Nowadays, there are many parents who are reluctant to receive treatment when their child’s jaundice worsens after birth, which causes some difficulties for our doctors because if the jaundice persists, it can cause damage to the brain. Neonatal bilirubin encephalopathy is a disease that has serious effects on the brain, and if it is not treated as early as possible, cerebral palsy may occur. As early as 1904, Schmofl’s autopsy of a neonate who died of severe jaundice revealed a yellow staining of the basal nucleus of the brain, which was first named kernicterus. This yellowish substance was analyzed and identified as unconjugated bilirubin. It can lead to toxic lesions of nerve cells, so it is also called “bilirubin encephalopathy”.
Pathogenesis
In children with bilirubin encephalopathy, the entire central nervous system is infiltrated with bilirubin, but the severity of the lesions varies from site to site. The most obvious site is the basal nucleus, which is bright yellow or dark yellow; other sites, such as the hippocampal sulcus, optic thalamus, subthalamic nucleus, pallidum, nucleus accumbens, parietal nucleus, caudate nucleus, ventricular nucleus, cerebellar lobules, and anterior horn of the spinal cord, are pale yellow; the white matter and gray matter of the cerebellum, cerebellum, and cerebral hemispheres can also be affected, but more lightly.
The selectivity of the lesion site may be related to the maturity of the enzyme system of the neuronal cells. Unconjugated bilirubin (UCB) has a toxic effect on brain cells. It has the greatest effect on the most physiologically active neuronal cells. Therefore the energy metabolism of the species cells is greater. Basal nucleus neuronal cells are most active in the neonatal period in terms of physiological and biochemical metabolism. Oxygen consumption and energy requirements are the highest, so the nucleus basalis is the most vulnerable. Free bilirubin inhibits oxygen utilization by brain tissue and affects cellular oxidation. The entry of bilirubin into brain cells may disconnect the coupling of mitochondrial oxidation in brain cells (uncoupling), so that the energy production of brain cells is inhibited and brain cells are damaged. Microscopic pathological changes are most evident in the swelling and pallor of neuronal cell mitochondria.
Unconjugated bilirubin has a toxic effect on neuronal cells, and it can cause brain damage and toxic encephalopathy by acting on brain cells through the blood-brain barrier. In a follow-up study of a group of neonates with hyperunconjugated bilirubinemia, Huimin Yu et al. found that in addition to severe hyperbilirubinemia, mild and moderate hyperbilirubinemia can also produce persistent neurotoxic effects on neonates, leading to abnormalities in neurological development. In recent years, Levine et al. found that hyperunconjugated bilirubinemia alone does not cause kernicterus in healthy neonates unless the neonate is asphyxiated, especially when in certain pathological states, such as immature or low birth weight infants, hemolytic diseases such as maternal-infant blood group (Rh, AB0) incompatibility, sepsis, hypoglycemia or hyperosmolarity, hypercapnia, hypoxemia The blood-brain barrier is open, and plasma bilirubin, including the albumin-linked bilirubin complex of free bilirubin, enters brain tissue in large quantities, binds to polar groups (gangliosides, neurosphingolipids) on brain cell membranes, and eventually aggregates and deposits on brain cell membranes in a saturated state, causing typical nuclear jaundice.
Clinically, total bilirubin level and unconjugated bilirubin level are used as risk factors for bilirubin encephalopathy to guide the prevention and treatment of neonatal hyperbilirubinemia, but their sensitivity is not reliable. Most scholars believe that mother-infant blood group, Coombs’ test and other homozygous immunohemolytic indications should be used as routine tests for cord blood; neonates with positive immunohemolytic indications are at high risk for bilirubin encephalopathy and should be closely observed and However, for term newborns without immune hemolysis indications, if there is no plantar yellow staining or jaundice gradually deepens, there is no need for close nuclear bilirubin measurement and early intervention; once Once there is plantar yellow staining and the serum bilirubin is higher than 256,5μmol/L (15mg/dl), breastfeeding can be stopped appropriately; when the serum bilirubin is higher than 307,8μmol/L (18mg/dl), phototherapy can be considered; when the serum bilirubin is 427,5umo]/L (25mg/dl), it is necessary to consider exchange transfusion, some foreign scholars clinical Some foreign scholars have concluded that the risk of bilirubin encephalopathy in preterm and term infants differs greatly at the same bilirubin level. Therefore, there should be different intervention standards for the two; for high-risk preterm infants with total serum bilirubin greater than 256,5μmol/L (15mg/dl), phototherapy should be given; for total serum bilirubin greater than 307,8μmol/L (18mg/dl), exchange transfusion should be considered.
