Specifically, depletion of neuronal reduced glutathione exacerbates oxidative injury Chen and Liao, ; White and Cappai, ; Brongholi et al. Finally, inflammation is a major component of neonatal HI injury. Low-dose treatment with intrauterine LPS dramatically increases severity of HI injury in neonatal mice, but protects against HI in adult rodents Wang et al.
There is now substantial experimental evidence that intrauterine inflammation can exacerbate neonatal HI Lehnardt et al. Microglia, the resident macrophages of the CNS, are among the first cells to become activated after HI Fujimoto et al. Activated microglia migrate to damaged regions Leonardo and Pennypacker, and produce inflammatory cytokines, glutamate, nitric oxide, and free radicals Wood, ; Kaur and Ling, Drugs that block microglial activation protect the neonatal brain Dommergues et al.
Following hypoxia-ischemia, compromise of the BBB allows the entry of macrophages Alvarez-Diaz et al. Astrocytes also play a role in inflammation Wang et al. CSF cytokines are elevated in term infants who later develop cerebral palsy Savman et al. The diverse network of interacting mechanisms demonstrate the molecular complexity of neonatal HI injury.
Potential protective treatments should strive to tackle common mediators of these cascades relevant to all three pathways, otherwise full protection will not be achievable.
Neonatal hypoxia ischaemia has been modeled extensively in mice and rats reviewed in Hagberg et al. Models intending to replicate the clinical symptoms of neonatal human HI can be roughly divided into the four categories discussed below.
All models have distinct advantages and disadvantages. A The Rice—Vannucci method as outlined in rats by Rice et al. B The general method with specifications taken from the pool of papers summarized in Supplementary Table 1.
C The range of inflammatory models reviewed in Dean et al. Most published studies modeling neonatal HI in animals have employed the Rice—Vannucci model Rice et al. Although, the model was initially described in rat Rice et al. Their initial study showed selective gray-matter sensitivity to neuronal necrosis, with gray matter injury observed in cortex, hippocampus, thalamus, and basal ganglia Rice et al. Histologically, there is a gradation of injury that correlates with the duration or severity of insult Towfighi et al.
White matter lesions have also been described in this model de Torres et al. However, bilateral common carotid artery ligation appears a stronger model of white matter damage Jelinski et al. Metabolic alterations in the Rice—Vannucci model include decreased cerebral blood flow Sakurada et al.
An inflammatory response has also been demonstrated Bona et al. Another convincing aspect of the Rice—Vannucci model is its ability to predict the therapeutic effect of hypothermia following the neonatal HI event. Mice treated with hypothermia showed smaller lesion volumes, in addition to better performance on the Morris water maze and circling tests Yager et al.
Many papers have investigated the behavioral outcomes of Rice—Vannucci injury in adult rodents. This model gives rise to well documented behavioral phenotypes including: impaired spatial learning and memory Balduini et al. Despite this broad range of documented effects, there are some contradictions between individual investigators reviewed in Lubics et al. The Rice—Vannucci model of neonatal hypoxia ischaemia has several advantages. One is its prevalence, allowing direct comparisons with many other published papers Vannucci et al.
Another is that the contralateral hemisphere, exposed to hypoxia in the absence of ischemia, appears normal Yager et al. Thorough behavioral characterization Arteni et al. One significant drawback of this model is the high variability in size and severity of infarct between animals, making comparisons between experimenters difficult Vannucci and Hagberg, ; Vannucci and Vannucci, Additionally, the invasive nature of severing the common carotid artery does not replicate human injury; such severe vascular abnormalities occur rarely, if at all Ment et al.
Some experimenters induce hypoxia in rodents exclusively using an oxygen deprivation chamber, without a preceding ischaemic procedure. These models are not as widely used as the Rice—Vannucci method, but have the potential to describe milder injuries and avoid the unphysiological occlusion of the common carotid artery.
There are currently no published reviews or meta-analyses of hypoxia-only investigations, Supplementary Table 1 contains a brief summary of published papers using hypoxia-only methodology compiled from Pubmed search results.
Historically, these methods have been used to investigate hypoxic brain biochemistry. Several studies have documented altered levels of neurotransmitters Hedner et al. However, there is little consensus over the direction or magnitude of changes Decker M. Hypoxia-only models have become an established model used to generate seizures in neonatal rats Jensen et al. Some pups were immediately restored to room air, whereas others underwent gradual reduction of CO 2 Helmy et al.
Pups which underwent hypoxia with immediate restoration of CO 2 had a greater mortality rate and higher seizure frequency. However, subsequent anatomical analysis of these brains at P8 Boss et al. Therefore, the hypoxia-only insult resulting in seizures appears to generate only subtle injury to the brain, far short of that seen in some human patients. The majority of hypoxia-only phenotypes are based on custom behavioral tests, making them difficult to compare to other established animal models.
Additionally, some studies report no behavioral deficit following neonatal hypoxia alone Buwalda et al. Although hypoxia-only models offer the potential to replicate the mechanism of hypoxia without major ischaemia seen in human neonatal HI patients, the models currently available are not ideal. One significant problem is the lack of methodological unity between different experimenters.
