**3. Hypoxic brain injury**

As the physiologist Haldane said: "Hypoxia not only stops the machine it wrecks the machinery" [2]. A healthy fetus can respond to, and tolerate, the early effects of hypoxia, and the degree of acidosis that occurs initially in response to the associated retention of carbon dioxide. Acute hypoxia promotes adenosine release, which reduces fetal cerebral oxygen consumption via action on neuronal A1 receptors on the cerebral arteries, and initiates vasodilatation through activation of A2 receptors; release of nitric oxide and opioids and direct effects of hypoxia on the vascular endothelium also contribute [53]. As a result, while fetal vascular resistance can decrease up to 50%, the net effect is to maintain CBF with only minimal reduction in oxygen delivery; but normal or elevated mean arterial blood pressure is critical in parallel, and once hypotension ensues the brain suffers from the resulting ischemia.

With moderate HI stress and evolving acidosis, the fetus also has the physiologic ability to preferentially perfuse the deep structures of the brain that have higher metabolic rates (brainstem, cerebellum, basal ganglia). However, this compensatory redistribution of blood from the anterior to the posterior circulation results in the brain's cortical areas being less well perfused, and hence, if ongoing hypoxia remains unrecognized and unrelieved over the course of an hour or more, the end result is damage to cortical white matter, and the watershed areas of the cerebral hemispheres. In contrast to this partial prolonged pattern of injury, situations occur where the HI event is near total in nature and the effect profound. With such insults, acidosis develops relatively abruptly, and little or no compensatory redistribution of blood to the deep brain structures occurs, because there is no time for effective redistribution of CBF to maintain their perfusion. Hence it is the basal ganglia and thalami that are predominantly injured, and damage happens over a much shorter time frame [9, 54–56]. In the premature, mild to moderate HI injury results in periventricular leukomalacia and germinal matrix bleeds, and in full term neonates parasagittal watershed infarcts are seen [55, 57]; severe injury in both term and preterm infants involves deep gray matter.

Distinction between partial/prolonged and near total/profound/patterns of injury is important from a diagnostic and prognostic standpoint, for understanding potential mechanisms for prevention, and over issues of causation in a medico-legal context. Modern neuroimaging is the definitive way to distinguish between them based on the selective geographic patterns of brain damage caused. Importantly however, mixed patterns of injury are also seen that involve both the cortex and deep structures [55, 57]. The mechanisms involved can be either superimposed insults involving periods of both partial/prolonged and near total/profound injury, or, situations where partial and prolonged injury is severe enough to extend to involve the deep brain nuclei, or vice versa, when a near total, profound event is extensive enough to also involve cortical damage [11, 58].

The time line of near-total HI events can be extrapolated from data obtained in animal studies, where fetal monkeys were exposed to complete (i.e. total) hypoxia and ischemia, generated by ligating the umbilical cord and preventing breathing. These animals could tolerate 10 minutes of HI insult without permanent effects if delivered and resuscitated immediately, but, where the HI event was continued beyond this 10-minute period for an additional 10 minutes, a progressive and cumulative increase in the level of neurological damage was then evident. Where the whole insult extended beyond 20 minutes, the fetal monkeys died, in spite of delivery and immediate resuscitation.

In applying these data to the human fetus, it is recognized that what occurs most often is a near total (profound) interruption of brain blood flow and oxygen delivery, rather than an event where hypoxia and ischemia are absolutely total in nature. Hence the time-line for tolerance of such events, and the period over which brain damage evolves, are accepted as being longer than in the landmark animal studies conducted by Myers [59–62]. For this reason, it is generally agreed that approximately 15 minutes, and possibly up to 20 minutes, of sudden profound asphyxia can be tolerated by the human fetus prior to brain damage beginning (in contrast to the 10 minutes seen in the animal model). Then, after this 'grace' period, damage to the brain begins to occur, and over a further period of 15 to 20 minutes the extent and severity of injury become progressively more profound over time. And beyond this time frame, a human fetus is usually born dead. It is important to recognize that the principal mechanism that causes fetal asphyxial brain injury is cerebral ischemia caused by the severe reduction in CBF that occurs as a result of hypoxic myocardial depression significantly reducing cardiac output (CO). The fetal heart has a fixed stroke volume, which means that CO, and the amount of blood supplied to the brain are a direct function of the rate of contraction; so, for example, with bradycardia where fetal heart rate slows to half normal, this equates to a 50% fall in CO, and a comparable reduction in CBF will result. CO also decreases where tachycardia accompanies hypoxic stress; at high heart rates poor contractility secondary to acidosis is then compounded by incomplete atrial filling in diastole.

