Asphyxial Brain Injury Research Articles

Therapeutic Hypothermia for Birth Asphyxia in Neonates.

India contributes to the highest neonatal mortality globally. Birth asphyxia is one of the leading causes of neonatal mortality in India. A large number of neonates who suffer from birth asphyxia progress to Hypoxic Ischemic Encephalopathy (HIE). The risk of a neonate progressing to severe form of HIE is many times higher in the low and middle income countries (LMICs) with ill developed health infrastructure. Till date LMICs have had a low institutional delivery rate, poor regionalization of care, lack of adequate transport facilities and ill equipped neonatal intensive care facilities. This has lead to a tremendous burden on the health care systems with a cohort of developmentally challenged neonates surviving into adulthood. Recently, Therapeutic Hypothermia (TH) has emerged as an evidence based intervention to reduce mortality and neurodevelopmental disability associated with asphyxia induced encephalopathy. TH has become the gold standard in the management of such cases in the western world. Extension of this knowledge to the LMICs and countries like India require a better understanding of the unique sociocultural issues associated with asphyxial brain injury in neonates. The high incidence of sepsis and presence of economic constraints make this problem more complex in such countries. The current review has tried to address these issues and looked at the basics of this complex topic from the perspective of a general pediatrician.

Therapeutic hypothermia translates from ancient history in to practice.

Acute post-asphyxial encephalopathy around the time of birth remains a major cause of death and disability. The possibility that hypothermia may be able to prevent or lessen asphyxial brain injury is a “dream revisited”. In this review, a historical perspective is provided from the first reported use of therapeutic hypothermia for brain injuries in antiquity, to the present day. The first uncontrolled trials of cooling for resuscitation were reported more than 50 years ago. The seminal insight that led to the modern revival of studies of neuroprotection was that after profound asphyxia, many brain cells show initial recovery from the insult during a short “latent” phase, typically lasting approximately 6 h, only to die hours to days later after a “secondary” deterioration characterized by seizures, cytotoxic edema, and progressive failure of cerebral oxidative metabolism. Studies designed around this conceptual framework showed that mild hypothermia initiated as early as possible before the onset of secondary deterioration, and continued for a sufficient duration to allow the secondary deterioration to resolve, is associated with potent, long-lasting neuroprotection. There is now compelling evidence from randomized controlled trials that mild induced hypothermia significantly improves intact survival and neurodevelopmental outcomes to mid-childhood.

Variations on fetal heart rate variability.

Intrapartum electronic fetal monitoring (EFM) is widely used throughout the developed and developing world. This practice is based on the understanding that fetal heart rate (FHR) is sensitive to hypoxia. During labour, the fetus may be exposed to acute hypoxia during uterine contractions or intrapartum insults, and has well‐established cardiovascular compensatory defence mechanisms, which ideally prevent hypoxic–ischaemic encephalopathy by maintaining perfusion pressure and substrate delivery to essential organs (Giussani et al. 1993). Failure of these compensatory mechanisms results in a progressively worsening metabolic acidosis. Development of severe acidaemia (pH < 7.05) is a key turning point after which fetuses are unable to maintain fetal cardiovascular defence mechanisms and cerebral perfusion, rendering them at risk of asphyxial brain injury (Gunn & Bennet, 2009). Therefore, intrapartum EFM aims to identify, via changes in FHR patterns, fetuses unable to initiate or maintain such compensatory adaptations in response to hypoxia, which become acidotic, and deliver them before they are at risk of asphyxia, severe acidosis, cardiovascular collapse, end organ damage or death.

Docosahexaenoic Acid Augments Hypothermic Neuroprotection in a Neonatal Rat Asphyxia Model

