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Fetal Heart Rate Overshoot During Repeated Umbilical Cord Occlusion in Sheep

From the Department of Obstetrics & Gynecology, and the Research Centre for Developmental Medicine and Biology, Department of Paediatrics, University of Auckland, Auckland, New Zealand.

Address reprint requests to: Jenny A. Westgate, MBChB, MD, University of Auckland, Research Centre for Developmental Medicine and Biology, Private Bag 92019, Auckland, New Zealand, E-mail: ja.westgate{at}auckland.ac.nz

	Abstract

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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.

A variable fetal heart rate (FHR) deceleration immediately followed by an acceleration is referred to as an overshoot FHR pattern. This pattern was described soon after the introduction of clinical fetal heart rate recording¹ and was noted to follow umbilical cord occlusion in both preterm human² and animal experiments.³ Several authors have attempted to ascribe clinical significance to this pattern. Goodlin and Lowe² reported that a deceleration-overshoot pattern was associated with newborns requiring resuscitation and suggested that the pattern might be caused by an acute fetal hypoxic insult. Shields and Schifrin⁴ described overshoot as one component of a chronic fetal distress pattern which was associated with subsequent cerebral palsy. They suggested that this combination of a normal baseline heart rate but absent variability and mild variable decelerations with overshoot was from attenuation of vagal control of heart rate, possibly caused by previous cerebral ischemia in the fetus. In experimental studies in fetal sheep, the overshoot pattern has been related to development of fetal acidosis and a decrease in cerebral glucose metabolic rate during recurrent umbilical cord occlusions.^5,6 However, definitive evidence for the prognostic importance of the overshoot FHR pattern in human labor has yet to be demonstrated.⁷

We recently characterized the effects of recurrent umbilical cord occlusions in chronically instrumented fetal sheep repeated at rates consistent with either early or active labor.^8–10 Occlusions of 1 minute duration repeated every 5 minutes were associated with variable fetal heart rate decelerations without significant changes in fetal blood pressure or acid-base status.⁹ Increasing the frequency of occlusion to 1 minute every 2.5 minutes or increasing the duration of occlusions to 2 minutes every 5 minutes, resulted in progressive fetal metabolic acidemia and hypotension,^8,9 with corresponding cerebral compromise.^9,11 We now report the relationship between overshoot FHR after decelerations and the duration of individual umbilical cord occlusions and the development of fetal compromise, with hypotension and acidosis.

	Materials and Methods

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Twenty-two Romney/Suffolk sheep were operated on under halothane anesthesia (2%) using sterile techniques, as described previously.^8,9 Polyvinyl catheters were inserted into the right and left brachial artery of the fetus and in the amniotic cavity, and an inflatable occluder cuff (In Vivo Metric, Healdsburg, CA) was placed around the umbilical cord. Two electrocardiogram (ECG) electrodes (Cooner wire AS633-3SSF) were placed subcutaneously, one over the apex of the heart and the other on the right shoulder. The maternal long saphenous vein was catheterized. After surgery ewes were housed in a cage with free access to water and hay, supplemented with sheep nuts and alfalfa. They were kept in a temperature-controlled room (16C, humidity 50%) and in a 12-hour light-dark cycle. Each received gentamicin (80 mg, intraamniotically) daily throughout the experiments. After completion of the studies, animals were euthanized by overdose of intravenous pentobarbital. Studies were approved by the Animal Ethics Committee of the University of Auckland.

Fetal arterial blood pressure (corrected for amniotic pressure) and fetal electrocardiogram (ECG) measurements were made continuously, saved to disk using customized programs (Labview, National Instruments, Austin, TX), and later transferred to CD-ROM storage media. The blood pressure signal was collected at 64 Hz and low-pass filtered at 30 Hz. The raw ECG was analog-filtered between 0.05 and 80 Hz and digitized at 512 Hz. Measurements started at least 12 hours before the experiment and were continued for at least 24 hours after the end of occlusions.

Experiments were started 3–5 days after surgery, at a gestational age of 126.3 ± 2.6 days (term is 147 days). Fetuses were allocated to one of the following groups: the 1:5 group (repeated total umbilical cord occlusion for 1 minute of every 5 minutes, n = 8), the 2:5 group (repeated total umbilical cord occlusion for 2 minutes of every 5 minutes, n = 4), or the 1:2.5 group (repeated total umbilical cord occlusion for 1 minute of every 2.5 minutes, n = 8). The cardiovascular and cerebral responses of these fetuses have been reported previously.^8–11 Umbilical cord occlusion was done by inflating the cuff with sterile saline and then deflating it after 1 minute. This procedure was repeated for up to 4 hours or until the fetal mean arterial blood pressure (MAP) had decreased below 20 mmHg during two successive occlusions, or the fetal blood pressure failed to recover to baseline levels when the next occlusion was due. Fetal arterial blood gas analysis, and measurements of glucose and lactate levels were done immediately before the first occlusion and after every sixth occlusion (ie, every 30 minutes in the 1:5 and 2:5 groups and every 15 minutes in the 1:2.5 group) and after the final occlusion.

