in all patients was 12.5 C
Hypothermic Circulatory Arrest
Limitations
• Duration of safe circulatory arrest at a given
temperature should not be seen as a clear-cut time
period, with successive biochemical alterations,
followed by ultrastructural, then structural changes
• Recovery of oxygen consumption is already impaired
after 15 minutes of ischemia at 18 C, and cerebralproduced lactate is detectable after 20 minutes of
ischemia
• Eletromagnetic signals of phosphocreatine decreases
rapidly, followed by that of adenosine triphosphate,
after circulatory arrest. These signals become hardly
detectable after 32 to 36 minutes of ischemia at 15 C in
animal. Parallel to their disappearance, signals of
inorganic phosphate & pH progressively rise within cell
Ischemic Brain Injury
Direct injuries
• Cellular injury occurs because of a rapidly occurring
intracellular acidosis and a more progressive
dissipation of ionic gradients across membranes after
cessation of blood delivery to neuron
• Accumulation of calcium within cell and attraction of
osmotically obligated water are striking
• Endothelial cells are also sensitive to ischemia and
vasoactive factors activation & productions are
impaired after ischemia and results in increased
cerebral vascular resistance
Ischemic Brain Injury
Secondary injuries
• Reperfusion injuries (secondary injuries) operate at a
cellular(oxygen provoke reactive free radicals) & at a
vascular (recirculation of blood induce aggregation &
adhesion of thrombocytes & neutrophil to endothelium)
level and these cellular complexes release potent
inflammatory mediators & vasoconstrictor agents
• Electrical hyperactivity of the brain after ischemia
can produce extensive damage, a cellular energetic
mismatch and the release of toxic neurotransmitters,
paradoxically vulnerable in the extracellular space
• Protracted cellular dysfunction and apoptosis lead
to
a delayed neuronal death
Postoperative Seizure
Risk factors
• Children with CHD are an at-risk population for
neurodevelopmental problems, with a high incidence of
microcephaly & congenital structural abnormalities, as
well as acquired lesions.
• Cerebral hypoperfusion and low cerebral oxygen
saturation are present in some children before surgical
intervention.
• Postoperative events, such as low cardiac output,
hypoxia, and hypotension, can cause CNS injury or
exacerbate existing injury.
• The use, duration, or both, of DHCA alone does not
explain the incidence of postoperative seizures
Postoperative Seizure
Risk factors
• Factors such as polymorphisms in genes regulating the
inflammatory response or neuronal repair are likely
important determinants of this variability.
• It is probably not possible to define a safe threshold for
exposure to DHCA, CPB, or both for all children below
which no injury will occur.
• Inability to identify or quantify an injury and its
sequelae does not mean an injury has not occurred.
As children mature, subtle deficits affecting learning,
attention, behavior, and other higher functions become
apparent.
Cerebral Blood Flow
Low-flow & intermittent perfusion
• Prevent anaerobic glycolysis and intracellular acidosis,
and prolong cerebral tolerance to ischemia
• Minimal flow rate in humans is 11ml/kg/min at 18 C, but
in clinical practice, minimal flow rate is ranging 5 to
30ml/kg/min at 18 C
• Metabolic homeostasis is maintained throughout when
intermittent perfusion was established after short period
of ischemia (every 20 minutes at 18 C for 2 minutes
perfusion)
Pulsatile flow
• Provides hemodynamic advantages over nonpulsatile
perfusion that become significant with borderline
pressure and flow
Blood Gas Managements
Alpha-stat strategy (patient temperature uncorrected)
• Alpha-stat management (mechanism prevailing in reptiles)
aims at maintaining normal acidemia and blood gases ( a
pH of 7.40 and a PaCO2 of 40mmHg) in the rewarmed (37C)
blood. In vivo, the hypothermic blood is alkalemic and
hypocapnic
• Alpha-stat management preserves autoregulation of brain
perfusion and optimizes cellular enzyme activity.
• In alkalemia and hypothermia, oxyhemoglobin dissociation
is shifted to right, corresponding to an increased affinity of
oxygen for hemoglobin.
