Late decelerations and brain tolerance of the fetal monkey to intrap-artum asphyxia K.

ADAMSONS,

R.

E.

MYERS,

Bethesda,

Maryland,

M.D., M.D., and

PH.D. PH.D.

Providence,

Rhode

Island

Eight monkey fetuses near term were subjected to regulated asphyxia during labor by mechanically constricting the maternal abdominal aorta and diminishing blood flow to the uterus. A magnitude of asphyxia was produced and maintained for an initiil three hours that was close to but not sufficient to elicit late decelerations. The asphyxia was then augmented during a fourth hour to cause late decelerations of magnitudes of 5 to 15 per cent of the initial heart rate. After termination of the fourth hour of asphyxia, the fetuses were delivered by hysterotomy and provided intensive care. During the three to nine months of survival after birth, all animals were neurologically intact; on necropsy the brains were free of pathologic changes both grossly and microscopically. These results support the thesis that fetal heart rate monitoring during labor exhibits a sensitivity sufficient to diagnose asphyxia of the fetus of clinical significance before it reaches a magnitude that may cause permanent neurological injury. These results are particularly pertinent to those clinical circumstances where the decreases in intervillous space blood flow brought about by uterine contractions are accentuated due to low maternal blood pressure. (AM. J. OBSTET. GYNECOL. 128: 893,1977.)

INCREASING RELIANCE has been placed upon the electronic monitoring of the fetal heart rate to diagnose fetal asphyxia during labor over the last five years. Transient decreases in heart rate following uterine contractions or “late decelerations” have long been identified as indicating a jeopardy of the fetus from asphyxia. ‘* ’ However, it is not clear whether a magnitude of asphyxia that elicits late decelerations can be tolerated by the fetus without injury to the brain. Most clinical studies do describe a lowering of the Apgar score and higher perinatal morbidity and mortality rates among those infants who exhibit late decelerations during labor. 2-4 Although these clinical studies are of unquestioned value in identifying patients at risk and in establishing criteria for the management of From the Laboratory of Perinatal Physiology, National Institute of Neurolo~&d and Comm&ca&e Disor&rs and Stroke. National Institutes of Health. and the Department of Obstetrics and G$ecology, Brown University School of Medicine. Received

for

Revised

March

Accepted

publication

March

Februa?

1, 1977.

14, 1977. 22, 1977.

Reprint requests: Dr. K. A&wnwm.s, Division of Biology and Medicine, 50 Ma&e St., Providence, Rhode Island 02908.

labor, they do not provide direct information with respect to the relationship between occurrence of late decelerations and the morphologic state of the nervous system. Studies with rhesus monkeys have demonstrated that late decelerations occur only when the oxygenation of the fetus is substantially reduced.5-7 These studies have shown that late decelerations occur following normal uterine contractions only when blood sampled from the abdominal aorta of the fetus shows a hemoglobin saturation with oxygen of less than 25 to 30 per cent. The experimental studies also have demonstrated that marked asphyxia of the monkey fetus also causes swelling of the brain* and patterns of brain injury that closely simulate brain damage patterns observed in man.’ These observations create a particular concern whether it is acceptable to depend upon the recognition of late decelerations as the warning sign of clinically significant asphyxia of the fetus. It seems possible that asphyxia of a magnitude sufficient to cause fetal heart rate changes may also be of a magnitude sufficient to cause injury to the fetal brain. The present study with the pregnant rhesus monkey used as a model investigates the impact of asphyxia of an extent sufficient to cause late decelerations, upon the neurological performance of the newborn animal

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and upon the morphologic integrity of the brain after the animal has survived for a prolonged time. The experiment was devised so as to approximate those circumstances under which asphyxia of the fetus may occur in man. An initial three hours of asphyxia of an intensity not quite sufficient to cause late decelerations was administered to duplicate the events that may occur during the second half of an active labor. It is known that the second stage of labor is associated with a progressive decrease in pH of fetal arterial blood in a substantial proportion of patients even in those instances in which no complications can be identified.9m’2 The fetuses, which had already sustained three hours of asphyxia, were then subjected to a fourth hour of more marked asphyxia that was associated with distinct late decelerations. An additional hour of the more marked asphyxia was utilized because an hour is estimated to be the outer limit of time that is required in the clinical setting to identify and confirm the presence of asphyxia of the fetus with biochemical means and, after the presence of asphyxia is confirmed, to extricate the fetus. The implications of exposure of fetuses to such terminal asphyxia were examined with respect to both survival of the newborn animal and occurence of damage to the brain.

