Characterization of the Short-Term Effects of Prenatal Asphyxia and Screening of Some Ethiopian Medicinal Plants for the Probable Preventive Role in Rats.
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Date
1997-04
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Addis Ababa University
Abstract
Perinatal asphyxia results from failure of normal respiratory gas exchange during or
soon after labor and it remains an important cause of permanent neurological deficit in
surviving infants. The most common features are hypoxia, hypercapnia, and metabolic
acidosis. The present sf1ldy was undertaken to fUrther characterize the short-term effect of
perinatal asphyxia and to investigate a possible preventive role of some Ethiopian medicinal
plants and hypothermia in rats.
The effect of perinatal asphyxia on survival pattern, brain and heart pH, levels of
amino acids, monoamines, and glycolytic intermediates was studied using in vivo microdialysis
and ex vivo biochemistry. Perinatal asphyxia was induced by immersing fef11S containing
uterus horns, obtained by cesarean section from term pregnant rats, in a water bath at 370C
for different periods (0-23 min), according to a non-invasive model that largely mimics the
conditions resulting in asphyxia during human labor (Bjelke et al. , 1991; Andersson et aI.,
1992; Herrera-Marschitz et al., 1993). Subcutaneous levels of pyruvate, lactate, glutamate,
and aspartate were monitored with microdialysis 80 ~lin-8 days following delivery. In parallel
experiments, pups were sacrificed 40 min after delivery and the brain and heart were removed
to measure pH In addition, pups were also sacrificed 80 min-8 days after delivery and the
brain was removed to measure striatal levels of pyruvate, lactate, glutamate, aspartate, and
monoamines.
At 37°C, a decrease in the rate of sU/vival was first observed following asphyxic
period longer than 16 min and no survival was observed after 22 min. pH decreased with the
length of asphyxia. In control pups (cesarean delivered), brain pH was (7.3±0.01;N=6) and
heart pH was (7.35±0.01; N=6). A significant decrease in pH was observed following 10-11
min and 5-6 min, in brain and heart respectively. After 80 min of delivery, a significant
increase in the levels of all the measured compounds, in subcutaneous and brain tissues, were
observed follOWing exposure to mild asphyxia. However, the levels started to decline when
asphyxia was prolonged With increasing age, the levels of the measured compounds in mild
• asphyxic pups were almost similar as that of the control pups. Nonetheless, the time needed to
recover depended upon how greatly the compound's metabolism was affected Lactate being
the most severely affected, much time was needed to reduce its level. Thus, changes in systemiC
pH, glycolytic intermediates, monoamines, and excitatory amino acids metabolism were observed following perinatal asphyxia. In particular, subcutaneous level of lactate preceded:
(q) a decrease in brain pH, (b) an increase in brain lactate level, (c) a decrease in the rate of
survival, and probably (d.) brain damage.
The possible protective effect of some herbal medicines was evaluated by injecting the
extract subcutaneously or using as a bathing fluid and subjecting the pups to asphyxia at
370 C. Asphyxia induction at 300C and I50C was also carried out to evaluate the protective
effect of hypothermia and to use it for comparison purpose. Survival was prolonged when
asphyxia was induced under hypothermic condition. No survival was observed after 50 min
and 140 min when asphyxia was induced at 300C and I50C respectively. Survival pattern after
treatment with plant extracts did not show any significant difference compared to saline
injected control group. Thus, hypothermia seems the only intervention that can provide good
protective effect amongst the interventions so far evaluated.
However, with improvement in obstetric management, its role has been shown to be limited. As
early as the 1930s, the cause of petlnatal brain damage was intimately tied up with attitudes
towards the use of sedatives, analgesics, and anesthetics duriug labor and delivery (Eastman,
1936). It was demonstrated that the excessive use of these agents caused "apnea neonatomm"
which was thought to be the principal cause of cerebral injwy (Sclueiber, 1938) and almost all
Wliters of the time suppOlted this view and equated "asphyxia neonatorum" with "apnea
neonatorwn". Although this view was later shown to be unlikely (Myers, 1977), the tendency to
consider birth apnea as a causative factor for cerebral injmy dominated-the 1940s-and the 1950s-. -
Hence, articles appeared in the I 940s strongly suggested a causal relationship between petlnatal
asphyxia and cettain patterns of nemopathogenic changes in the brain. It was stated that the
brain swelling and necrosis obsetved in newborns who died after cesarean delivety because of
premature detachment of the placenta was due to asphyxia (Clifford, 1941). The injwies at buth
were thought to be associated either to trawna to the head or to fetal systemic hypotension
caused by asphyxia (Malamud, 1959,1963; Norman, 1969). It was believed that cerebral venous
congestion causes the haemorrhagic infarction that often affects the brains ofbitth-injw·ed babies
(Schwartz, 1961). The congestion was atttibuted to the rapid passage of the fetal head ii-om a
wne of high pressure within the utems to one oflow pressw·e outside (Schwaltz, 1961). The
infarction of the cerebrum associated with birth injwy was caused by fetal circulatOlY failure,
generalized venous congestion, and cerebral venous stasis-thrombosis (Towbin, 1970). Thus, a
nwnber of causes have been proposed for petlnatal brain damage of which petlnata1 asphyxia is
one of the candidates.
