Harmen H. de Haan

Brief repeated umbilical cord occlusions cause sustained cytotoxic cerebral edema and focal infarcts in near-term fetal lambs.

The aim of this study was to determine whether asphyxia induced by clinically relevant, brief repetitive umbilical cord occlusions is associated with cerebral compromise. Chronically instrumented fetal lambs were studied at 126.5 ± 2.8 d of gestation (mean ± SD, term 147 d). Occlusions were performed 1 out of every 2.5 min (group I, n = 7), 2 out of every 5 min (group II, n = 9), or not at all (shams, group III,n = 5), and discontinued at a predetermined threshold of severe or persistent hypotension. After 58 ± 8 and 24 ± 2 occlusions, in groups I and II, respectively, the pH was 6.83 ± 0.09, Pco2 9.52± 1.4 kPa, base excess -23.5 ± 3.7 mM, and lactate 14.1 ± 1.6 mM. Two fetuses (out of group II) did not recover from the final occlusion. Ongoing asphyxia was associated with progressive suppression of the EEG, which occurred faster and with more epileptiform and spike activity in group II. Cortical impedance remained elevated for 15.0 ± 4.0 and 11.5± 4.4 h, for groups I and II, respectively (NS). Focal infarcts occurred in the parasagittal cortex, thalamus, and cerebellum, in 6 out of 14 surviving asphyxiated fetuses. Mild selective neuronal loss was observed in these regions in 13 out of 14 fetuses. Infarction was associated with a longer period of blood pressure below baseline levels, with more epileptiform activity, and with slower normalization of the EEG. In a paradigm mimicking birth asphyxia, histologic damage similar to that observed clinically was found. The results suggest that brief repeated insults interact, leading to cardiac compromise and cumulative cell membrane damage in the fetal cerebrum.

Magnesium sulfate therapy during asphyxia in near-term fetal lambs does not compromise the fetus but does not reduce cerebral injury

OBJECTIVE Our purpose was to investigate (1) the safety of fetal magnesium sulfate treatment and (2) possible beneficial effects on the brain during perinatal asphyxia. STUDY DESIGN In 20 chronically instrumented fetal lambs (gestational age 125.8 +/- 3.5 days) four total umbilical cord occlusions for 5 minutes were repeated at 30-minute intervals. Fetuses received either saline solution (n = 11) or magnesium sulfate (n = 9) as a bolus of 300 mg intravenously 2 hours before occlusions, followed by an infusion of 100 mg/hr until 1 hour after occlusions. RESULTS In the treated fetuses plasma magnesium levels rose from 0.85 +/- 0.20 to 2.23 +/- 0.40 mmol/ L. Occlusions induced asphyxia, associated with mortality; 4 of 11 fetuses in the control group versus 1 of 9 in the magnesium-treated group died (not significant). Fetal electroencephalographic activity decreased and cerebral impedance increased during occlusions. Maximum spike and seizure activity occurred 5 to 10 hours after asphyxia. Neuronal loss was primarily localized in the corpus striatum. Magnesium caused no alterations in blood pressure, heart rate, or cerebral and peripheral blood flow, nor did it influence electrophysiologic responses or neuronal loss. CONCLUSIONS Administration of magnesium sulfate was safe but did not offer significant cerebral protection from asphyxia in the near-term fetal lamb.

Effects of asphyxia on the fetal lamb brain

OBJECTIVE Our purpose was to study the effect of fetal asphyxia on the release of hypoxanthine and xanthine in cerebrospinal fluid and on brain histologic characteristics. STUDY DESIGN In seven fetal lambs (3 to 5 days after surgery, gestational age 124.3 +/- 2.6 days) asphyxia was induced by restriction of uterine blood flow. RESULTS Fetal pH and base excess were reduced to 6.99 +/- 0.02 and -17.6 +/- 0.9 mmol/L, respectively. Cerebral blood flow increased during asphyxia and returned to normal in the recovery phase. Maximum concentrations of cerebrospinal fluid hypoxanthine and xanthine were reached in the normoxemic recovery phase. This high level of substrates during normoxemia facilitates oxygen free radical formation and may thus aggravate postasphyctic brain damage. Histologic evaluation of the brain 3 days after the insult showed a variable degree of edema. Coagulative neuronal changes, characteristic of irreversible cell death, were only occasionally detected. These changes were most obvious in the Purkinje cells of the cerebellum. CONCLUSIONS Fetal asphyxia induced by uterine blood flow restriction is associated with high levels of cerebrospinal fluid hypoxanthine and xanthine in the recovery phase. Microscopically detectable brain damage, although not extensive, is mainly located in the cerebellum.

