Does hypoxemia prevent brain damage in birth asphyxia?

Medical Hypotheses Med.4 HJQOU~SM (1993) 41,344341 0 Lagann OIuup UK L&l 1993

Does Hypoxemia Asphyxia?

Prevent Brain Damage in Birth

DE. BALLOT, A.D. ROTHBERG, V.A. DAVIES, J. SMITH’ and G. KIRSTEN* Department of Paediatrics and Child Health, Johannesburg Hospital, University of the Witwatetsrand, Private Bag X39, Johannesburg 2000, South Africa and ‘Department of Paediatrics, Tygerberg Hospital, University of Stellenbosch, South Africa (Correspondence to DEB).

Abstract-The clinical syndrome of hypoxic ischemic encephalopathy (HIE) which occurs in association with birth asphyxia, is thought to represent a reperfusion injury consequent upon the generation of cyotoxic oxygen derived free radicals. It has recently been suggested that resuscitation of asphyxiated infants with unrestricted oxygen may aggravate the brain damage by causing hyperoxia and increased free radical production. To determine whether sustained hypoxemia may be protective in birth asphyxiated infants, we investigated the relationship between HIE and persistent pulmonary hypertension of the neonate (PPHN). The latter condition is also related to intrauterine and intrapartum birth asphyxia but is associated with persistent hypoxemia in the infant. In a retrospective analysis of 39 asphyxiated neonates admitted to the neonatal intensive care unit, we found that 28 had HIE, 10 had PPHN and only 1 had both HIE and PPHN. We therefore suggest that the hypoxemia due to PPHN may limit the production of oxygen derived free radicals in asphyxiated neonates and hence protect against the development of HIE. These findings lend support to current research into air vs. oxygen resuscitation for infants with birth asphyxia.

Many aspects of birth asphyxia (BA) and its management remain controversial (l-3). The issues under debate include the relative contributions of antepartum and intmpartum asphyxia to the clinical presentation of BA (l), the contribution of BA to neonatal morbidity and mortality (4-7), and the optimal acute management of the infant asphyxiated at birth (2, 8). BA may be associated with damage to various organs, and manifestations include hypoxic ischemic encephalopathy (HIE), persistent pulmonary hypertension (PPHN) and meconium aspiration syndrome Date received 28 December 1992 Date accepted 7 January 1993

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(MAS). The kidney, gut and heart may also be affected (1, 2, 9). HIE and PPHN are both regarded as consequences of chronic intrauterine asphyxia rather than the outcome of an acute asphyxial event (9, 10). In HIE the proposed mechanism of damage is that of reperfusion injury (11) in which generation of cytotoxic free radicals and excitatory amino acids, particularly glutamate, together with altered calcium balance result in cerebral damage (2,12-14). Posmatally, grades of neurological impairment are described, ranging from hyperalertness through stupor (with or without

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DOES HYPOXEMIA PREVENT BRAIN DAMAGE IN BIRTH ASPHYXIA?

seizures) to deep coma (15). In PPHN, chronic intrauterine asphyxia may result in maldevelopment of pulmonary vessels with hypertrophy and extension of pulmonary arterial smooth muscle into the normally non-muscular intra-acinar arteries (10, 16). In this situation, the postnatal picture is one of persistent right to left shunting of blood with consequent hypoxemia. This is often refractory despite aggressive ventilation and pharmacotherapy, and may necessitate extracorporeal membrane oxygenation (ECMO) (17). While both HIE and PPHN are associated with BA, it has been our clinical impression that these conditions seldom co-exist in a single patient. Furthermore, survivors of HIE, particularly grades 2 and 3, are at risk for neurological handicap, including cerebral palsy (9), while the neurological outcome in the survivors of PPHN appears to be different. In a review of subjects with PPHN treated with hyperventilation, the majority were developmentally normal on follow up (18), although there may be an increased risk of deafness (19). The risk of neurological handicap in PPHN appears to be related to the degree of perinatal asphyxia, rather than the condition or treatment per se (18). These different neurological sequelae in two conditions associated with chronic intrauterine hypoxia and BA suggest that there are factors in subjects with PPHN which prevent the postnatal development of HIE. We propose that one factor is the persistent hypoxemia of PPHN which may have a role in cerebral protection by limiting the generation of oxygen derived free radicals. Hyperoxia induced oxygen toxicity is related to increased production of superoxide radicals (20) and there is experimental evidence to support the role of oxygen derived free radicals in reperfusion injury (11-14). Based on the hypothesis that hyperoxia might be deleterious in the resuscitation of the asphyxiated neonate, current research is evaluating the role of limited oxygen in neonatal resuscitation (21). However, this approach is not widely accepted and current resuscitation protocols do not comment on the possible reduction of post-ischemic injury, including HIE, by restricting the use of oxygen (1, 22). To further advance the hypothesis that infants with hypoxemia associated with PPHN do not usually manifest signs of HIE, we conducted a retrospective review of a group of asphyxiated infants born at or transferred to the Johannesburg hospital. Subjects and methods The neonatal computer database was used to review all admissions to the neonatal intensive care unit of the Johannesburg hospital between 1 January 1986 and 30 June 1992. Ventilated infants with the fol-