• At deep temperature reduction, oxygen diluted in blood
represents the major source of oxygen to tissues
• When a pH more alkaline than alpha stat (alkaline-stat
regulation), brain tissue pH was more higher
Blood Gas Managements
pH-stat strategy (patient temperature corrected)
• The pH-stat managements (mechanism prevailing in
hibernating animals) aims at maintaining normal values
in vivo, in the hypothermic blood. When rewarmed to
37C, the blood becomes acidemic & hypercapnic
• The pH-stat stategy results in a powerful & sustained
dilation of cerebral vessels because of high level of carbon
dioxide
• Autoregulation of brain perfusion is lost & cerebral blood
flow greatly increased, resulting a quick & even cooling
• Hypercapnia shifts oxyhemoglobin dissociation curve
toward the left & results in an increased availability of
oxygen to tissues
Management of Temperature
Cooling
• A slow rate of cooling or rewarming and a high blood
flow are the two factors ensuring homogenous changes
of the body temperature.
• Occlusive vascular disease & altered vascular reactivity
may reduce cerebral perfusion and delay temperature
equilibration
• Oxygen availability is reduced during hypothermia and
parallel decrease in metabolic rate is likely to preserve a
balance between availability & requirement of oxygen
• Increased hematocrit could compensate for decreased
oxygen availability related to hypothermia , so cooling
should be performed slowly & with an adequate Hct.
Management of Temperature
Rewarming
• Restart perfusion slowly after circulatory arrest, ensuring optimal
hemodynamic conditions, and avoiding cerebral hyperactivity
• Initial “cold blood-low pressure reperfusion” with a sufficient Hct.
washes out metabolites, buffers free radicals, and provides substrates
before cerebral electrical activity
• Hyperglycemia, stimulated by release of endogenous catecholamines,
increases intracellular acidosis & prevent metabolic homeostasis
• During rewarming , cerebral vascular resistance & energetic metabolism
are impaired in proportion to ischemia, glucose is in part diverted to less
efficient anaerobic pathway, and oxidative phosphorylation is disturbed
• This vulnerable period can last for 6-8 hours after reperfusion, and
hyperthermia exacerbates cerebral activity & disturbs cellular
metabolism, so a relative hypothermia is beneficial
Acid-Base Regulatory Strategy
 pH-stat strategy
•
•
•
•
Aim ; constant pH,
Total CO2 ; increased
Intracellular state ; acidosis
Alpha-imidazole & buffering ; excess(+) charge &
 Alpha-stat strategy
•
•
•
•
Aim; constant OH/H,
Total CO2 ; constant ,
Intracellular state ; neutral
Alpha-imidazole & buffering ; constant net charge &
pH-STAT
Advantages
• Enhance cerebral blood flow
• Enhance cerebral oxygenation
• Maintain normal intracellular pH during
cooling
• Improve brain cooling & faster recovery
of intracellular pH, cerebral high energy
metabolites and oxygenation after HCA
pH-STAT
Disadvantages
• Detrimental to cardiac & brain function
• Increase the risk of cerebral embolism
• Increase the regional ischemia
(steal through collateral)
Alpha-STAT
Advantages
• Maintain cerebral autoregulation
• Maintain cerebral flow/metabolism
coupling
• Less neuropsychological damage
• Reduction of global cerebral perfusion
in low temperature is disadvantageous
Alpha-STAT
Disadvantages
•
•
•
•
Less metabolic suppression in hypothermia
Intracellular alkalosis during cooling
Need of higher hematocrit
Disturbed cerebral oxygenation during fast
rewarming
Optimal Neurologic Protection
Variables
•
•
•
•
•
•
•
•
•
Perfusion pressure
Flow rate
Duration of cooling
Duration of circulatory arrest
Hematocrit
Ultrafiltration
Blood gas strategy
Presence of collateral flow
Impact of age
pH-STAT
Advantages
•
•
•
•
•
•
•
•
•
•
•
•
Better brain cooling efficacy & slower cortical deoxygenation
Increase the prearrest Sco and Sco half-life
Increase cortical O2 supply & slow cortical oxygen consumption
Improve the neurologic outcome in pediatric patients
Similar nerodevelopmental outcome
Inhibit lactate build-up and glutamate excitotoxicity during arrest
and early reperfusion
Improve the cerebral perfusion during rewarming
Increase the cerebral tissue oxygenation
Similar leukocyte/Endothelial interaction during hypothermic
bypass
Better immature brain protection
Better outcome in immature brain tissues with AP collateral.