There is little consensus on age of animal, background strain, oxygen partial pressure, time of exposure to hypoxia, or body temperature see Supplementary Table 1. One example demonstrating the relevance of close control of these variables is temperature.
Therefore, far more care is needed to justify the design of hypoxia-only experiments before these models can be considered dependable models of human neonatal HI. Intrauterine infection is strongly associated with preterm birth and brain injury Stoll et al. Many models have been described which introduce different inflammation-inducing molecules at different ages Dean et al. Administration of live E. The effects of bacterial mimetics such as the cell wall component lipopolysaccharide LPS , have also been investigated.
Intracervical injection in embryonic day 15 E15 mice was associated with mild white matter injury but no behavioral deficits Bell and Hallenbeck, ; Poggi et al. Other inflammatory models include viral infection simulated by injection of poly I:C , a synthetic double stranded viral RNA, injection of which is associated with long-term behavioral deficits Shi et al.
Postnatal administration of inflammatory agents is widely used in rodents to model postnatal infection. Subcutaneous injection of live E. However, most techniques which employ live bacterial injection have very high mortality rates Rodewald et al. Postnatal intraperitoneal injection of LPS can also cause white matter damage and cerebral cytokine response Brochu et al. Repeated daily injection of LPS in mice resulted in elevated serum IL-6, reduced gray matter volume, decreased oligodendrocyte numbers, and decreased myelin staining Wang et al.
One of the strengths of the inflammation model is that it reflects the exposure to infectious or inflammatory agents present outside of the highly sterile individually ventilated cages where many academic institutions keep experimental animals.
Most of the inflammatory risk factors for increased severity of HI injury in human patients, such as maternal infection Stoll et al. However, there is currently debate concerning the relevance of maternal inflammation to fetal brain damage Leviton et al.
The debate intensifies when fetal systemic inflammation is contrasted with neuroinflammation. Although the majority of publications cited above administer pro-inflammatory agents by intracerebral injection, some studies have administered LPS by intravenous injection reviewed in Wang et al.
In fetal sheep, intravenous LPS causes white-matter specific damage Garnier et al. However, the results of these experiments could be explained by a secondary neuroinflammatory response to systemic inflammation causing the white matter injury. Separating these parameters in future experiments will prove demanding. Data suggest that gene expression in mouse models of inflammation closely corresponds to that seen in humans Takao and Miyakawa, , however, postnatal murine response to inflammation is likely different to that experienced by a human fetus.
An important limitation of inflammatory studies is impact on cardiovascular function and the potential for secondary cerebral HI Eklind et al. Another is that varying results have been reported. This may be due to differences in LPS used between groups, purification method Westphal, ; Lam et al.
Alternatively, there is increasing evidence that the considerable individual variability in response to clinical sepsis between patients is related to host genetics Christaki and Giamarellos-Bourboulis, Therefore, although inflammation is doubtless an important factor in neonatal brain injury, the variation between different models makes these methods difficult to evaluate.
In many ways, non-rodent models are more representative of neonatal HI as it affects human patients. Here follows a brief flavor of techniques. Relatively few studies have investigated neonatal HI in primates. Classical studies asphyxiated term monkey fetuses by covering their heads with a rubber sac and clamping the umbilical cord Fahn et al.
Fetuses resuscitated after 20 min had extremely high mortality. However, 12 min of asphyxia were required to produce any neuropathologic injury.
The fetuses displayed damage predominantly within the brainstem. In a model of partial ischemia Fahn et al. At birth, these displayed opisthotonus, decerebrate posturing, and convulsions. There is one model of white-matter injury based on baboons delivered prematurely by hysterotomy Inder et al.
Premature baboons were treated in an intensive care setting. Approximately half displayed white-matter injury. Analysis of behavior has not been undertaken. More work has been carried out in fetal sheep. Umbilical cord occlusion and term asphyxia has been carried out Gunn et al. White matter injury has also been investigated Ting et al. Neuropathologic injury after carotid artery occlusion for 30 min caused both gray and white matter involvement, with cortical damage and selective neuronal necrosis in thalamus and striatum Reddy et al.
Several laboratories have developed models in sheep after systemic endotoxemia Duncan et al. Unfortunately, no behavioral outcomes are currently available in sheep. Finally, other small laboratory animals have been investigated. Preterm rabbit fetuses exposed to sustained placental insufficiency via intrauterine occlusion of the descending aorta displayed significant alterations in motor responses to olfactory stimuli, coordination of suck and swallow, and marked hypertonia, reminiscent of spastic quadriplegia Yoon et al.
Diffusion-weighted imaging detected a threshold in white matter loss below which all rabbit kits developed hypertonia, Drobyshevsky et al. Another promising model is that of the spiny mouse, a rodent which shows a similar level of brain development to a human neonate at birth Brunjes, , , ; Gozzo et al. In brief, large animals can better replicate the conditions of a single human fetus exposed to a non-sterile environment.