Second, bilirubin linkage status and free bilirubin level Serum bilirubin includes.
1, unconjugated bilirubin: bilirubin unconjugated with glucuronic acid.
2, Conjugated bilirubin: containing monoglucuronide-conjugated bilirubin and diglucuronide-conjugated bilirubin.
Unconjugated bilirubin exists in plasma mainly in the form of bilirubin linked to albumin (AB2-), and only a small portion exists in the form of free bilirubin. Free bilirubin includes divalent anion (B2-), monovalent anion (BH+) and bilirubin acid (BH2). A dynamic equilibrium is maintained in the body between AB2-, BH+, and BH2. The direction of movement of this dynamic equilibrium is related to the level of self-protein, the level of unconjugated bilirubin, the albumin-bilirubin association force, and the level of H+. When the albumin-bilirubin linkage is reduced (e.g., in low birth weight infants, hypoxemia, hypovolemia, hyperosmolarity, hyperthermia, hypercapnia and other pathological states) or when the amount of albumin-bilirubin linkage is reduced (e.g., free fatty acids, salicylic acid, sulfonamides, cephalosporins and furosemide, and other competitive linkers are increased in the body), the albumin-bilirubin linkage can be affected, resulting in increased levels of free bilirubin in the body The level of free bilirubin is increased. Some foreign scholars believe that a free bilirubin level of >20,0μmol/L (1,17mg/dl) is the critical value for the occurrence of bilirubin encephalopathy. Other scholars found that albumin could protect brain cells from the toxic effects of bilirubin when in vitro cell culture was performed.
Since free bilirubin associates with brain cells, aggregates and passes through biological membranes, causing cell damage, free bilirubin levels are theoretically the most direct and sensitive indicator of bilirubin toxicity. However, it is almost impossible to detect bilirubin that is not linked to self-proteins, i.e. plasma free bilirubin. Although peroxidase oxidation can theoretically be used to detect free bilirubin, the accuracy of the results and the reliability of its clinical application need to be further validated. In contrast, plasma albumin associates with bilirubin to reduce the toxicity of bilirubin to neuronal cells, and thus the bilirubin/albumin (B/A) ratio has become a risk factor for assessing bilirubin toxicity. Since each albumin molecule has one high-affinity, and two low-affinity bilirubin association sites; when B/A < 1, the bilirubin-albumin association is strong; B/A > 1, part of the bilirubin-albumin association is loose; B/A > 3. Part of the bilirubin is free to free bilirubin. b/A = 1 corresponds to 8,5 mg bilirubin/lg albumin. In vivo. Due to the presence of endogenous competitive conjugates, actual full-term newborns bind only 0,5 to 1,0 mol of bilirubin per mol of albumin, and even less in preterm and low birth weight infants. Thus, in full-term newborns with B/A <0,5, bilirubin is easily associated with self-protein and not easily associated with nerve cells; when B/A >1, the amount of free bilirubin increases and is easily associated with nerve cells.
Some foreign scholars believe that bilirubin is deposited in cells in the form of BH2, and the amount of BH2 deposition can be expressed by the bilirubin toxicity index (IBT). According to the dynamic equilibrium constant K=10-15,5 for AB2-+2H+=A+BH2, IBT=log【AB2-】/【A】-2pH+15,5; where【AB2-】approximate to the non-linked bilirubin concentration, 【A】reserve albumin is a spare high-affinity bilirubin-linked site albumin, and its amount can be determined by MADDS method, IBT depends on pH Dependent on the relationship between bilirubin solubility and free bilirubin concentration, under acidic conditions B2→BH+→BH2; BH2 internal hydrogen bonding, external hydrophobic groups. The solubility is low; under alkaline conditions, BH2→BH+→B2-, B2- external hydrophilic group, high solubility. If the solubility is greater than the free bilirubin concentration (IBT is negative), BH2 is not easily deposited in the cell membrane, if the solubility is lower than the free bilirubin concentration (IBT is positive), BH2 is easily deposited in the cell membrane.