Increased SJVo2 & decreased AV oxygen and glucose difference
Mechanisms of Brain Protection
By changes in temperature
1. Alterations in metabolic rate
2. Alterations in membrane stability
( including blood-brain barrier )
3. Alterations in membrane depolarization
4. Temperature-induced ion homeostasis
( including calcium fluxes )
5. Neurotransmitter release or uptake
6. Enzyme function
(phospholipase, xanthine oxidase, or NO synthase)
7. Free radical production or endogenous scavenging
Hypothermic Circulatory Arrest
Focal neurologic injury
• Due to interruption of blood in a terminal vascular
territory usually following embolism of material or gas
• Less frequently, a prolonged subliminar perfusion of
the brain can result in a localized necrosis in the
transition area between two vascular territories
(watershed lesion)
• The clinical expression is typical motor-sensory deficit,
aphasia, or cortical blindness
• Age, atherosclerosis, and manipulation of aorta are risk
factors, but not duration of circulatory arrest
Hypothermic Circulatory Arrest
Diffuse neurologic injury
• Due to a global cerebral ischemia that induces various
levels of cellular dysfunction, and areas with reduced
perfusion (atherosclerosis), or increased metabolic
activity (hyppocampus), are most vulnerable
• The spectrum ranges from transient confusion, stupor,
delirium, agitation, and debilitating ones like seizures,
parkinsonism, and coma
• Age, improper conduct of CPB, and prolonged duration
of circulatory arrest are common risk factors
• Disorders that impair vascular reactivity and cerebral
autoregulation, like diabetes, and hypertension, has been
associated with increased incidence
Brain Protection
Methods
•
•
•
•
•
•
•
•
•
•
Documented. Possible. Hypothetical
Slow cooling & rewarming
0
Ice-packing of the head
0
Wait for electrical silence
0
Continuous antegrade perfusion
0
Intermittent antegrade perfusion
0
Continuous retrograde perfusion
0
High hematocrit
0
Pharmacologic blockade of neurotransmitter
0
Pharmacologic enhance of vascular function
0
Pharmacologic prevention of reperfusion injury
0
Neuroprotection of Valproate
Mechanisms
• Valproate acts on phosphatidylinositol 3-kinase/protein
kinase B pathway in an insulin-dependent manner to
protect against apoptosis in cerebellar granule cells
• In addition, lipid peroxidation and protein oxidation
during oxidative stress are reduced by chronic
treatment with valproate
• The expression of endoplasmic reticulum stress proteins,
which inhibit oxygen free radical accumulation, is
enhanced after treatment with valproate
Methods for Brain Protection
 Antegrade cerebral perfusion
• Perfusate temperature is usually set at 18C and the flow is 1020ml/kg/min or pressure between 40-50mmHg in radial artery
• Left common and subclavian artery be occluded to avoid a steal
 Retrograde cerebral perfusion
• The risk rises after 60 minutes of DHCA, perhaps at the extinction
of intracellular energy substrates
 Integrated perfusion
• Circulatory arrest is established only after electrical silence and
jugular venous saturation over 95%
• During 10-20 minutes preceding circulatory arrest, temperature of
the perfusate lowered to 13 C to further reduce brain temperature
• A short period of retrograde cerebral perfusion can be performed
to wash out emboli of the arch arteries before antegrade perfusion
• Arch arteries are connected to a graft for antegrade perfusiom
Cardiopulmonary Bypass
Effect on the brain
• Generally, transient & permanent neuro or
neuropsychiatric injury occurs in as many as
25% of all infants undergoing cardiopulmonary
bypass with or without circulatory arrest.
• Although the subtle neurologic injury is
common in adult undergoing CPB, the
physiologic impact of bypass in adults is very
different from that of children.
Perfusion Strategies
Effect on the brain
1. Non-pulsatile vs. pulsatile perfusion
2. Aortic and venous cannulation
Venous obstruction by large, stiff venous cannulas
Preferential flow with aortic cannula placement
3. Air embolism
Cannulation
Aortic cross-clamp removal
High pump flow rate
Use of agents that increase perfusion pressure
Cardiopulmonary Bypass
Brain injury in adults
1. Atheromatous emboli
2. Fixed cerebrovascular stenosis
3. Moderate hypothermia is used.
4. Relative vasodilation by PH-stat
1) Increased cerebral delivery of embolic material
2) Steal blood flow away from post-stenotic area
Cardiopulmonary Bypass
Brain injury in infants
1 Hypoperfusion during low or no blood flow
2 Deep hypothermia is used.
3 Cerebral oxygen supply will be enhanced .
4. High incidence of air embolism
(1) Presence of intra- and extracardiac communication
between systemic and pulmonary circulation
(2) Increased amount of intracardiac surgery
Cardiopulmonary Bypass
Risk factors of brain injury
in children
• Intra and extracardiac communication
• Increased amount of intracardiac surgery
• Use of pH strategy (cerebral hyperemia,
increased brain edema)
• Increased metabolic demand for neuronal
growth, myelinization in neonate
Ischemic Brain Injury
 At normothermic state
1.