The relationships between the geographic pattern of asphyxial brain injury and type of resulting disability have been defined [63], and the predictors of long-term morbidity delineated [64]. Near-total insults of moderate duration and degree which have the basal ganglia and thalamic pattern of damage, predominantly lead to athetoid or dystonic cerebral palsy, with intact or mildly impaired cognitive development. When severe, near-total insults damage the cerebral cortex in addition to the deep brain structures; and severe spastic quadriplegia results, with microcephaly, significant cognitive deficits and cortical visual impairment. The extent of injury is strongly associated with the intensity of resuscitation, the degree of encephalopathy, and severity of seizures [55, 65]. Prolonged partial insults of moderate degree with

**71**

*Pathogenesis and Prevention of Fetal and Neonatal Brain Injury*

injury confined to watershed regions cause variable degrees of cognitive deficit and epilepsy, and can be associated with spastic quadriplegia. But, when more severe or prolonged, injury causes extensive cortical brain involvement, or global brain injury; the end result is spastic quadriplegia, severe cognitive impairment, cortical visual impairment, and microcephaly. In addition, symptomatic brainstem involvement can

**Hypoxic ischemic encephalopathy (HIE)** is a clinically defined syndrome of disturbed neurological function in the earliest days of life, caused by intrapartum or late antepartum brain hypoxia and ischemia [67]. HIE evolves clinically following significant HI insult, and is a major predictor of neurodevelopmental disability. HIE develops in 1 to 8 per 1000 live births in developed countries, and up to 26 per 1000 worldwide [65, 67]; not all cases of neonatal encephalopathy are due to anoxia or HI injury [8, 58], but epidemiological studies confirm the association of HIE with pregnancy related risks, and intrapartum risk factors that predispose the fetus to hypoxia; 15-20% of affected infants die; in about 25% of survivors permanent neurologic deficits remain. Prospective studies employing MRI suggest that the majority of HIE occurs as a result of HI insult and brain injury at or near the time of birth [41]. Postnatal exacerbation of intrapartum acquired injury occurs relatively rarely (10%), but is a potentially preventable

Hallmarks of neonatal encephalopathy are neurological depression, with altered level of consciousness and often respiratory depression, abnormal muscle tone and power, disturbances of cranial nerve function, and seizures. HI injury is strongly suggested in a neurologically depressed infant by associated acidosis, and further

Acidosis has two components: respiratory - from retained carbon dioxide, and metabolic - from accumulation of fixed acids (lactic acid and β-hydroxybutyrate). While acidosis present at birth usually resolves in the first hours of life, HIE progresses with further depression of consciousness, abnormalities in tone and movement, and onset of seizures. Infants exhibit a range of behaviors and alterations of conscious level from lethargy and obtundation to irritability and a hyper-alert state. Similarly, disorders of tone range from a marked decrease to hyper-tonicity. Abnormal movements include tremors, jitteriness, mouthing and blinking, and 'bicycling' of the legs, through to frank seizures. Other manifestations include apnea, with bradycardia and impaired oxygen saturation, shrill cry, feeding difficulty (due to poor coordination of suck or altered peristalsis, and occasionally brain stem damage), absence of the Moro and/or gag reflexes, and exaggeration of deep tendon reflexes. Decerebrate or decorticate posturing may be seen. Sarnat et al. defined three levels of severity (mild, moderate and severe); these are linked to the probability that HIE will result in permanent neurological consequences [69]. The pathophysiology of HIE is now better understood and treatment with hypothermia has become the foundation of therapy [67]. All affected infants require supportive management that anticipates and limits the adverse effects on the brain of fluctuations in cerebral perfusion, metabolic instability, sepsis, suboptimal respiration, and any situation that increases oxygen and energy demands. This involves correction of hypotension, attention to glucose, fluid and electrolyte homeostasis, maintenance of PaCO2 in the normal range, and treatment of seizures [58, 67]. Neuroimaging (US, CT, MRI) is best done at defined periods after injury [41, 57]; MRI in particular can then define the diagnosis, pattern, severity, timing and prognosis, and help rationalize hypothermia and other interventions, including the withdrawal of support. Several neuroprotective agents that can be combined with hypothermia have entered clinical trials; new biomarkers for HIE are being sought [70]. Affected survivors need follow up to manage their handicaps.