Offline analysis of the raw MAP and ECG data was done using customized Labview programs. One-second averages of MAP were calculated for each fetus; these data were used to derive the minimum MAP at the end of each occlusion. One-second averages of R-R intervals were used to calculate FHR. Overshoot was defined as an acceleration of the FHR immediately after an occlusion that was 15 beats or more above the baseline FHR immediately before the occlusion. The overshoot height (in beats per minute [bpm]) was the difference between the baseline FHR and the FHR of the overshoot acceleration for each occlusion. The rate at which MAP fell during intervals without and with overshoot was calculated by subtracting minimum MAP at the end of each interval from minimum MAP after the first occlusion in each interval and dividing the difference by the number of minutes in each interval.

As the individual experiments in the 1:2.5 and in the 2:5 groups were of unequal duration, the data in all groups have been presented for three time intervals (the first 30 minutes, the middle 30 minutes [defined as the median ± 15 minutes], and the final 30 minutes of occlusions). For statistical analysis of metabolic and cardiovascular changes, within-group comparisons were made by one-way analysis of variance with time as a repeated measure; when there was a significant change over time, we performed post-hoc pair-wise comparisons using Tukey test. The rates of decrease of MAP with and without overshoot in the 1:2.5 group were compared with the Mann-Whitney U test. Differences in proportion were compared by the Fisher exact test. Data are shown as mean ± standard deviation or median (25th, 75th percentile) as appropriate.

	Results

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The MAP and acid-base data for 16 of these fetuses have been previously reported.^8–10 There were no significant differences in gestational age, preocclusion MAP, or acid-base data between the groups. Overshoot never occurred in the 1:5 group, whereas overshoot was seen with every occlusion in the 2:5 group, starting with the first occlusion (P < .002, Fisher exact test). In contrast, in the 1:2.5 group overshoot was not seen at the start of the occlusion series but developed toward the second half of the experiment, after 91.6 ± 42.5 min (44.1 ± 32.4 occlusions, Table 1, P < .001, compared with 1:5 group, Fisher exact test). Representative patterns of the FHR from each occlusion protocol are shown in Figure 1.

View larger version (26K): [in this window] [in a new window]   Figure 1. Representative patterns of the fetal heart rate (FHR) from each occlusion protocol. (a) Overshoot FHR acceleration after release of occlusions was not seen in the 1:5 group (1-minute occlusions repeated every 5 minutes) (b) but was seen from the first occlusion in the 2:5 group (2-minute occlusions every 5 minutes). (c) In contrast, the 1:2.5 group (1-minute occlusions repeated every 2.5 minutes) did not have overshoot initially, but it occurred from the middle of the occlusion series, at a mean pH of 7.17.

In the 2:5 occlusion group all fetuses rapidly became progressively hypotensive and acidotic, and the occlusions were terminated after 116.3 ± 22.9 minutes (23.3 ± 4.6 occlusions). The MAP at the end of each occlusion decreased steadily from the third occlusion to 16.2 ± 0.2 mmHg when occlusions were stopped. The metabolic status of these fetuses also deteriorated progressively; by the end of the occlusions pH was 6.82 ± 0.06, BD 22.9 ± 3.2 mmol/L, and lactate 15.0 ± 2.1 mmol/L (P < .001, compared with baseline).

In the 1:2.5 occlusion group the fetuses also became hypotensive and acidotic but not as rapidly as in the 2:5 group. Occlusions were terminated after 183.1 ± 412.8 minutes (76.6 ± 21.5 occlusions). The MAP at the end of each occlusion decreased from the fourth occlusion, stabilized in the mid 30 minutes, and decreased again in the last 30 minutes of occlusions to 15.5 ± 3.0 mmHg. By the end of the occlusions pH was 6.92 ± 0.03, BD 19.2 ± 1.5 mmol/L, and lactate 14.6 ± 0.8 mmol/L (P < .001, compared with baseline). Table 1 shows the metabolic status of each fetus in the 1:2.5 group when the overshoot FHR pattern began to occur. Once the overshoot pattern began, fetal MAP decreased more rapidly (median decrease before overshoot 0.11 mmHg/minute (0.03, 0.15) versus 0.25 mmHg/minute (0.21, 0.35) after overshoot developed, P < .01). However, there was no significant difference in the rate of decrease of pH, BD or lactate once overshoot developed.