Material and methods Eight pregnant rhesus monkeys near term were used. All animals were obtained from the breeding colony of the Laboratory of Perinatal Physiology. During the 12 hours prior to study, all animals were deprived of food but allowed free access to water. On the morning of the study, they were anesthetized with intravenous sodium pentobarbital, 35 mg. per kilogram. The maternal abdomen was prepared in a sterile manner and a midline incision was made with exposure of the uterus. The uterine fundus was incised in a location well away from the margins of the placental discs. The left leg of the fetus was delivered, and a P.E. No. 50 polyethylene catheter was inserted into the left femoral artery, advanced to the level of the abdominal aorta,. and secured in place. The leg was returned to the uterus; a second catheter was positioned in the amniotic cavity, and the uterine incision was closed with 2-O chromic sutures. Lost amniotic fluid was replaced by physiologic saline injected through the intrauterine catheter. The uterus and its contents were next reflected forward; the aorta of the mother was identified, and a segment distal to the origin of the renal arteries was freed. One end of a cord was passed behind the freed segment of the aorta, and a sling was formed by leading the free ends of the cord through a 6 cm. length of

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stiff polyethylene tubing and attaching both to a sc’rew micrometer. By adjusting the tension applied to the sling by the micrometer screw, the degree to which the aorta was compressed could be regulated. This compression of the maternal aorta permitted the blood pressure in the distal maternal aorta and its branches to be adjusted up or down at will. The end of the polyethylene tubing through which the two strands of the sling were passed was exteriorized through a stab wound in the lateral abdominal wall of the mother. All incisions were then closed, and the mother was repositioned on her side. The blood pressures and heart rates of the mother and fetus and the intrauterine pressure were recorcled continuously. Samples of maternal and fetal arterial blood were withdrawn at intervals and analyzed fin pH, PoZ and Pcoz. The maternal rectal temperature was maintained in the range of 37” to 38” C. by a servo-controlled heat shield positioned over the animal and a warm water blanket placed underneath. Depth of anesthesia was maintained constant by the hourly intramuscular injection of pentobarbital, 5 to 10 mg. per kilogram. The mothers and fetuses were observed for- 30 to 10 minutes while the control values of all parameters measured were determined. The constricting sling was then tightened which lowered blood pressure in the distal aorta and decreased blood flow through the uterine arteries. Throughout the entire procedure, the pressure in the maternal common iliac artery distal to the point of constriction was continuously monitored. When the asphyxia of the fetus brought about by the reduced blood pressure in the uterine arteries was sufficient to cause late decelerations, the uterine artery blood pressure was regulated upward very slightly by readjusting the micrometer screw. This caused the late decelerations to disappear. Periodic further acljustments of the tension maintained on the sling were then necessary to maintain the asphyxia of the fetus at such a magnitude that the spontaneous uterine contractions failed to elicit late decelerations. After three hours of asphyxia in this range, the blood pressure in the maternal iliac artery was again adjusted downward to provoke late decelerations of a magnitude that ranged between 5 and 15 per cent of the control rate. The fetuses were subjected to a full fourth hour of such more marked asphyxia, and then they were delivered by hysterotomy. All newborn animals had immediate intubation and mechanical ventilation with an Amsterdam infant respirator which utilized 100 per cent oxygen at an inflation pressure less than 20 mm. Hg. As soon as the newborn animals began breathing on their own, the

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endotracheal tube was removed, and the infants were transferred to an incubator. The oxygen tension of the atmosphere contained in the incubator was adjusted to maintain the oxygen pressure of blood taken from the newborn abdominal aorta in the range of 55 to 80 mm. Hg. The vital signs, blood composition, and blood pressure of the newborn animals were closely monitored until the animals began to respond to stimulation which usually occurred any time after eight to 24 hours. The arterial catheter was removed after 24 hours, and the infants were maintained on formula by bottle. All infants were examined neurologically at weekly intervals over the first two months and at monthly intervals thereafter. During these examinations, the animals were tested for their general alertness and responsiveness to stimulation. Gait and stance were recorded as were bodily postures. The range and conjugateness of eye movements and the fullness of visual fields was tested. All extremities were examined with respect to reaction to stimulation and the degree of control of motor reactions. Muscle tone was estimated by palpation and by moving the limbs passively. Muscle strength was tested as was coordination of the extremities in picking up food objects. A particular note was taken of limb positioning both when the animals were at rest and when they were walking. The animals’ tolerance to limb placement in abnormal positions was also determined. Three to nine months after delivery, the animals were anesthetized with intravenous pentobarbital, 35 mg. per kilogram. The chest was opened, and a cannula was placed in the ascending aorta. The right auricle was amputated, and the vascular system was perfused with a formaldehyde-saline solution. The brains were removed and fixed for an additional 10 days in 10 per cent formalin. All brain specimens, coronal brain slices, and thionine-stained microscopic serial sections were evaluated in detail for pathologic changes.