III. Functional state of blood-brain barrier and bilirubin level in the brain There are three kinds of barriers in the central nervous system.
1. blood-cerebrospinal fluid barrier, which exists in the epithelium of vascular endothelium, basement membrane and choroid plexus.
2. the cerebrospinal fluid-brain barrier, present in the ventricular canal membrane and the soft and other glial membranes of the brain surface
3. the blood-brain barrier, present in the capillary endothelium, basement membrane and glial membranes in the brain.
It is customary to refer to the above three barriers generically as the blood-brain barrier. The brain capillary endothelial cells are tightly connected to each other, and it is much tighter than the connection of body capillary endothelial cells, which almost closes the cell gap and restricts the diffusion of solute molecules, so that a concentration gradient is established on both sides of the cells. When the capillary pressure suddenly increases, or when hypertonicity causes the capillary endothelial cells to crumple, the endothelial cell gaps widen and permeability increases. On the other hand, there is a basement membrane layer, about 70-100nm, which is tightly wrapped around these small vessels and attached to the terminal part of the neuroglia around the vessels, so that there is no gap around the periphery of the capillaries, and it acts as a barrier. The physiological significance of the blood-brain barrier is to maintain a constant environment for the central nervous system, and the material exchange between blood and brain depends on the The physiological significance of the blood-brain barrier is to maintain a constant environment for the central nervous system.
The occurrence of bilirubin encephalopathy depends on the bilirubin level in the brain, and the bilirubin content in the brain is not only related to the plasma bilirubin concentration, but also depends on the functional state of the blood-brain barrier. When the blood-brain barrier function is sound, free bilirubin in plasma can pass through the blood-brain barrier in the form of B2–→BH+–→BH2–→BH+–→B2-transformation; when regional cerebral blood flow increases, it can promote free bilirubin to pass through the blood-brain barrier; when free bilirubin in plasma increases (such as unconjugated bilirubin increases, albumin decreases, albumin bilirubin linkage decreases, etc.), intracerebral bilirubin increases. In immature infants, neonates with hypoxia, dehydration, hyperthermia, hypertonicity, hypercapnia and sepsis, the blood-brain barrier is open, and not only free bilirubin can pass the blood-brain barrier, but also albumin-linked bilirubin complexes can pass the blood-brain barrier. The bilirubin level in the brain rises sharply, which can cause the occurrence of bilirubin encephalopathy. The cerebrospinal fluid bilirubin level can better reflect the functional state of the blood-brain barrier and the bilirubin level in the brain. In normal full-term newborns, the average cerebrospinal fluid bilirubin is (4,10±1,71) μmol/L [(0,24±0,10) mg/dl]; in immature infants, low birth weight infants, neonatal hypoxia, acidosis and sepsis and other pathological states, the average cerebrospinal fluid bilirubin is (10,43±3,59) μmol/[(0,61±0,21) mg/dl]; there is a significant difference. ; there was a significant difference between the two. Significant increase in cerebrospinal fluid bilirubin was common in high-risk neonates with plasma bilirubin levels >342 μmol/L (20 mg/dl), and plasma free bilirubin was also significantly increased [(44, 70±0, 18) μmol/L, peroxidase method], and most were accompanied by symptoms of bilirubin encephalopathy.
