Physical Address
304 North Cardinal St.
Dorchester Center, MA 02124
Hypoxic-Ischemic Injury in the Term Infant: Pathophysiology
Introduction
This chapter addresses the pathophysiology of hypoxic-ischemic injury. This is a dynamic process, characterized by an evolving cascade of events that may continue for days to weeks, months, and years after the initial insult. The neuropathology following primary, latent, secondary, and tertiary phases of injury include selective neuronal necrosis, parasagittal cerebral injury , and cerebral white matter injury (see Chapter 22 ). Though one or the other of these patterns may predominate in infants with hypoxic-ischemic disease, magnetic resonance imaging (MRI) studies do show considerable overlap (see Chapter 24 ). Several pathogenetic themes recur, including initiating factors, principally ischemia, impinging on specific anatomical and metabolic cellular and regional characteristics that underlie a maturation-dependent vulnerability. Ischemia is linked to a variety of deleterious perinatal events and to impaired cerebrovascular autoregulation. Regional patterns of ischemic injury occur especially in vascular border zones and end zones. At the cellular level, ischemia leads to cell death, both neuronal and oligodendroglial, via a cascade of events that particularly include excitotoxicity. The pathophysiological events and the cascade to cell death most often occur over relatively protracted temporal periods and thereby afford opportunities for preventative/ameliorative interventions (see Chapter 24 ). Expanding our knowledge of the key mechanisms of hypoxia-ischemia is vital to further improve outcomes.
This chapter is divided into two major sections. Part A emphasizes the principal patterns of injury and their pathogenesis, with a particular focus on ischemia as the dominant insult. Pathogenetic factors emphasized include the severity and timing of the usual insult and the regional vascular and cellular factors important in determining the locus of the pathology. Part B will emphasize the cellular and molecular details operative in the progression to cell death and to recovery mechanisms. These progressions develop in identifiable phases; that is, primary, latent, secondary, and tertiary. Understanding of these details provides insight into the formulation of interventions to prevent or ameliorate cellular injury (see Chapters 16 and 24 ).
PART A
CENTRAL IMPORTANCE OF ISCHEMIA AND PATTERNS OF INJURY
Cerebral Ischemia, Impaired Cerebrovascular Autoregulation, Pressure-Passive Cerebral Circulation
The final pathway to neuronal and preoligodendroglial death in the major forms of hypoxic-ischemic brain injury in the term infant begins with ischemia. Studies in human infants provide excellent support for the role of diminished cerebral blood flow (CBF) secondary to systemic hypotension. Impaired vascular autoregulation has been documented in the hours to days after the hypoxic-ischemic insult, and CBF becomes passively related to arterial blood pressure ( Box 23.1 ). This impairment renders the infant exquisitely vulnerable to decreases in blood pressure characteristic of a severe insult, and those regions most vulnerable are in the distribution of selective neuronal necrosis, the watershed/ parasagittal region of the cerebrum, and cerebral white matter (see later). The data of Pryds and co-workers clearly show that postinsult term infants with impaired autoregulation have the poorest neurological outcome ( Fig. 23.1 ).
BOX 23.1
Selective Neuronal Necrosis: Pathogenesis
Cerebral ischemia
Impaired cerebrovascular autoregulation with pressure-passive cerebral circulation
Systemic hypotension
Factors related to the hypoxic-ischemic insult
Severity and temporal characteristics
Preceding/concomitant infection/inflammation
Regional vascular factors
Regional distribution of excitatory (glutamate) receptors on neurons a
a Single most important factor for determining regional distribution of selective neuronal necrosis.
The causes of a pressure-passive circulation in newborns following hypoxia-ischemia may relate to (1) hypoxemia or hypercarbia, or both, associated with the primary insult; (2) postinsult impairment in vascular reactivity presumably related to the effect of one or more of the vasodilatory compounds that accumulate secondary to ischemia-reperfusion (see Chapter 16 ); (3) an “immature” autoregulatory system with limited capacity for reactivity because of the deficient arteriolar muscular lining of penetrating cerebral arteries and arterioles in the third trimester ; (4) an autoregulatory system with a lower limit so close to the range of normal blood pressure that even slight hypotension places CBF on the downslope of the curve; or (5) a combination of these factors. Whatever the mechanisms, the clinical implications are clear. Decreases in arterial blood pressure lead to decreases in CBF and injury to certain vulnerable brain cells— that is, neurons in the distribution of selective neuronal necrosis—and regions; that is, the parasagittal cerebrum and cerebral white matter (see later).
PATTERNS OF INJURY
The three principal lesions associated with hypoxia-ischemia in the term newborn are selective neuronal necrosis, parasagittal cerebral injury , and cerebral white matter injury . The neuropathology of these lesions is discussed in Chapter 22 and the MRI findings are discussed in Chapter 24 . The pathogenesis of each is discussed next.
Selective Neuronal Necrosis
Cerebral ischemia , with deprivation of oxygen and glucose, followed by reperfusion and a cascade of metabolic events is the likely pathogenetic sequence responsible for selective neuronal necrosis (see Box 23.1 ). Selective neuronal necrosis is the most common variety of injury observed in neonatal hypoxic-ischemic encephalopathy and refers to necrosis of neurons in a characteristic, although often widespread, distribution. MRI studies show an overall incidence of approximately 80% in infants with hypoxic-ischemic disease (see Chapter 24 ). Neuronal necrosis often coexists with other distinctive manifestations of neonatal hypoxic-ischemic encephalopathy, and it is unusual to observe one of the other varieties of neonatal hypoxic-ischemic encephalopathy without some degree of selective neuronal injury as well. The topography of the neuronal injury depends principally on the severity and temporal characteristics of the insult (see later).
Three Basic Patterns of Selective Neuronal Necrosis
Three basic patterns of injury , derived primarily from correlative clinical and brain imaging findings, can be distinguished in term and near-term infants ( Table 23.1 ). These patterns include diffuse neuronal injury (cerebral cortical, deep nuclear, brainstem) , a cerebral cortical–deep nuclear neuronal predominance that includes the basal ganglia (especially putamen) and thalamus, and a deep nuclear–brainstem neuronal predominance. Two other patterns, pontosubicular neuronal injury and cerebellar injury, are relatively uncommon (see Chapter 22 ).
TABLE 23.1
Major Patterns of Selective Neuronal Injury and Characteristics of Usual Insult in Term Newborns
| PATTERN a | SEVERITY AND TIMING OF USUAL INSULT b |
|---|---|
| Diffuse (cerebral cortex, deep nuclear, brainstem) | Severe, prolonged |
| Cerebral cortex–deep nuclear c | Moderate, prolonged |
| Deep nuclear c –brainstem | Severe, abrupt |
a The patterns reflect areas of predominant neuronal injury; considerable overlap is common.
b Severity and timing of insult are estimates, based on clinical and experimental studies (see text).
c Deep nuclear: basal ganglia (especially putamen) and thalamus.
The regional distribution of selective neuronal necrosis caused by ischemia relates to three principal factors (see Box 23.1 ). These include factors related to the severity and temporal characteristics of the insult(s), regional vascular factors, and the regional distribution of excitatory glutamate receptors on neurons. These three factors are discussed next.
You're Reading a Preview
Become a Clinical Tree membership for Full access and enjoy Unlimited articles
If you are a member. Log in here