be associated with severe patterns of injury, and lead to non-survival [66].

*DOI: http://dx.doi.org/10.5772/intechopen.93840*

component in many instances [11, 67].

confirmed by concomitant multi-organ injury [58, 65, 68].

#### *Pathogenesis and Prevention of Fetal and Neonatal Brain Injury DOI: http://dx.doi.org/10.5772/intechopen.93840*

*Advancement and New Understanding in Brain Injury*

and preterm infants involves deep gray matter.

extensive enough to also involve cortical damage [11, 58].

delivery and immediate resuscitation.

neonates parasagittal watershed infarcts are seen [55, 57]; severe injury in both term

Distinction between partial/prolonged and near total/profound/patterns of injury is important from a diagnostic and prognostic standpoint, for understanding potential mechanisms for prevention, and over issues of causation in a medico-legal context. Modern neuroimaging is the definitive way to distinguish between them based on the selective geographic patterns of brain damage caused. Importantly however, mixed patterns of injury are also seen that involve both the cortex and deep structures [55, 57]. The mechanisms involved can be either superimposed insults involving periods of both partial/prolonged and near total/profound injury, or, situations where partial and prolonged injury is severe enough to extend to involve the deep brain nuclei, or vice versa, when a near total, profound event is

The time line of near-total HI events can be extrapolated from data obtained in animal studies, where fetal monkeys were exposed to complete (i.e. total) hypoxia and ischemia, generated by ligating the umbilical cord and preventing breathing. These animals could tolerate 10 minutes of HI insult without permanent effects if delivered and resuscitated immediately, but, where the HI event was continued beyond this 10-minute period for an additional 10 minutes, a progressive and cumulative increase in the level of neurological damage was then evident. Where the whole insult extended beyond 20 minutes, the fetal monkeys died, in spite of

In applying these data to the human fetus, it is recognized that what occurs most often is a near total (profound) interruption of brain blood flow and oxygen delivery, rather than an event where hypoxia and ischemia are absolutely total in nature. Hence the time-line for tolerance of such events, and the period over which brain damage evolves, are accepted as being longer than in the landmark animal studies conducted by Myers [59–62]. For this reason, it is generally agreed that approximately 15 minutes, and possibly up to 20 minutes, of sudden profound asphyxia can be tolerated by the human fetus prior to brain damage beginning (in contrast to the 10 minutes seen in the animal model). Then, after this 'grace' period, damage to the brain begins to occur, and over a further period of 15 to 20 minutes the extent and severity of injury become progressively more profound over time. And beyond this time frame, a human fetus is usually born dead. It is important to recognize that the principal mechanism that causes fetal asphyxial brain injury is cerebral ischemia caused by the severe reduction in CBF that occurs as a result of hypoxic myocardial depression significantly reducing cardiac output (CO). The fetal heart has a fixed stroke volume, which means that CO, and the amount of blood supplied to the brain are a direct function of the rate of contraction; so, for example, with bradycardia where fetal heart rate slows to half normal, this equates to a 50% fall in CO, and a comparable reduction in CBF will result. CO also decreases where tachycardia accompanies hypoxic stress; at high heart rates poor contractility secondary to

acidosis is then compounded by incomplete atrial filling in diastole.