Fourth, the functional state of brain cells and energy metabolism level Bilirubin has a toxic effect on neuronal cells, and some foreign scholars found that bilirubin can inhibit neuronal cell membrane biological function, reduce intracellular nucleic acid and nucleoprotein synthesis, and affect mitochondrial oxidative activity and energy metabolism in the isolated feast test. Some scholars have also found that bilirubin causes decreased depolarization of synaptic membranes at nerve endings, reduced synthesis and release of dopamine and uptake of kojic acid: cell membrane Na+-K+ATPase, Ca2+Mg2+ATPase, protein coenzyme A and c activities are inhibited, and cellular nucleic acid and protein synthesis are blocked. These toxic effects were correlated with the duration of exposure of neuronal cells to certain concentrations of bilirubin. With short exposure times, these inhibitory effects can be corrected by equal amounts of mol albumin, but with longer exposure times, the inhibitory effects are difficult to reverse. Some foreign scholars have revealed in vivo tests that bilirubin can inhibit the energy metabolism level of brain cells and reduce the electrical activity in the brain (including low amplitude and prolonged conduction time), reduce the phosphocreatine and ATP content in the brain, adenosine energy load, and the energy metabolism of brain cells and changes in brain phone action, the extent of which is consistent with the concentration of bilirubin in the eyes.
Bilirubin can block brain cell membrane potential conduction, affect the functional state of brain cells, and reduce the level of brain cell energy metabolism, thus. Detection of electroencephalographic changes in neonates with hyperbilirubinemia, sensory and behavioral changes associated with brain nuclei, and brain energy metabolism levels can directly reflect the extent of bilirubin damage to the brain.
Brainstem auditory channels are particularly sensitive to the toxic effects of bilirubin. Epidemiological studies have shown a high correlation between neonatal hyperbilirubinemia and central sensory conduction disorder deafness. Animal studies and neonatal clinical studies have shown that hyperbilirubinemia significantly affects brainstem auditory evoked potentials (BAEP), resulting in prolonged central conduction times (prolonged inter-peak interval between 1 and V transitions); abnormal BAEP can be reversed by timely intervention to reduce plasma bilirubin and free bilirubin levels; detection of BAEP is a simple, easy, accurate and reliable method to assess bilirubin neurotoxicity.
The brainstem auditory pathway (brain nerve VIII) is anatomically close to the brainstem cry control neuronal complex (brain nerves IX and VII). Bilirubin can cause characteristic changes in the cry. Early literature described bilirubin encephalopathy cry as a high pitched cry (higH+pitched cry). Later, some scholars used the spectiographic method to measure the parameters of pain-induced cry in 100 healthy neonates one day after birth and used it as a control to study the characteristics of cry in neonates with hyperbilirubinemia, which resulted in an increase in maximal pitch, furcation and biphonation. The results showed an increase in the highest pitch, furcation and biphonation, and a high correlation between the presence of biphonation and neurobehavioral abnormalities. A computerized analysis of the cry spectrum showed that the percint phonation reflects the level of pressure and neural control in the inferior vocal tract; the basal cry frequency reflects the vocal tonicity; and the high tone resonance frequency (F1 and F2) reflects the level of neural control in the superior vocal tract. The sound composition, fundamental frequency and high-pitched resonance frequency of cry in hyperbilirubinemic neonates are positively correlated with the conduction time and serum bilirubin in BAEP, thus the analysis of cry changes in hyperbilirubinemic neonates can be used to assess bilirubin neurotoxicity.
Bilirubin toxicity can also cause alterations in brainstem visual evoked potentials, resulting in longer wave latencies and lower wave amplitudes. The former correlates significantly with the morbidity and mortality of children with hyperbilirubinemia, while the latter correlates insignificantly with morbidity and mortality. Some scholars in China performed brainstem visual evoked potential measurements on a group of hyperbilirubinemic neonates and compared them with the control group by age and degree of jaundice, and found that the changes in brainstem visual evoked potential were correlated with blood bilirubin concentration, and the latency of visual evoked potential P1 wave was prolonged when the total serum bilirubin concentration was greater than 256 μmol/L (15 mg/dl), and such changes were also affected by This change is also influenced by fetal maturity, age, and the presence of asphyxia.