The relationship between the size of the overshoot acceleration and minimum MAP at the end of each occlusion is shown in Figure 2. The height of the overshoot increased as MAP decreased in the 1:2.5 group but decreased as MAP decreased in the 2:5 group.

View larger version (16K): [in this window] [in a new window]   Figure 2. Relationship between size of the overshoot acceleration (beats per minute [bpm]) and changes in mean arterial pressure (MAP) at the end of each occlusion. In the 1:5 group MAP remained stable and overshoot was not seen. The height of overshoot acceleration in the 2:5 group was maximal at the beginning of the occlusion series and decreased as MAP decreased, whereas overshoot increased with time after it first appeared at approximately the midpoint of the occlusion series in the 1:2.5 group, despite a decrease in MAP.

	Discussion

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The overshoot pattern occurred after the first occlusion in the 2:5 occlusion group, when by definition the fetuses were neither acidotic nor hypotensive. In contrast, overshoot did not occur during the initial stages of either of the 1-minute occlusion series. In the 1:5 group, despite continuing occlusions for 4 hours, overshoot did not occur. The fetuses remained normotensive, with minimal acidosis throughout. In contrast, when the frequency of occlusions was increased to one every 2.5 minutes, progressive hypotension and acidosis developed. Under these conditions, overshoot occurred in all fetuses in association with worsening acidosis and a variable degree of hypotension. The mean pH associated with overshoot was 7.17, consistent with the pH of approximately 7.15 reported by Saito et al⁵ in four fetal sheep subjected to 1-minute cord occlusions. These data suggest that the appearance of overshoot is related to reflex mechanisms.

The mechanisms underlying the overshoot FHR pattern are not known but are believed to involve two factors, reduced vagal stimulation during the occlusion and beta-adrenergic myocardial stimulation immediately after the occlusion ends.⁴ The initial component of an FHR deceleration caused by umbilical cord occlusion is vagal, mediated by the carotid chemoreflex¹³; however, as the occlusion is continued, decelerations are maintained by direct hypoxic myocardial depression. Thus, the longer the occlusion, the less vagal reflex tone contributes to bradycardia.^13,14 Consistent with a role of reduced myocardial vagal tone in the overshoot pattern, atropine produces overshoot tachycardia in humans^15,16 and fetal sheep.^14,17 Nevertheless, catecholamine stimulation is also required, because the FHR overshoot induced by atropine can be abolished by concurrent administration of propranolol.⁵ This finding suggests that overshoot is caused by beta-adrenergic stimulation that is unopposed because vagal tone has been inhibited.

We propose that 2-minute occlusions are sufficient to trigger FHR overshoot from the beginning because the insult is long enough to result in complete loss of vagal tone by the end of the occlusion. In contrast, after only 1 minute of occlusion there is likely to be some persisting vagal stimulation, combined with markedly less catecholamine release compared with 2-minute occlusions,¹³ preventing subsequent tachycardia. The later development of overshoot with 1-minute occlusions is likely to reflect greater catecholamine release resulting from worsening systemic compromise.¹⁸ In these experiments we applied fixed insults at fixed time periods to achieve reproducible FHR patterns. Clinically the duration, frequency, and strength of contractions vary considerably both between and within individual labors. Nevertheless, contractions lasting approximately 1 minute are typical for active labor, so overshoot might be a useful marker for acidosis developing in association with variable decelerations. This might enable, for example, selective use of scalp pH testing to identify fetuses with clinically significant compromise requiring further intervention. Further experimental data are needed to elucidate the mechanisms associated with the overshoot pattern, as well as clinical studies to identify the frequency and circumstances in which the overshoot FHR pattern occurs.

	Footnotes

 
Supported by USPHS grant RO1 HD-32752, the Health Research Council of New Zealand, the Lottery Grants Board of New Zealand, and the Auckland Medical Research Foundation.

PII S0029-7844(00)01123-6

Received July 17, 2000. Received in revised form September 18, 2000. Accepted October 12, 2000.

	References

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6. Okamura K, Tanigawara S, Shintaku Y, Watanabe T, Endoh H, Akiyama H, et al. Alteration of FHR pattern and cerebral metabolic rate of glucose of the fetus measured by positron emission tomography during progress of acidemia. The significance of overshoot acceleration in FHR. J Perinat Med 1989;17:289–95.[Medline]

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