Fetal heart rate changes do not reflect cardiovascular deterioration during brief repeated umbilical cord occlusions in near-term fetal lambs☆☆☆★★★

OBJECTIVE Brief repetitive total umbilical cord occlusions were used to induce fetal asphyxia and to evaluate the interrelationships with hypotension and fetal heart rate decelerations. STUDY DESIGN In 21 chronically instrumented fetal lambs (gestational age 126.8 +/- 0.6 days), repetitive total umbilical cord occlusion was performed 1 out of 2.5 minutes (n = 7), 2 out of 5 minutes (n = 9), or not at all (shams, n = 5). Occlusions proceeded until fetal blood pressure was < 20 mm Hg or failed to recover to baseline before the next occlusion. RESULTS At the nadir of asphyxia pH (mean +/- SEM) was 6.84 +/- 0.02, base excess 23.1 +/- 1.0 mmol/L, and lactate 14.2 +/- 0.4 mmol/L. Two fetuses died. The pattern of fetal heart rate decelerations remained relatively consistent throughout the experiments. In contrast, after an initial phase of sustained hypertension a progressive fall in trough blood pressure occurred after approximately 15 minutes of occlusion. The blood pressure recovery time in almost all fetuses lengthened abruptly near the end of the occlusion series, at a variable metabolic threshold. This was accompanied by a significant delay in fetal heart rate recovery in only five fetuses. CONCLUSIONS Fetal compromise presented with the development of hypotension, without change in the pattern of fetal heart rate response. These data illustrate the limited diagnostic value of fetal heart rate monitoring to identify the development of cardiovascular compromise associated with severe decelerations in the previously healthy fetus.

Fetal heart rate overshoot during repeated umbilical cord occlusion in sheep

Objective To assess the clinical utility of overshoot fetal heart rate (FHR) decelerations by examining their occurrence after umbilical cord occlusions of varying frequency and length in near-term fetal sheep. Methods Fetuses were allocated to the following three groups: 1-minute umbilical cord occlusion repeated every 5 minutes (1:5 group, n = 8) or every 2.5 minutes (1:2.5 group, n = 8) or 2-minute occlusions repeated every 5 minutes (2:5 group, n = 4). Occlusions were continued for 4 hours or until fetal mean arterial pressure decreased below 20 mmHg during two successive occlusions. Results In the 1:5 group, fetuses tolerated 4 hours of occlusion without hypotension or clinically significant acidosis and overshoot never occurred. In the 2:5 group, fetuses rapidly became hypotensive and acidotic, and occlusions were terminated at 116.3 ± 22.9 min (mean ± standard deviation). Overshoot was seen after every occlusion, starting with the first occlusion. In the 1:2.5 group, fetuses became progressively acidotic and hypotensive and occlusions were stopped at 183.1 ± 42.8 min. Overshoot occurred after 91.6 ± 42.5 minutes, at a pH of 7.17 ± 0.06, base deficit 9.3 ± 4.5 mmol/L. After the appearance of overshoot there was a more rapid decrease in fetal mean arterial pressure (0.25 [0.21, 0.35, 25–75th percentile] mmHg/minute versus 0.11 [0.03, 0.15] mmHg/minute before overshoot appeared, P < .01). Conclusion These data suggest that overshoot is related to longer (2-minute) occlusions or to developing fetal acidosis and hypotension during 1-minute occlusions. This pattern could have clinical utility, as 1-minute contractions are typical of active labor.

Do fetal electrocardiogram PR-RR changes reflect progressive asphyxia after repeated umbilical cord occlusion in fetal sheep?

The aim of this study was to determine whether there is a relationship between changes in PR-RR correlation of the fetal ECG and progressive changes in fetal acid-base status and blood pressure (BP) during repeated umbilical occlusion. Chronically instrumented fetal sheep at 126.8 ± 0.6 d (mean± SEM) were randomized to receive 1 min of total umbilical cord occlusion either every 5 min for 4 h (1:5 group; n = 8), or every 2.5 min until BP fell <2.7 kPa (20 mm Hg) on two successive occlusions (1:2.5 group; n = 8). The PR-RR correlation was determined in 5- or 2.5-min intervals. Umbilical cord occlusion caused variable decelerations with initial sustained hypertension. In the 1:5 group BP remained elevated throughout, and there was little change in acid-base status (pH = 7.34 ± 0.07, base deficit = 1.3 ± 3.9 after 4 h). In contrast, after the third occlusion the 1:2.5 group showed progressive hypotension during occlusions, and severe progressive metabolic acidemia (pH 6.92 ± 0.1, base deficit 17.0 ± 4.7 mmol/L after the last occlusion). In both groups, the PR-RR relationship switched from positive to negative with the onset of occlusions, then reverted to positive after a variable interval. In the 1:2.5 group later reversion of the PR-RR to positive was associated with earlier and more prolonged hypotension during the middle and end of the occlusion series (p < 0.001). We conclude that the initial switch to a negative PR-RR relationship during repetitive umbilical occlusion was due to a reflex-mediated response unrelated to fetal acidosis or hypotension. Both stable well compensated fetuses and severely hypoxic, hypotensive fetuses subsequently showed a positive PR-RR correlation.