In recent years, 31P-nuclear magnetic resonance spectroscopy (31P-NMRspectroscope) has been applied to detect pH and energy metabolism levels in body tissues, and 31P-NMR spectroscopy in animal models of bilirubin encephalopathy: Pcr and Pr peaks indicate phosphocreatine and inorganic phosphorus content, respectively, and Pcr/Pr can sensitively reflect changes in brain energy metabolism before and after blood-brain barrier opening. Since bilirubin neuron toxicity involves pH-dependent bilirubin/biofilm complex formation and reduced energy metabolism levels in brain cells. Thus, the use of 31P-NMR ferry spectroscopy to assess the energy changes within the brain regions associated with bilirubin toxicity and to investigate the reversible effects of various relevant factors (including pH) and interventions on brain energy metabolism deserve further investigation.
The deposition of bilirubin varies at different sites in the brain, with the highest amount of bilirubin deposited at the brainstem, followed by the Purkinje cell level in the cerebral cortex, and then the basal nucleus, such as the granular layer of pyramidal cells in the hippocampus. The deposition of bilirubin in different parts of the brain is influenced by several factors.
1, determined by the structural characteristics of the bilirubin molecule, which is a polar compound and is easily bound to the polar groups of the neural cell membrane for deposition.
2. The local deposition of bilirubin in the brain is positively correlated with the local cerebral blood flow and blood flow velocity in parallel.
V. Neurotoxic mechanism of bilirubin The exact mechanism of bilirubin damage to brain cells is not yet certain. As early as in the 1950s, some foreign scholars found that bilirubin concentration up to 300 μmol/L almost completely inhibited mitochondrial phosphorylation in mouse hepatocytes and partially inhibited biological oxidation. The same inhibitory effect was also seen in brain cells. Other scholars incubated neuroblastoma cells N115 in different concentrations of bilirubin and found that 60% of the bilirubin was confined to the mitochondria of N115 cells, which is the earliest site of the toxic effect of bilirubin. Some scholars gave bilirubin to mice after opening the blood-brain barrier by hypertonic treatment, and found that nucleotide diphosphate, nucleotide triphosphate, inosine phosphate, coenzyme I+ (NAD’), glucose 6-phosphate (G-6-P) and fibrinogen degradate (FDP) decreased and glycerol 3-phosphate increased in brain tissue after 30 min, emphasizing that the main toxic effect of bilirubin The main toxic effect of bilirubin is the dissociation of mitochondrial oxidative phosphorylation, causing a significant Ran uniform acute energy metabolism disorder, decreased energy load, decreased glucose and glycogen, increased lactate, and increased lactate/pyruvate ratio, indicating that aerobic oxidation of sugar is inhibited and anaerobic enzymolysis is enhanced.
It is currently believed that bilirubin is toxic to nerve cells in the following ways.
1, when bilirubin acts with neuronal cell membranes, hydrogen ions (H+) cause bilirubin ions to change from divalent anions to monovalent anions, and monovalent bright ions act as proton shuttle (proton shuttle) to strictly regulate the concentration of hydrogen ions for oxidative phosphorylation.
2, physiological pH conditions bilirubin monovalent anion (B-) dominates, B2–→B–→BH+, BH+ associates with membrane phospholipids to form complexes, disrupting membrane structure and subsequently affecting mitochondrial function.
3. Bilirubin competitively inhibits mitochondrial malate dehydrogenase.
Recent studies on bilirubin have focused on the effect of bilirubin on the synaptic membrane transmission function of neurons. Bilirubin interacts with synaptic membranes in three steps. First, unit bilirubin ions form electrostatic complexes with ganglioside and neurosphingolipid cationic groups, a process that is extremely short (<15s) and facilitated by low pH; second, bilirubin encapsulates human synaptic membranes with a hydrophobic core; and finally, when the membrane is saturated with bilirubin, it causes membrane-induced bilirubin deposition.
Bilirubin inhibits and alters Na+-K+ ATPase activity, K+ inward flow is blocked thereby altering the ion concentration inside and outside the nerve cell, the cell membrane potential decreases, and the excitability of nerve conduction is reduced. Bilirubin inhibits the phosphorylation of type I synaptic transmitters, reduces tyrosine uptake and dopamine synthesis, and in animal experiments, high concentrations of bilirubin directly inhibit synaptic depolarization.