Background: In neonatal rats, early post-hypoxia-ischemia (HI) administration of the omega-3 fatty acid docosahexaenoic acid (DHA) improves sensorimotor function, but does not attenuate brain damage. Objective: To determine if DHA administration in addition to hypothermia, now standard care for neonatal asphyxial brain injury, attenuates post-HI damage and sensorimotor deficits. Methods: Seven-day-old (P7) rats underwent right carotid ligation followed by 90 min of 8% O₂ exposure. Fifteen minutes later, pups received injections of DHA 2.5 mg/kg (complexed to 25% albumin) or equal volumes of albumin. After a 1-hour recovery, pups were cooled (3 h, 30°C). Sensorimotor and pathology outcomes were initially evaluated on P14. In subsequent experiments, sensorimotor function was evaluated on P14, P21, and P28; histopathology was assessed on P28. Results: At P14, left forepaw function scores (normal: 20/20) were near normal in DHA + hypothermia-treated animals (mean ± SD 19.7 ± 0.7 DHA + hypothermia vs. 12.7 ± 3.5 albumin + hypothermia, p < 0.0001) and brain damage was reduced (mean ± SD right hemisphere damage 38 ± 17% with DHA + hypothermia vs. 56 ± 15% with albumin + hypothermia, p = 0.003). Substantial improvements on three sensorimotor function measures and reduced brain damage were evident up to P28. Conclusion: Unlike post-HI treatment with DHA alone, treatment with DHA + hypothermia produced both sustained functional improvement and reduced brain damage after neonatal HI.

The acidosis paradox: asphyxial brain injury without coincident acidemia

The acidosis paradox: asphyxial brain injury without coincident acidemia

The acidosis paradox: asphyxial brain injury without coincident acidemia.

The acidosis paradox: asphyxial brain injury without coincident acidemia.

Cerebral Hypothermia in the Management of Hypoxic-Ischemic Encephalopathy

After completing this article, readers should be able to: 1. Describe the phases of hypoxic-ischemic encephalopathy (HIE). 2. Describe the role of hypothermia in experimental HIE. 3. Delineate the optimal level of cooling of the brain for treating HIE. 4. Describe the process of selective head cooling. Moderate-to-severe hypoxic-ischemic encephalopathy (HIE) continues to be an important cause of acute neurologic injury at birth, occurring at a rate of approximately 1 to 2 per 1,000 term live births. The possibility that hypothermia might be able to alleviate asphyxial brain injury is a “dream revisited.” Hypothermia initially was used in the therapy of infants following perinatal asphyxia in 1959, but this report and subsequent studies did not include control groups of infants treated at normal temperatures. Thus, neither the safety nor the efficacy of therapeutic hypothermia was proven. Recent studies have examined systematically the parameters required for successful neuronal rescue, including the delay in initiating cooling after the insult, its duration, and the depth of cooling attained. Such studies have confirmed that brief hypothermia during resuscitation has modest (and often transient) benefits, but moderate prolonged hypothermia still may be protective when delayed by many hours after severe hypoxia-ischemia (HI). Based on this work, a series of small trials have examined the feasibility of both whole body cooling and head cooling with mild systemic hypothermia in the severely asphyxiated newborn. The effects of neuroprotective hypothermia in experimental models is understood most easily in relationship to the timing of neuronal loss after HI. Considerable evidence from both clinical and experimental studies in the term fetus, newborn, and adults suggests that injury to the brain is not a single event occurring at, or just after the insult. Rather, it is an evolving process that leads to cell death well after the initial insult. Several phases are defined by key …

Human Perinatal Asphyxia: Correlation of Neonatal Cytokines with MRI and Outcome

Clinical studies of the preterm neonate and animal models of asphyxial brain injury both support a role for proinflammatory cytokines in central nervous system (CNS) injury. There are fewer studies of perinatal CNS injury in the full-term neonate. We have performed a prospective cohort study of full-term infants with perinatal asphyxia. Using archived neonatal blood samples, we have analyzed the serum levels of several proinflammatory cytokines. Preliminary results demonstrate an increase in IL-1, IL-6, and TNF-α in those children who are deceased at 1 year or who have a diagnosis of cerebral palsy versus those with normal neuromotor outcome. Further analysis will include correlations of cytokine levels with injury on MRI spectroscopy, with neonatal clinical markers of encephalopathy, and with later neurodevelopmental outcome.

Asphyxial brain injury—the role of the IGF system

Transient neural injuries, such as asphyxia, can trigger considerable delayed neuronal death. Inappropriate induction of apoptosis is thought to play an important role in this process. Our studies have shown marked changes in the IGF system in the brain in response to these injuries with an induction of insulin growth factor (IGF)-1 and insulin growth factor binding protein (IGFBP)-2 and IGFBP-3 in glial cells in the region of injury. This suggests that the IGF-1 system may be an endogenous neuroprotective system. Earlier administration of IGF-1–2 h after injury reduced the phase of secondary neuronal loss suggesting that IGF-1 may well have therapeutic potential as a neuronal rescue agent. The action of IGF-1 appears to involve binding proteins, transport to the site of injury and the IGF-1 receptor and inhibition of apoptosis, but might also involve generation of GPE which itself appears to be neuroprotective. Together these results indicate considerable potential of these agents to treat stroke, perinatal asphyxia and other forms of acute brain injury.