Results Control values. The mean values and ranges for the various constituents of maternal arterial blood during the control period were: pH = 7.43 (range = 7.39 to 7.47), PoZ = 88 (range = 79 to 102) mm. Hg. and Pcoz = 32 (range = 29 to 34) mm. Hg. The corresponding values for the fetuses were: pH = 7.28 (range = 7.21 to 7.32), Pq = 26 (range = 22 to 30) mm. Hg, and PC@ = 41 (range = 37 to 44) mm. Hg. The mean arterial blood pressure of the mothers averaged 110 (range = 96 to 132) mm. Hg, and the heart rate averaged 160 (range = 145 to 175) beats per minute. The corresponding values for the eight fetuses

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were 48 (range = 43 to 55) mm. Hg and 208 (range = 170 to 230) beats per minute. Periodic uterine contractions were present in all of the animals. These contractions increased in both frequency and amplitude over the five-hour observation period in all instances. During the fourth and final hour of more marked asphyxia, the duration of uterine contractions ranged between 28 and 54 seconds while the intervals between contractions ranged between 55 and 240 seconds. The intrauterine pressure between contractions ranged between 7 and 12 mm. Hg. The amplitude of maximum uterine contractions ranged between 22 and 60 mm. Hg. Regulation of blood pressure in the common iliac artery of the mother. At the end of the 30 minute control period, the mean blood pressure in the common iliac artery of the mother was reduced to a range of 32 to 44 mm. Hg in order to reduce the supply of oxygen to the fetus to a level at which uterine contractions of moderate intensity and normal duration began to cause late decelerations. Once late decelerations appeared, the blood pressure in the maternal common iliac artery was again adjusted upward to 40 to 45 mm. Hg until the late decelerations disappeared. Further periodic upward adjustments of maternal iliac artery blood pressure were made thereafter to continue to maintain the oxygen concentration of fetal arterial blood at a value such that the fetus continued to exhibit late decelerations of small magnitude. At the termination of the three hours of asphyxia of lesser magnitude in the fetus, the blood pressure in the maternal iliac artery was again adjusted downward for a final (fourth) hour of more marked asphyxia associated with late decelerations. Because all fetuses were significantly acidotic by this time, it was necessary to reduce the blood pressure of the mother only to the range of 60 to 80 mm. Hg to increase again the asphyxia of the fetuses sufficiently to lead to late decelerations of a small magnitude as described. Blood composition and vital signs of the fetuses during asphyxia. The fetuses showed no significant changes in vital signs during the three-hour period during which the oxygen deprivation was of a magnitude just short of that required to cause late decelerations. The mean blood pressure averaged 44 (range = 40 to 48) mm. Hg and the heart rate averaged 196 (range = 180 to 220) beats per minute. On the other hand, the hydrogen ion concentration of fetal arterial blood increased to values that corresponded to a pH of 7.16 (range = 7.08 to 7.22), the oxygen tensions declined to a mean of 18 (range = 14 to 20) mm. Hg, and the carbon dioxide tensions increased to a mean of 54 (range = 52 to 59) mm. Hg.

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Fig. 1. Cross sections through the middle third of the postcentral gyrus of two 6-month-old rhesus monkeys (Nissl stain). A: Control animal delivered spontaneously at term. B: Experimental animal subjected fo four hours of moderate asphyxia at term delivery (pH range = 7.21 to 7.14; PO, range = 16 to 13 mm. Hg, and PC@ range = 44 to 57 mm. Hg). Note the similarity in density and distribution of nerve cell types in the six cortical layers in both specimens. The middle third of the postcentral gyrus is particularly prone fo injury following exposure to partial asphyxia at birth.

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Fig. 4. Cross section through the central nucleus of the right inferior colliculus of the same animals as illustrated in Fig. 1. Comparison of the appearance of this nucleus in the two animals shows no evidence of pathologic change following exposure to moderate asphyxia for four hours of the animal depicted in B. The inferior colliculus is the brain structure most vulnerable to injury when monkey fetuses are exposed to total asphyxia.