2.
3.
4.
5.
6.
7.
8.
ATP, phosphocreatine depletion
Release of excitatory neurotransmitters
Altered ionic permeability
Calcium influx
Phospholipase C & A2 release free fatty acid,
such as arachadonic acid
Leukotriene level increase dramatically after ischemia
Nucleases become active after ischemia
Enzymatic breakdown of ADP & AMP
Cardiopulmonary Bypass
 Hypothermic effects on the brain
1. Cerebral blood flow decreases in a linear
relationship with temperature.
2. Cerebral metabolism decreases exponentially
with a reduction in brain temperature.
3. Flow / metabolism coupling ratios increase
with decreasing temperature.
4. Effects of CO2 regulation
5. CO2 management
alpha-stat, pH-stat, alkaline stat
Ischemic Brain Injury
Effect of hypothermia
• Preventing excitatory neurotransmitter
release
• Restricting membrane permeability
• Preventing calcium entry into the cell
Hypothermic Brain Injury
Etiology of brain injury
• Temperatures of 10℃ and below are probably
not deleterious as long as hemodilution is used.
• In general, capillary sludging, massive air
emboli, inadequate cerebral cooling, cerebral
steal appear to be more important factors.
Brain Death
Etiologies of cardiac dysfunction
1. Direct cardiac myocyte injury
2. Catecholamine induced myocardial damage
3. Impairment of the beta-adrenoreceptoradenylyl cyclase system, as well as hormone
depletion
4. Systemic vascular resistance decrease as a
consequence of loss of sympathetic tone
Cerebral Function with CPB
Effects of hemodilution
• Degree of hemodilution during CPB and stroke is
biologically plausible
• Hemodilution may increase embolic load to the brain
by increasing cerebral blood flow (which is two to three
times higher at a hematocrit of 15% than at 25%)
• The effects of hemodilution on oxygen delivery is
impaired in ischemic brain cells.
• Cells in ischemic areas of the brain may not receive
adequate supplies of oxygen with severe hemodilution
to levels that are commonly used during CPB
Cerebral Ischemic Injury
Prevention by hypothermia
1. The normothermic brain
2. The hypothermic brain
3. Deep hypothermic circulatory arrest
with intermittent perfusion
4. Low flow CPB
5. Direct brain injury from hypothermia
Neural damage after Ischemia
Pathophysiology
•
•
•
•
•
•
•
Excitotoxicity
Cell death mediated by nitrous oxide
Calcium overload in the cell
Eicosanoid formation
Inflammatory reaction
Apoptosis
Free radicals
Hypothermia on Brain
Protective effect mechanism
• Preservation of high energy phosphate
store
• Preventing excitatory neurotransmitter
release( glutamate, dopamine )
• Restricting membrane permeability
• Preventing calcium entry into the cell
Glucose Regulation
Effects of hypothermic CPB
• Conclusive evidence of the detrimental effect of
hyperglycemia during complete, incomplete and
focal cerebral ischemia
• The role of glucose in potentiating cerebral
injury appears due to two factors ;
ATP utilization and lactic acidosis (inhilbitor
of the enzyme phosphofructokinase).
Cardiopulmonary Bypass
Rewarming from hypothermia
1. In response to a period of hypothermic, hemodiluted,
nonpulsatile perfusion, brain responds with hyperemia,
increased oxygen extraction & increased metabolism
during rewarming and weaning period of CPB.
2. After TCA, cerebral blood flow, & cerebral metabolism
are reduced below baseline measurements and oxygen
extraction doesn’t increase with reperfusion, the rate
at which brain recovers ATP, pH, & PO2 is markedly
delayed when compared to continuous flow CPB.
3. By increasing efficiency of pump flow (pulsatility),
increasing pump flow rate or increasing hematocrit,
oxygen delivery should improve during rewarming.
Cerebral Ischemia
Effect of hyperglycemia
• Although a strong argument can be made for the
detrimental effects during ischemia, there is very little
evidence supporting worsening neurologic outcome in
hyperglycemia during CPB or TCA.
• One can not ascribe the neuropathologic insult to
hyperglycemia alone.
• The damaging effect may well be age-related and other
associated factors (flow, pressure, periods of hypoxia,
thrombocytopenia, vascular responses).
Cerebral Ischemia
Effect of hypoglycemia
1. Hypoglycemia is a frequent concern in neonate and
children during the perioperative period.