The toxic effect of bilirubin on nerve cells occurs: bilirubin first aggregates at the nerve terminal and reduces membrane potential and nerve conduction, at this time, if the bilirubin action time does not exceed 2h, the neuron-specific enolase brigade in serum or cerebrospinal fluid is seen to increase, and the neuronal damage is reversible. If bilirubin continues to accumulate and associate with gangliosides, neurospheres and other cell membrane components, neurons are more severely damaged and substance transport, neurotransmitter synthesis and mitochondrial function are impaired, which can be avoided and reversed if a certain amount of albumin is given. If the disease continues to progress, the neuronal cell bodies take up bilirubin retrogradely and bilirubin is deposited in the damaged area, and histological swelling of neuronal cells is seen: consolidation, disintegration and phagocytosis, and gliosis. Acute clinical symptoms and neurological sequelae are seen.
Clinical manifestations
The jaundice in children with bilirubin encephalopathy is more severe, with severe yellowing of the skin and mucous membranes throughout the body, and the serum bilirubin is often above 307,8-342 μmol/L. A small number of children may not have obvious jaundice, but autopsy can confirm nuclear jaundice, which is mostly seen in terminally mature children, especially those with combined respiratory failure.
Bilirubin encephalopathy is usually seen 4-10 d after birth, with neurological symptoms appearing as early as 1-2 d after birth and rarely after 12 d. In the case of hemolytic jaundice, it appears earlier, mostly at 3-5 d after birth. immature children or those with other causes are mostly seen 6-10 d after birth. nuclear jaundice due to congenital glucuronosyltransferase deficiency mostly occurs 2-5 weeks after birth. The threshold value of serum bilirubin for the occurrence of bilirubin encephalopathy is 307,8 to 342 μmol/L. Bilirubin encephalopathy is very likely to occur above this concentration, but it can also occur when the serum bilirubin is lower than the threshold value, even as low as 68,4 μmol/L, when prematurity, asphyxia, respiratory distress or hypoxia, severe infection, hypoalbuminemia, hypoglycemia, hypothermia, acidosis or weight below 1,5 kg. Bilirubin encephalopathy. Neurological symptoms can appear 1 to 2 days after birth. In mild cases, mental depression, weakness in suckling, vomiting and drowsiness can be seen, and sometimes hypotonia, which can be completely recovered with timely treatment; if jaundice continues to increase, neurological symptoms can also increase (extrapyramidal involvement), which can be seen as high pitched crying, paroxysmal eye movement disorders (such as If the jaundice continues to worsen, the neurological symptoms may also worsen (extrapyramidal involvement) and may be seen as high pitched crying, paroxysmal eye movement disorders (such as double heel gaze or upward turning), increased limb tone, clenching of both hands, straightening and abduction of both arms, or coracoacusis, or even respiratory failure and death: at this point, even if the patient survives treatment, there are often central neurological sequelae (such as mental retardation, tardive dyskinesia, restricted eye movements, hearing loss).
Van Praagh divided the progressive onset of neurological symptoms into 4 phases, namely, warning phase, spastic phase, recovery phase, and sequelae phase, with phases 1 to 3 occurring in the neonatal period and phase 4 occurring after the neonatal period (Table 9-7).
Stage 1 (warning stage) lasts about 12 to 24 h. Serum unconjugated bilirubin 256,5 to 427,5 μmol/L is early and presents with hypotonia of skeletal muscles, lethargy, diminished sucking reflex or refusal of breast milk, depression, vomiting, and may be accompanied by fever and sudden increase in jaundice. In individual cases of fulminant bilirubin encephalopathy, respiratory failure and general muscle relaxation can occur in this stage and death can occur, but in general cases, complete recovery can be achieved with timely treatment.