Asphyxia is defined as suffocation with anoxia and increased carbondioxide. It atises
from impairment of normal respit·atOlY gas exchange with resulting hypoxia/ischemia,
hypercapnia, and metabolic acidosis. The term perinatal asphyxia is often used to indicate an
impainnent of gas exchange during or soon after labor (Nelson and Leviton, 1991; Martin and
Nelson, 1993). The tenn hypoxic-ischemic or postasphyxial encephalopathy is often used to
describe the illness thought to stem from such impaiIment. In most instances, during the
peIinatal peIiod, hypoxemia and/or ischemia occm as a result of asphyxia (Hull and Dodd,
1991). When descIibing oxygen deptivation in hllJDan, the tenn asphyxia is used, because it is
not known whether the insult is hypoxic, ischemic, or more probably a combination.
Fmthennore, regarding the fetus, the telms hypoxia and ischemia have been used
interchangeably, because, the most common cause of hypoxia in the fetus is hypoperfusion or
ischemia. Hypoxia can also cause ischemia, as it is capable of producing hypotension and
reduced cardiac output. Thus, in asphyxia, the major additional feature is hypercapnia, which
results in a nllJDber of other metabolic disorders, such as acidosis and physiological effects
including cerebral vasodilatation (Volpe, 1987). Hypoxia and partial regional ischemia
commonly occm together, therefore, it appears that the regional distIibution of ischcmia in the
face of hypoxia is a major determinant of the relatively selective nature of peIinatal asphyxial
brain injury. Hence, this type of brain injmy is refelTed to as hypoxic-ischemia.
PelIDatal asphyxia can occm in the human fetus or neonate as an acute total asphyxial
episode resulting ii-om cord prolapse that leads to complete cessation of blood flow (Leech and
Alvord, 1977), and as a prolonged partial asphyxial episode resulting from placental abruption
that may occm during a long and complicated labor (Clifford, 1941). In order to understand the
patterns of pelIDatal brain damage, two models in monkeys have been developed: acute total
asphyxia (Ranck and Windle, 1959) and prolonged partial asphyxia (Brann and Myers, 1975;
Myers, 1972, 1977). The first model that replicated acute total asphyxia caused a lesion
affecting spinal cord, brainstem and thalamus without brain swelling. TIle second model that
replicated prolonged partial asphyxia, however, produced a different pattern of cerebral affecting mainly the COltiCal and subcortical stmctures with brain swelling (Myers, 1972). The
reason for the different distribntion of the lesions depends upon the redistribution of regional
cerebral blood flow and the degree of neuronal maturation dwing asphyxia. In most cases, tbe
total pelinatal insnlt in hmnans most likely resnlts from prolonged partial asphyxial episode, and
sometimes from partia~ combined with terminal acnte asphyxial episode (Scott, 1976; Braun,
1986). Heuce, fetal partial asphyxia of any cause, independent offetal circnlatOlY collapse and
head compression, is believed to be the Priru31Y event that sets in motion a vicious cycle ofbraiu
swelling, leading to stasis of blood flow and, fiually to cerebral necrosis (Br3lill and Myers,
1975).
IufOlmatiou about the specific effect of birth asphyxia on the fetus or neouates has beeu
possible only since the development of new techniques for detennining blood pH and blood
gases. The introduction of risk scoring and assessment of fetal behavior has finther improved the
identification of the fetus at risk for a.phyxia (Brallll, 1986; Lowet ai, 1992). Thus, Apgar
(1953) developed a SCOling system to infer the occurrence of birth asphyxia and to quantifY its
sevelity from several indicators, such as: (i) type of breatlling; (ii) healt rate; (iii) color of the
skin; (iv) muscle tone; and (v) response to different sensory stimnli. UnfOltwlately none of these
indicators is an accurate predictor of outcome, rather they are probably best used to indicate the
need for active resuscitation (Hnll and Dodd, 1991). Biochemical data such as umbilical pH and
gas levels obtained soon after birtb may be used to validate the judgement tbat the
pathophysiological changes obselved during birth 31'e asphyxial in natme. But these putative
markers of asphyxia do not always conelate well with one another.
Because of the poor predictive value of the traditional indicators, alternativesand Sarnat, 1976). HIE develops in the first few hours and days of life and is characterized by
abnonnalities of tone, feeding, level of consciousness, and in the more severe cases, seizures and
finally coma with the need for ventilatOlY support. The postasphyxial encephalopathy is graded
into mild (no seizure), moderate (seizures) and severe (coma). Those infants with mild
encephalopathy have a unifonnly good outcome, those with moderate encephalopathy have a
20-30% chance of severe handicap, and the majOlity of infants with severe encephalopathy die
(Hull and Dodd, 1991). Hence, HIE has been found to be a much more accurate predictor of
outcome (Robertson and Finer, 1985), however, the recent identification of a group of infants
with typical encephalopathies (Hull and Dodd, 1991), without previous evidence of asphyxia
cast some doubt on the casual relation between the two phenomena. Thus, there is still no
reliable clinical indicator of birth asphyxia. Nevertheless, with the development of magnetic
resonance spectroscopy, a potential independent indicator of brain asphyxial states has emerged
(Martin and Nelson, 1993).
Several animal models have been developed to assess the role of asphyxia in mediating
brain damage (see Raju, 1992). In the present thesis, the short-telm effect of perinatal asphyxia
and its prevention was studied in rat using a novel non-invasive model that largely mimics the
conditions resulting in asphyxia during human labor (Bjelke etaI., 1991; Anderson etal., 1992;
Herrera-Marschitz etaI., 1993)
sought. This effort led to the identification of the abnOlmal neurological signs known as
hypoxic-ischemic encephalopathy (HIE), that was used as an assessment of asphyxia (Samatsinewy
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Keywords
Effects of Prenatal Asphyxia