EFFECTS OF SURGERY AND ASPHYXIA ON LEVELS OF NUCLEOSIDES, PURINE BASES, AND LACTATE IN CEREBROSPINAL FLUID OF FETAL LAMBS

ABSTRACT: During severe oxygen shortage, the fetal brain resorts to anaerobic metabolism and AT? becomes catabolized. High levels of nucleosides, hypoxanthine, and xanthine (ATP catabolites) in cerebrospinal fluid (CSF) may therefore be associated with increased neonatal neurologic morbidity. In 22 fetal lambs (3 to 5 d after surgery, gestational age 123.5 ± 3.5 d), arterial oxygen content was progressively reduced to 35% of the baseline value with a balloon occluder around the maternal common internal iliac artery. This resulted in a 1-h period of asphyxia, leading to a pH of 7.02 ± 0.03 and a base excess of −17.0 ± 1.0 mM. Mortality was 50%. CSF was sampled from the spinal cistern and analyzed using HPLC. During reoxygenation, hypoxanthine and xanthine may serve as substrate for xanthine oxidase with concomitant production of oxygen-derived free radicals, which may aggravate cerebral damage. The main difference between surviving and nonsurviving animals was the speed of increment of ATP catabolites in CSF: in the surviving group levels increased steadily, recovery values being significantly elevated compared with asphyxia values, whereas in the nonsurviving group the rise was rapid and levels during asphyxia did not differ significantly from levels during recovery. We conclude that 1) catheterization of the spinal cistern leads to increased levels of CSF hypoxanthine, xanthine, and inosine, and 2) during fetal asphyxia, levels of these ATP catabolites and lactate in CSF increase. 3) Maximum levels are reached during the recovery period and are similar for surviving and nonsurviving animals, but during asphyxia CSF levels of hypoxanthine and lactate were higher in the nonsurviving fetuses. 4) The rate of increase of ATP catabolites in CSF is higher in the nonsurviving animals and may therefore be predictive for fetal death.

Neuronal death after perinatal asphyxia

During perinatal asphyxia several mechanisms aim to limit cerebral damage. However, when the degree of asphyxia passes beyond a certain threshold, brain damage is inevitable. This review focuses on the various factors determining the final cerebral outcome. Metabolic and biochemical events, such as the intracellular level of calcium, the formation of oxygen derived free radicals, the release of excitotoxic neurotransmitters and the interrelationship of these parameters are discussed. Furthermore, steps possibly useful to pharmacologic intervention aiming to reduce cerebral damage are presented.

The T/QRS ratio of the electrocardiogram does not reliably reflect well-being in fetal lambs

OBJECTIVE Our purpose was to determine the diagnostic power of the T/QRS ratio of the electrocardiogram to predict fetal well-being. STUDY DESIGN In 47 fetal lambs (3 to 5 days after surgery, gestational age 123.5 +/- 3.0 days) asphyxia was induced by restriction of uterine perfusion. Fetuses were either pretreated with an adenosine transport inhibitor (n = 16) or a calcium channel blocker (n = 12) or served as controls (n = 19). Arterial oxygen content > or = 1.5 mmol/L or pH > or = 7.15 were chosen as limits for fetal well-being. RESULTS Arterial oxygen content was reduced from 3.3 (+/- 1.0) to 1.3 (+/- 0.5) mmol/L, and pH decreased to 7.03 (+/- 0.10). Mortality was 53%. Both drugs did not affect well-being, survival, or the T/QRS ratio. Maximum T/QRS ratios were reached at the peak of asphyxia. Sensitivity and specificity of the T/QRS ratio were 24.0% and 42.6% to predict hypoxemia and 25.1% and 45.3% to predict acidemia. Pearson correlation coefficients for T/QRS ratio versus oxygen content and pH were 0.169 and 0.192, respectively. CONCLUSIONS (1) In fetal lambs the T/QRS ratio failed to predict hypoxemia or acidemia. (2) Fetal survival was not correlated with the height of the T/QRS ratio during or after asphyxia.

PROLONGED SELECTIVE CEREBRAL COOLING PREVENTS CYTOTOXIC EDEMA AND IMPROVES RECOVERY AFTER CEREBRAL ISCHEMIA IN FETAL SHEEP • 1257

PROLONGED SELECTIVE CEREBRAL COOLING PREVENTS CYTOTOXIC EDEMA AND IMPROVES RECOVERY AFTER CEREBRAL ISCHEMIA IN FETAL SHEEP • 1257