However, none of these models have access to the same extent of transgenic manipulation or validated behavioral tests that are possible in rodent studies. These models are invaluable for aiding comparison of brain development at birth which occur between species Clancy et al. For the foreseeable future, insights from both rodent work and larger animals will be important for better understanding neonatal HI. The subplate is an early-born transitory neuronal layer of cerebral cortex which serves an important role in the establishment of thalamocortical connectivity during development reviewed in Judas et al.
An erratic beat, or decelerations of the heart may be a sign of oxygen deprivation. Lack of movement may also be a sign of hypoxia. Medical professionals should always carefully monitor potential signs of hypoxia because a lack of oxygen can cause serious and permanent birth injuries, including HIE and cerebral palsy. Types of intrapartum hypoxia on the cardiotocograph CTG : do they have any relationship with the type of brain injury in the MRI scan in term babies?
Your email address will not be published. Save my name, email, and website in this browser for the next time I comment. Trial Attorneys Serving Families Nationwide. Law Offices in Houston and Waco, Texas. Many birth injuries are caused by medical negligence. Once the neonate is older than 3 weeks, hypoxemia induces a sustained hyperventilation which is the response observed in older children and adults.
There are several causes of hypoxia during the neonatal period. These include congenital heart disease, pulmonary disease bronchopulmonary dysplasia , pulmonary hypertension, airway obstruction, and sepsis. At some point, repetitive episodes of severe hypoxia cause global neuronal, cortical, midbrain, and cerebellar damage, even to the "spared" CNS.
Damage is typically to the watershed areas of the cerebral cortex, an event closely correlated to cerebral palsy and developmental disabilities in later life. The human fetus may experience these episodes during a high-risk pregnancy, well before birth, with recovery of biochemical markers of distress, such as metabolic acidosis Bloom, If myocardial contractility is impaired following severe or sustained hypoxia, the resultant reduction in cardiac output may further compromise cerebral blood flow and other organ perfusion.
Again, depending on degree of insult, this can be associated with acute myocardial dilatation and resultant tricuspid regurgitation, myocardial ischemia, and hypotension.
Such hypotension is usually resistant to volume resuscitation-dopamine has been shown to be more effective in restoring blood pressure in these infants.
Renal impairment is commonly reported following hypoxic-ischemic insult at birth. Again, depending on degree of insult, impairment can take the form of mild oliguria with minor electrolyte abnormality and minimally elevated creatinine, to full-blown renal failure requiring dialysis. Elevated liver enzymes are also common following acute hypoxia, but irreversible liver damage is very rare.
Liver enzymes levels are often telling in identifying the existence of a perinatal insult. Similarly, coagulation impairment should also be anticipated in severely affected newborns; however, treatment is supportive and resolution is the norm. Fetal cardiovascular and endocrine response may be altered not only in acute hypoxia but also in chronic hypoxia. This is important because recurrence of mild hypoxic insults may not be infrequent in human pregnancies, where blood flow to the placenta, uterus, and fetus is repeatedly compromised by many physiologic and environmental influences.
In states of considerable chronic hypoxia, such as may occur in a variety of clinical situations, fetal growth retardation is not uncommon.
Depression of growth factors during hypoxic states has an important protective effect by conserving fetal substrate for energy as opposed to growth needs Noori et al.
Possibly the most common approach for the pediatric clinician involves the evaluation of the hypoxic infant during this transitional period. Differentiating between the many etiologies for newborn hypoxia is undoubtedly an incredible challenge for the pediatric specialist in the newborn nursery. While there are several common causes for newborn cyanosis-primary pulmonary disease and sepsis-a myriad of disorders spanning all organ systems exist as possibilities. It was the intention of this series to supply the practitioner with a basic knowledge of the breadth of these possibilities, as well as a systematic approach to the assessment of these term newborns to assure accurate diagnosis, treatment, and referral.
A summary of these categories of disorders, along with characteristic history and typical physical, laboratory, and radiologic findings can be found in Table 3. Anderson, P. Cardiovascular function during development and response to hypoxia. In: R. Polin, W. Abman Eds. Philadelphia, PA: Saunders. Anderson-Berry, A. Neonatal sepsis. Bauer, C. Acute neonatal effects of cocaine exposure during pregnancy. Archives of Pediatric and Adolescent Medicine, , Bloom, R.
Resuscitation of the newborn. In: A. Martin Eds. St Louis, MO: Mosby. Castrodale, V. The hypotonic infant: Case study of central core disease.
Neonatal Network, 22 , Figueroa, R. Identification and management of the fetus at risk for acidosis. Spitzer Ed. Philadelphia, PA: Mosby. Golombek, S.
The use of inhaled nitric oxide in newborn medicine. Heart Disease, 2 , Gressens, P. The central nervous system: Hypoxic ischemic encephalopathy. Martin, A. Walsh Eds. Hofmeyr, G. Planned caesarean section for term breech delivery. Cochrane Database Review , 3, CD Jensen, A.
Effects of reducing uterine blood flow on fetal blood flow distribution and oxygen delivery. Journal of Developmental Physiology, 15 , Levy, K. Obstetric and neonatal effects of drug abuse. Emergency Medicine Clinics of North America, 8 , Noori, S.
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