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The corresponding mean arterial blood oxygen content, as calculated from the corresponding PO*, pH, and hematocrit values, was 4.4 ml. per 100 ml. of fetal arterial blood. At the end of the fourth and final hour of more marked asphyxia (when the fetal oxygen stores were depleted so as to cause late decelerations), all fetuses had sustained significant decreases in both mean blood pressures and mean heart rates. The mean blood pressures between late decelerations of the eight fetuses as determined during the last 10 minutes of exposure to asphyxia averaged 38 (range = 36 to 42) mm. Hg and the heart rate averaged 174 (range = 162 to 182) beats per minute. The final average pH value of fetal abdominal aortic blood was 7.13 (range = 7.05 to 7.17); the mean P@ value was 13 (range = 12 to 16) mm. Hg, and the mean PC% value was 59 (range = 56 to 64) mm. Hg. Thirty minutes after the fetuses were delivered, when they were breathing oxygen-enriched air, their blood pressures and heart rates were slightly lower than those observed in utero during the control period. The mean blood pressure averaged 47 (range = 44 to 51) mm. Hg and the heart rate averaged 196 (range = 188 to 216) beats per minute. The hydrogen ion concentration had decreased significantly by this time so that the pH values averaged 7.22 (range 7.19 to 7.26), the Pa values averaged 78 (range = 56 to 94) mm. Hg, and the PC% values averaged 38 (range = 32 to 41) mm. Hg. Neurological and neuropathologic findings. The neurological examinations of the eight newborn animals repeatedly failed to demonstrate any abnormalities. Throughout survival, all animals appeared normally alert and responsive to stimulation. They began sitting and standing and, later, walking at the expected times. Gait and stance appeared entirely normal. Extraocular movements were full and visual fields were intact as tested by confrontation. Muscle tone and strength and use of all extremities were within normal limits. None of the animals showed any tendency to abnormal posturing either at rest or during movement, and all responded actively when pricked with a pin over widespread areas of the body on both sides. Examination of the gross brain specimens and coronal brain slices taken from the brains of all eight animals failed to uncover any pathologic abnormalities. Study of serial microscopic sections taken from the brains also failed to reveal any areas of nerve cell loss or other type of pathologic change. Fig. 1 depicts a photomicrographic view taken from the postcentral gyrus of experimental monkey 175 1 subjected to in-

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i5, 1977 G+mecol.

trauterine asphyxia and of control monkey 1726 delivered vaginally without documented asphyxia. Both animals were 6 months old at the time they were killed, and neither showed any neurological abnormalities. As is evident from the photomicrographs, the numbers and distributions of cell types within the six laminae of the cortex of the two animals are similar. The absence of pathologic changes in this zone of cortex is of- particular significance because this area shows a predilection for injury as a result of exposure to partial asphyxia.’ Fig. 2 presents the microscopic appearance of the right inferior colliculus taken from the same two animals illustrated in Fig. 1. The inferior colliculus, the first structure to show injury in newborn animals following exposure to total asphyxia.’ also gives no evidence of pathologic change in the animals that sustained the intrapartum asphyxia, as is evident from the microscopic sections illustrated in Fig. 2.

Comment The anesthetized mature monkey fetuses showed a considerable tolerance to marked reductions in oxygen tension. None of the animals subjected to four hours of. moderate asphyxia exhibited any brain injury detectable by either neurological evaluation of the animals in the newborn or juvenile stage or by gross or microscopic examination of the brains. Previous work has demonstrated that brain injury-usually associated with brain edema-can be produced in term monkey fetuses only when the oxygen content of blood taken from the fetal abdominal aorta decreases below 2 ml. per 100 m1.6-8. l3 Be cause late decelerations are regularly elicited in rhesus monkey fetuses by uterine contractions of normal duration when fetal oxygenation is already reduced by a less marked amount, it was inferred that late decelerations might appear before brain injury during heightening asphyxia. Besides verifying this supposition, the present investigation provides additional information regarding the duration of moderate asphyxia that term monkey fetuses can sustain without injury to the nervous system. Several important considerations must be borne- in mind in interpreting the present results. First, the present animals were anesthetized throughout their exposure to asphyxia. Since barbiturate anesthesia significantly extends mature monkey fetuses’ tolerance to total asphyxia (anoxia) , ‘* the use of anesthesia in the present study may also have extended the fetuses’ tolerance to partial asphyxia (hypoxia). If so, fetuses that are not anesthetized may develop brain injury when exposed to partial asphyxia of a magnitude not sufficient to cause brain injury in the present study. Thus, there are several reasons why direct inferences