lowing characteristics were included in the analysis: 1 min Apgar ~6; birth weight >2000 g and/or gestational age >34 weeks; diagnosis of HIE or PPHN. In this way only relatively mature, moderately to severely asphyxiated infants were included in the analysis. HIE was diagnosed according to the clinical staging of Samat and Samat (15) and all grades of HIE were included in the study. The grade of HIE was not always specified on the database, so this is not included in the analysis. Infants with PPHN who had seizures with no other specified cause (e.g. metabolic) were regarded as having HIE. PPHN was suspected in infants with prolonged hypoxemia, and the diagnosis was confirmed by echocardiography and/or by demonstrating a significant gradient in arterial PO2 between preductal and postductal sites. Infants with PPHN due to pulmonary hypoplasia or diaphragmatic hernia were excluded from the analysis. In infants with respiratory distress and HIE and/or PPHN, meconium aspiration syndrome was suspected on the basis of a history of meconium stained liquor and meconium in the airways at delivery; in these cases the diagnosis was confirmed by chest X-ray. Statistical analysis included descriptive statistics, unpaired t tests and Fisher’s exact test, and was by means of a personal computer using Statpak Version 4.0 (Northwest Analytical, Portland, Oregon). Results A total of 39 infants (11 females and 28 males) were included in the review. Characteristics of these infants are shown in the Table. 28 infants had HIE, 10 had PPHN and only 1 had both PPHN and HIE. The latter is included in the Table with the HIE group. He weighed 3720 g at 40 weeks and survived the neonatal period. 13 infants with HIE had seizures. The HIE and PPHN groups were comparable, except that the infants with PPHN had significantly higher Apgar scores and were of a lower gestational age. Discussion In this group of severely ill asphyxiated neonates, all of whom required ventilation, PPHN and HIE co existed in only 1 subject. This is an important finding given that these two conditions may represent different consequences of similar intrauterine circumstances. In both groups there was a bias towards intrauterine growth retardation which supports exposure to prolonged intrauterine asphyxia; however the significantly lower gestational age of the PPHN group might be the key as to why the two groups respond

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MEDICAL HYp0TBE8Es

Table Characteristics of asphyxiated infants admitted to NICIJ’

Number Male/Female Neonatal factors Birth weight (kg) Gestational aae (wks) SGAJAGA

-

.

1 minute Apgar 5 minute Apgar Outb3m Meumiurn aspiration syndrome Duration ventilation (days) Duration hospitalization (days) Deaths Maternal factors Maternal age (yrs) Parity Normal vaginal delivery C Section (fetal distress) Assisted delivery Breech Hypertension

HIE

PPHN

P value

29 2217

10 614

NS

2.95 dzO.54 39.1 i2.3

2.% dIO.5 37.2 *l .I 3t7 4.1 kO.8 6.9 f2.1 3 3 5.9 +4.3 15.6 f10.4 4

NS 0.014 NS 0.002 0.036 NS NS NS NS NS

28.6 k7.2 1.6 +1.3

NS NS NS NS