The relationships between the geographic pattern of asphyxial brain injury and type of resulting disability have been defined [63], and the predictors of long-term morbidity delineated [64]. Near-total insults of moderate duration and degree which have the basal ganglia and thalamic pattern of damage, predominantly lead to athetoid or dystonic cerebral palsy, with intact or mildly impaired cognitive development. When severe, near-total insults damage the cerebral cortex in addition to the deep brain structures; and severe spastic quadriplegia results, with microcephaly, significant cognitive deficits and cortical visual impairment. The extent of injury is strongly associated with the intensity of resuscitation, the degree of encephalopathy, and severity of seizures [55, 65]. Prolonged partial insults of moderate degree with

**70**

injury confined to watershed regions cause variable degrees of cognitive deficit and epilepsy, and can be associated with spastic quadriplegia. But, when more severe or prolonged, injury causes extensive cortical brain involvement, or global brain injury; the end result is spastic quadriplegia, severe cognitive impairment, cortical visual impairment, and microcephaly. In addition, symptomatic brainstem involvement can be associated with severe patterns of injury, and lead to non-survival [66].

**Hypoxic ischemic encephalopathy (HIE)** is a clinically defined syndrome of disturbed neurological function in the earliest days of life, caused by intrapartum or late antepartum brain hypoxia and ischemia [67]. HIE evolves clinically following significant HI insult, and is a major predictor of neurodevelopmental disability. HIE develops in 1 to 8 per 1000 live births in developed countries, and up to 26 per 1000 worldwide [65, 67]; not all cases of neonatal encephalopathy are due to anoxia or HI injury [8, 58], but epidemiological studies confirm the association of HIE with pregnancy related risks, and intrapartum risk factors that predispose the fetus to hypoxia; 15-20% of affected infants die; in about 25% of survivors permanent neurologic deficits remain. Prospective studies employing MRI suggest that the majority of HIE occurs as a result of HI insult and brain injury at or near the time of birth [41]. Postnatal exacerbation of intrapartum acquired injury occurs relatively rarely (10%), but is a potentially preventable component in many instances [11, 67].

Hallmarks of neonatal encephalopathy are neurological depression, with altered level of consciousness and often respiratory depression, abnormal muscle tone and power, disturbances of cranial nerve function, and seizures. HI injury is strongly suggested in a neurologically depressed infant by associated acidosis, and further confirmed by concomitant multi-organ injury [58, 65, 68].

Acidosis has two components: respiratory - from retained carbon dioxide, and metabolic - from accumulation of fixed acids (lactic acid and β-hydroxybutyrate). While acidosis present at birth usually resolves in the first hours of life, HIE progresses with further depression of consciousness, abnormalities in tone and movement, and onset of seizures. Infants exhibit a range of behaviors and alterations of conscious level from lethargy and obtundation to irritability and a hyper-alert state. Similarly, disorders of tone range from a marked decrease to hyper-tonicity. Abnormal movements include tremors, jitteriness, mouthing and blinking, and 'bicycling' of the legs, through to frank seizures. Other manifestations include apnea, with bradycardia and impaired oxygen saturation, shrill cry, feeding difficulty (due to poor coordination of suck or altered peristalsis, and occasionally brain stem damage), absence of the Moro and/or gag reflexes, and exaggeration of deep tendon reflexes. Decerebrate or decorticate posturing may be seen. Sarnat et al. defined three levels of severity (mild, moderate and severe); these are linked to the probability that HIE will result in permanent neurological consequences [69].

The pathophysiology of HIE is now better understood and treatment with hypothermia has become the foundation of therapy [67]. All affected infants require supportive management that anticipates and limits the adverse effects on the brain of fluctuations in cerebral perfusion, metabolic instability, sepsis, suboptimal respiration, and any situation that increases oxygen and energy demands. This involves correction of hypotension, attention to glucose, fluid and electrolyte homeostasis, maintenance of PaCO2 in the normal range, and treatment of seizures [58, 67]. Neuroimaging (US, CT, MRI) is best done at defined periods after injury [41, 57]; MRI in particular can then define the diagnosis, pattern, severity, timing and prognosis, and help rationalize hypothermia and other interventions, including the withdrawal of support. Several neuroprotective agents that can be combined with hypothermia have entered clinical trials; new biomarkers for HIE are being sought [70]. Affected survivors need follow up to manage their handicaps.