Stage 2 (spastic phase) generally lasts 12 to 24 h, with the longest duration not exceeding 48 h. The prognosis is poor, with about 3/4 of children dying of respiratory failure and unconjugated bilirubin exceeding 427, 5 μmol/L. The main clinical features are spasms, corneal inversion and fever, generally characterized by the appearance of spasms as the entry into stage II. In severe cases, the head is tilted backwards, the corneal arches are reversed, paroxysmal convulsions or continuous tonic spasms are present, often accompanied by eye rotation or downward vision, obvious facial and limb twitching, shrill cries, and irregular breathing. Respiratory distress; its fever often appears before the spasms, and the body temperature is usually 38-40°C. Sclerosis, nasal flow with hemorrhagic foam, and death complicated by diffuse intravascular coagulation or central respiratory failure may also occur.
Stage 3 (recovery period) lasts about 2 weeks, mostly starting at the end of the first week after birth, if you can get through the first two stages, the convulsions gradually reduce and then disappear completely. The symptoms of the acute stage can disappear after 1 to 2 weeks.
Stage 4 (post-acute phase) appears about 1 month after the disease or later, and usually lasts for life, and is ineffective for all kinds of treatment. Serum unconjugated bilirubin exceeding 427 or 5 μmol/L, mainly manifesting as relatively persistent or persistent lifelong extrapyramidal neurological abnormalities, is characteristic of the sequelae of bilirubin encephalopathy, i.e., bilirubin encephalopathy quadruplex.
1, tardive dyskinesia: 100% of children exhibit this symptom, which is characterized by involuntary, purposeless and uncoordinated movements of the hands and feet, either light or heavy, and intermittent.
2, eye movement disorder: 0%, manifested as eye rotation difficulties, especially upward rotation difficulties. Often “doll eyes” or “sunset eyes”.
3.Hearing impairment: about 50%, manifested as deafness, deafness, deafness to high frequency tones.
4, enamel hypoplasia: about 75%, green teeth or brown teeth, incisors have curved moon defects, are enamel hypoplasia, mostly seen in children with Rh blood type incompatibility hemolytic disease. In addition to tetralogy of Fallot, there are salivation, convulsions, weakness of head raising, and mental retardation.
These include: convulsions or clonus, weakness of head elevation and salivation.
In any typical case of a child with high UCBemia who develops nuclear jaundice without any treatment, the progressive neurological symptoms can be divided into 4 stages, as described above. At present, clinical workers are alert to the occurrence and development of nuclear jaundice and are able to closely monitor the resting child and take preventive and curative measures in a timely manner, so that the typical side of the disease has become rare. Premature or low birth weight infants with nuclear jaundice often lack the typical symptoms of cramping. The timely treatment of clinical comorbidities (such as asphyxia, hypoglycemia, hypocalcemia, etc.) can make the neurological symptoms and staging time frame vary, so the clinical symptoms vary in severity and atypical cases are becoming more common. In children with untreated or slow development of disease and symptoms, sequelae may still appear later, but some sequelae seem to recover gradually after 2 to 3 months, and their prognosis is not yet certain. In the second year, the coracoacusis may continue to decrease, but some children still have irregular, involuntary twitching and increased or decreased muscle tone (flaccid paralysis); in the third year, although all the above neurological symptoms still exist, including involuntary choreiform twitching of the limbs, difficulty in speech and pronunciation, high-frequency loss of hearing, and difficulty in eye upward rotation or strabismus. In the third year, all the above neurological symptoms are still present, including involuntary choreoathetosis, difficulty in speech articulation, high frequency hearing loss, difficulty in eye upward rotation or strabismus, hypotonia and ataxia. Some children have only mild or moderate neuromuscular incoordination, deafness or mild cerebral dysfunction, which may be present alone or simultaneously until the child goes to school, and intellectual development and motor impairment may occur in parallel.
Diagnosis
The main thing is to monitor the serum total bilirubin concentration. Once the bilirubin concentration is found to be more than 256,5μmol/L (15mg/dl) it is time to pay close attention to the appearance of neurological symptoms.