Newer concepts and approaches to neonatal brain asphyxia.

The asphyxial injury to neonate brain seems to be mediated through a cascade of biochemical events during ischaemia--reperfusion which includes excitatory amino acids, free radicals and accelerated programmed cell death (Apoptosis). The diagnosis of asphyxia requires rigorous approach based on background clinical information, certain diagnostic tests and exclusion of alternative diagnosis which may have similar clinical presentation. The treatment currently employed for the management of birth asphyxia controversial and requires critical appraisal. The future strategies for management include a number of approaches based on putative mechanism for asphyxial brain injury but they are still being evaluated as research and should not be used for clinical purposes in human newborns as yet.

Intrapartum fetal asphyxial brain injury with absent multiorgan system dysfunction

Current understanding of the physiologic mechanisms of intrapartum fetal asphyxial brain injury has suggested a strong association with multiorgan system injury. Thus the purpose here is to describe 14 cases of severe fetal brain injury with absent multiorgan system dysfunction (MSD). The study population was drawn from a national registry for brain injured infants. MSD was defined by clinical criteria demonstrated to reflect asphyxial injury to the pulmonary, renal, cardiac, hematologic, hepatic, and gastrointestinal systems. Involvement of one other organ in addition to the brain was defined as multiorgan system dysfunction. All infants were diagnosed with hypoxic-ischemic encephalopathy (HIE) in the neonatal period and went on to have permanent central nervous system (CNS) injury and MSD criteria were not met. Of the 292 term, singleton infants with HIE and permanent neurologic injury, 57 (20%) satisfied the entry criteria; of these, 14 (36%) had no MSD. The underlying basis for the fetal brain injury were: uterine rupture, 6 (43%), prolonged FHR deceleration, 5 (36%), fetal exsanguination, 1 (7%), cord prolapse, 1 (7%), and maternal cardiopulmonary arrest, 1 (7%). The mean duration of the prolonged FHR deceleration was 32.1 +/- 9.1 (range 19-51) minutes. All infants were later diagnosed with cerebral palsy. Intrapartum fetal asphyxial brain injury may not necessarily proceed through a physiologic mechanism in which the fetal circulation is centralized and endorgans damaged. These acute injuries, associated with a prolonged FHR deceleration, may be linked to severely decreased cardiac output and hypotension that cause vulnerable portions of the brain to be injured before other organs.

Near-infrared Spectroscopy in Asphyxial Brain Injury

Near-infrared spectroscopy is capable of providing noninvasive quantification of several important indices of cerebral hemodynamics, including cerebral blood flow, cerebral blood volume, and its response to changing arterial carbon dioxide tension. Preliminary results in term infants following acute perinatal asphyxia suggest that cerebral blood flow and volume are elevated, and the normal control mechanisms are abolished. These hemodynamic disturbances occur prior to the later development of secondary energy failure with its poor prognosis and may allow valuable prognostic information to be obtained in the first hours after birth.

Cerebrovascular Mechanisms in Perinatal Asphyxia: The Role of Vasogenic Brain Edema

Previous studies from our laboratory have demonstrated penetration of Evan's blue dye into the brain in profound fetal asphyxia, suggesting that vasogenic brain edema (BE) might be an immediate contributing factor in asphyxial brain injury. We modified the 125I-labeled albumin method of Pappius and McCann to quantitate vasogenic BE after acute fetal asphyxia. With 51Cr-labeled red cells to measure intravascular volume, and 125I-labeled albumin to measure total tissue plasma, the equivalent extra vascular plasma volume, i.e., vasogenic BE, was calculated. Twenty chronically prepared animals were studied, six nonasphyxiated controls and 14 asphyxiated (of which sex term animals were normotensive and five term and three premature animals were hypertensive during asphyxia). No difference in extra vascular plasma volume was found between asphyxiated and control animals in any of four brain regions. We conclude that, although blood brain barrier function might be impaired, vasogenic BE is not quantitatively significant immediately after severe fetal asphyxia.