* Reduced hepatic function
* Decreased glycogen storage
2. The hypoglycemia can result in neurologic injury
throughout the perioperative period.
3. The addictive effect of hypoglycemia, even if mild, may
cause additional alterations in cerebral autoregulation
and culminate in increased cortical injury.
Cardiopulmonary Bypass
During arch reconstruction
• Hypothermia at 18 ºC
• Low flow rate without circulatory arrest
* 0.4 ~ 0.8 L/min/BSA
* 20 ml/kg/min
• Route of brain perfusion
* Innominate artery through distal ascending aorta
* Ascending aorta with proximal arch clamp
* Through the shunt of innominate artery
Cerebral Function
Principles of regulation
• Normally, cerebral blood flow is independent of cerebral perfusion
pressure over a range of 50-150mmHg, with the primary determinant
of flow being cerebral metabolic rate.
Outside of this range of autoregulation, CBF is directly related to CPP.
• Variables such as the methods of acid-base management, mean arterial
pressure, flow rate, and type of perfusion, and their effect on cerebral
circulation remain controversial.
• Global increase in CBF due to elevation of PaCO2, and associated
cerebral vasodilation may critically reduce perfusion pressure and
jeopardize of areas of brain dependent on flow through stenosed vessels.
• Cerebral hyperperfusion may potentially deliver more gaseous and
particulate microemboli into cerebral circulation.
• Cerebral blood flow is also affected by anesthetic agents.
Ph-stat in Infants
Explanations for protection
• Extracellular acidosis may inhibit cerebral
excitotoxicity.
• CO2 exert a direct suppressive effect on brain
metabolic rate of oxygen.
• Higher intra-ischemic carbon dioxide appears
neuroprotective.
• Hypercarbic acidotic reperfusion improves
recovery of systolic ventricular function and
coronary blood flow by decreased uptake of
lethal calcium and coronary vasodilation
beneficial.
Intermittent Circulatory Arrest
Principles of intermittent perfusion
• A certain periods of reperfusion does not result in full
repletion of intracerebral high energy phosphate stores
or resortation of intracellular pH.
• A second period of hypothermic arrest or perhaps a brief
period of hypotension in the postoperative period may
results in greater neurologic injury than anticipated
because of reduced cerebral energy stores and altered
vascular responses after TCA.
Intermittent Circulatory Arrest
 Advantage & rationale
1. Brain is an organ with a high energy demand &over 90%
of energy produced by mitochondria in the brain is derived
from oxygen & glucose.
2. Brain oxygenation steadily decreased during retrograde
cerebral perfusion and insufficient supply.
3. Establishment of optimal periods of circulatory arrest &
recirculation to prevent anaerobic metabolism to reduce
ischemic brain damage
4. Aerobic metabolism is maintained during the 1st 20 minutes
of DHCA but rapidly changed over to anaerobic metabolism
after the 1st 30minutes of DHCA.
5. Brain edema increases as anaerobic metabolism continues.
Cardiopulmonary Bypass
 Cerebral vulnerability
Microcirculatory dysfunction after TCA
Increased capillary permeability
Increase metabolic rate after TCA
(hyperthemia)
Decreased substrate delivery
( hypoglycemia)
Worsening right ventricular function
(elevation of venous pressure)
Hypothermic Circulatory Arrest
Development of seizures
1. The frequency of seizures was found to be
associated with the duration of circulatory
arrest.
2. The perioperative seizures have little effect on
subsequent cognitive development. (?)
3. There is a strong correlation between
occurrence of perioperative seizures & retarded
motor development.
Hydroxyethyl Starch
Natures
• Hydroxyethyl starch solution is an artificial colloidal
solution, and it causes transport of water into
intravascular space
• Iinhibit leukocyte adhesion and chemotaxis and
decreased vascular permeability in endothelial tissue
• These kinds of solutions prevent the capillary leakage
developed during CPB.
• Solutions like HES can prevent the activation of
inflammatory process during CPB as well as the
following leukocyte activation and tissue edema.
• HES increased prothrombin time, activated partial
thromboplastin time, coagulation time, and bleeding
time
S-100 Protein
Nature
1. A type of protein synthesized in the astroglial cells
in the CNS
2. Structural damages to the brain causes a selective
leakage into the cerebrospinal fluid.
3. Less selective permeability of the blood-brain
barrier & higher protein turnover in the children
4. Low renal excretion rate in the young children
5. Biologic half-life of S-protein has been estimated
about 2 hours.