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can not be drawn from the results of the present study to the situation of a woman in labor where anesthesia has not been used. The magnitude of asphyxia utilized in the present study was carefully regulated throughout the period of exposure. The cardiovascular performance of each fetus, though somewhat depressed, was we11 maintained, and care was exercised that the fetuses not sustain additional total asphyxia at delivery or during the newborn period. In contrast, the human fetus, in most clinical situations associated with impaired fetal oxygen supply, suffers from progressive reductions in blood oxygen content as labor progresses.” Furthermore, the human fetus nearly always sustains additional marked though transient reductions in oxygenation during the second stage of labor. This latter circumstance is particularly unfortunate since the prior exposure to hypoxia may reduce the fetal tolerance to anoxia so that a superimposed episode of total asphyxia, though of short duration, may injure the fetal brain.15 This variable and inhomogeneous nature of asphyxia of the fetus in man must be kept in mind when comparisons are made between the controlled asphyxia as produced in our experimental studies and asphyxia as it affects man. Fetal asphyxia was produced by reducing the perfusion pressure of the uterine blood vessels. Earlier studies have demonstrated that the amplitudes of late decelerations are related to the magnitudes of oxygen deprivation of the fetus and to the durations and amplitudes of the uterine contractions.6 However, as unpublished studies in our laboratory have demonstrated, the magnitudes of late decelerations are also greatly influenced by the blood pressure level of the

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REFERENCES Hon, E. H.: Observations on “pathologic” fetal bradycardia, AM. 1. OBSTET. GYNECOL. 77: 1084. 1959. 2. CaldeyroIBarcia, R., Casacuberta, C., Bustos, R., Guissi, G., G&n, L., Escarcena, L., and Mendez-Bauer, C.: Correlation of’intrapartum changes in fetal heart rate with fetal blood oxygen and acid-base state, in Adamsons, K., editor: Diagnosis and Treatment of Fetal Disorders, New York, 1968, Springer-Verlag, New York, Inc., pp. 205-

mother. Thus, the blood pressure of the mother and the characteristics of the uterine contractions must be taken into account in assessing the significance of late decelerations. The present data support the assumption made by most clinicians that late decelerations appear before permanent nervous system injury develops as a consequence of asphyxia. If the present findings hold true for unanesthetized animals, it can be concluded that the continuous monitoring of the fetal heart rate provides a highly reliable method of surveillance of the fetus during labor to diagnose fetal asphyxia before it reaches a magnitude sufficient to cause brain damage. The present findings specifically pertain to clinical situations in which perfusion of the intervillous space has been reduced due to decrease in maternal blood pressure. lntervillous space blood flow is particularly susceptibIe to retardation or interruption by increases in intrauterine pressure under these circumstances. The more marked reductions in intervillous space blood flow associated with uterine contractions, observed in the presence of maternal hypotension, lead to more rapid decreases of greater magnitude in oxygenation of the fetus and, hence, in heart rate changes of greater magnitude. On the other hand, when blood flow through the intervillous space is reduced due to a generalized constriction of uterine blood vessels, the effects of uterine contractions of the same magnitude on the intervillous space blood flow and, hence, on fetal arterial blood For may be slight. These considerations have bearing upon the interpretation and the diagnostic significance of late decelerations in the hypertensive parturient patient.

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Kubli, F. W., Hon, E. H., Khazin, A. F., and Takamura, H .: Observations on heart rate and pH in the human fetus during labor, AM. J. OBSTET. GYNE~OL. 104: 1109, 1969. 4. Wood, C., Lumley, I., and Renou, P.: A clinical assessment of foetal ‘diignostic methods, Br. J. Obstet. Gynaecol. 74: 823, 1969. 5. Myers, R. E., Mueller-Heubach, E., and Adamsons, K.: Predictability of the state of fetal oxygenation from quantitative analisis of components of la;

Late decelerations and brain tolerance of the fetal monkey to intrapartum asphyxia.

Late decelerations and brain tolerance of the fetal monkey to intrap-artum asphyxia K. ADAMSONS, R. E. MYERS, Bethesda, Maryland, M.D., M.D., a...
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