[Prevention and treatment
Prevention of hyperbilirubinemia in newborns is the main point of prevention of hyperbilirubin encephalopathy. Drug therapy, light therapy and blood exchange therapy can all reduce serum bilirubin. Prompt treatment of asphyxia, hypoglycemia, acidosis and infection can reduce the risk of unconjugated bilirubin developing into bilirubin encephalopathy. Intrauterine diagnosis and treatment of neonatal hemolytic disease is one of the ways to prevent the development of nuclear jaundice. For neonatal hyperbilirubinemia, early management is necessary to prevent its development into nuclear jaundice.
First, prenatal prevention Do prenatal examination and education, try to prevent preterm delivery and obstructed labor. Prevent maternal infections, treat maternal diseases, monitor maternal serum antibody titers, replace plasma, take phenobarbital, and prepare for blood exchange. Do not abuse vitamin K and sulfonamides before delivery.
II) Postpartum prevention
1, newborns, especially premature babies should not use vitamin K3, sulfonamides, sodium benzoate caffeine and salicylic acid and other drugs. Prevention of neonatal infections should not be used neonatal mycophenolate, new penicillin II and sulfisoxazole and other drugs.
2, if jaundice occurs early, the rapid progress (bilirubin in 10mg / dl or more) should be given early plasma or albumin, reduce the risk of free bilirubin through the blood-brain barrier, while phototherapy. Both treatment and prophylaxis can be applied.
3, the diagnosis and treatment of comorbidities neonatal high unconjugated bilirubinemia, often coexist with asphyxia. Hypoxemia, hypoglycemia, acidosis, can affect the blood-brain barrier permeability, timely correction. It can avoid or reduce the risk of developing nuclear jaundice in trapped high unconjugated bilirubinemia.
4, drug therapy Enzyme inducers: such as phenobarbital, Nicotinamide, etc. can stimulate the bracket glucuronyl transferase, so that unconjugated bilirubin into conjugated bilirubin, and can improve the permeability of the capillary bile ducts, biliary effect, but the effect is slow, since the widespread application of phototherapy, has been less applied.
5.Blood exchange therapy While closely monitoring the development of neonatal hyperunconjugated bilirubinemia, make all preparations for blood exchange, such as blood distribution, application of albumin before blood exchange and other measures.
For premature infants with imperfect blood-brain barrier function, low birth weight infants or jaundiced infants with open blood-brain barrier, even if the serum bilirubin is not very high when drowsiness, unresponsiveness, hypotonia and gaze appear, we should pay enough attention and conduct close detection and intervention. There are reports of early intervention and phototherapy for newborns with cord blood bilirubin ≥3mg/dl in 3 d, ≥6mg/dl in 24 h, ≥9mg/dl in 48 h, and ≥12mg/dl in 72 h. In more than 100 cases, intermittent phototherapy was administered. There were more than 100 cases in total, and the use of intermittent phototherapy and continuous phototherapy depended on the condition of the children. None of the cases had bilirubin encephalopathy and none of the cases had died, which achieved very good therapeutic results.
For severe hyperbilirubinemia, exchange transfusion therapy is performed to save the life of the child. For milder hyperbilirubinemia, pharmacological therapy, such as Niclosamide and phenobarbital, can also be given. Plasma or albumin is limited to early application, especially in premature infants, in order to prevent the occurrence of bilirubin encephalopathy, a high-dose intravenous infusion of gammaglobulin can treat hyperbilirubinemia caused by neonatal hemolytic disease is also on trial, and recently the introduction of metalloporphyrin therapy for hyperbilirubinemia, domestic Yu Shanlu and other studies on the application of metalloporphyrin in hyperbilirubinemia, the results show that metalloporphyrin in The results show that metalloporphyrin has a broad application prospect in the prevention and treatment of neonatal hyperbilirubinemia and prevention of bilirubin encephalopathy, and has more positive significance than the traditional prevention and treatment methods.
Third, for those who have developed nuclear jaundice, symptomatic treatment is given according to the manifestations of each stage. The sequelae stage can guide early intervention for intellectual and motor development, and even some children lead to lifelong disability, and it is best to cooperate with the doctor’s treatment.