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Center for Perinatal Biology, School of Medicine, Loma Linda University, Loma Linda, California 92350
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The purpose of this study was to devise a means to use laser-Doppler flowmetry to measure cerebral perfusion before birth. The method has not been used previously, largely because of intrauterine movement artifacts. To minimize movement artifacts, a probe holder was molded from epoxy putty to the contour of the fetal skull. A curved 18-gauge needle was embedded in the holder. At surgery, the holder, probe, and skull were fixed together with tissue glue. Residual signals were recorded after fetal death and after maternal death 1 h later. These averaged <5% of baseline flow signals, indicating minimal movement artifact. To test the usefulness of the method, cerebral flow responses were measured during moderate fetal hypoxia induced by giving the ewes ~10% oxygen in nitrogen to breathe. As fetal arterial PO2 decreased from 21.1 ± 0.5 to 10.7 ± 0.4 Torr during a 30-min period, cerebral perfusion increased progressively to 56 ± 8% above baseline. Perfusion then returned to baseline levels during a 30-min recovery period. These responses are quantitatively similar to those spot observations that have been recorded earlier using labeled microspheres. We conclude that cerebral perfusion can be successfully measured by using laser-Doppler flowmetry with the unanesthetized, chronically prepared fetal sheep as an experimental model. With this method, relative changes of perfusion from a small volume of the ovine fetal brain can be measured on a continuous basis, and movement artifacts can be reduced to 5% of measured flow values.
movement artifacts; hypoxia; probe holder
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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A MEANS TO MEASURE CEREBRAL blood flow on a continuous basis in the mammalian fetus would be a useful investigative tool, but it has been difficult to develop largely because of technical reasons. Although labeled microspheres have provided much useful information, they provide measurements at only a limited number of points in time. Laser-Doppler flowmetry provides continuous readings and has been used in adult studies to measure perfusion of the skin, kidneys, brain, and other organs (10, 18). However, laser-Doppler technology has been difficult to apply in utero because of movement artifacts (19).
In this report, we present our adaptation of laser-Doppler flowmetry to measure brain perfusion continuously in the chronically prepared, late-term fetal sheep. We report that movement artifacts can be reduced to negligible levels by using a custom-fabricated probe holder that is molded to the shape of the skull and secured in place with tissue glue. To a great extent, the holder prevents shifts of the probe tip, relative to the substance of the brain, as are caused by maternal, uterine wall, and fetal movements.
The principle of laser-Doppler flowmetry is based on the fact that blood cells moving within a tissue reflect laser light, causing a Doppler shift of the wavelength. The magnitude and frequency distribution of the Doppler-shifted light are proportional to the number and velocity of blood cells moving within the illuminated volume of tissue. Laser-Doppler methodology is applied by directing a continuous laser beam to the tissue via an optical fiber, which then receives and carries the backscattered light to a photodetector. Emitted and backscattered light are continuously compared by a microprocessor to estimate blood flow in the tissue (21). The signal is independent of the direction of red cell movement and thus is an index of total perfusion rather than axial flow through an individual vessel. Previous studies have demonstrated that relative changes in the laser-Doppler signal obtained from cerebral tissue correlate well with blood flow measured by radioactive microspheres or the hydrogen-clearance technique (17, 25).
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Fabrication of the Probe Holder
To reduce movement artifact, a probe holder was custom fabricated to fit the contours of the fetal skull. As the first step, a blunt 18-gauge stainless steel needle was curved through 90° with a radius of ~5 mm. This was done by hand with pliers, with care taken not to occlude the lumen of the needle. Next, the holder itself was shaped from epoxy putty (QuikPlastik, Polymeric Systems, Phoenixville, PA) by using an ovine fetal calvarium as mold template, with the needle embedded in the putty during the shaping, as shown in Fig. 1. After the epoxy putty had hardened, the laser-Doppler probe, a light-transmitting filament, was coated with quick-setting, two-component epoxy glue and was passed through the needle such that the distal end would extend 1 cm. Care was taken not to touch the end of the filament with the epoxy. The points where the probe entered and exited the holder were sealed with additional epoxy glue. Polyvinyl tubing was then passed over the long end of the probe filament and onto the 18-gauge needle, and the junction was sealed with additional epoxy glue. After the glue had hardened, the entire assembly was gas sterilized in preparation for surgery. No effort was made to coat the surface of the holder with agents such as silicon because no signs of tissue reaction were detected after up to 10 days of placement on the fetal skull.
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Surgical and Postoperative Procedures
Western ewes carrying fetuses at 125-127 days of gestation were used during development of the methodology. After the animals fasted overnight, anesthesia was induced with thiopental sodium (0.5 g iv). The ewe was placed in the supine position and intubated, and inhalational anesthesia was maintained by administration of 1.5-2.5% halothane in oxygen. Under aseptic conditions, the maternal abdomen and uterus were opened, and the fetal head was delivered. An incision was made on the fetal scalp to expose the skull. A 1.5-mm burr hole was drilled 5 mm right of the midline and 5 mm posterior to the coronal suture. The flow probe tip, extending from the fabricated unit, was inserted to a depth 5 mm below the dura into the parasagittal parietal cortex, as shown in Fig. 1. The holder was secured to the skull with tissue glue, thereby rigidly fixing the probe and fiber-optic filament with respect to the skull and brain. The attachment of the probe holder is illustrated in Fig. 1.To complete the surgery, polyvinyl catheters were placed in the fetal carotid artery for arterial blood sampling and in the amniotic fluid for measurement of amniotic fluid pressure and administration of drugs and antibiotics. A thermocouple was placed in a central vein to record core body temperature. Incisions in the fetal skin were closed, and the fetal head was eased back into the uterus. The proximal ends of the catheters and laser-Doppler filaments were exteriorized through an incision in the maternal flank and stored in a pouch attached to the maternal skin. For the first 3 postoperative days, 900,000 U penicillin were given to the ewe intramuscularly, and 500 mg ampicillin and 40 mg gentamicin were given to the fetus by instillation into the amniotic fluid.
Experiments to demonstrate the usefulness of laser-Doppler flowmetry were begun after the fetus had recovered from surgery for 3 days. Fetal blood gases, blood pressure, and core temperature were recorded daily. On the morning of the experiments, ewes were placed in a metabolic cart in the laboratory at 20°C and allowed to become accustomed to the room for 1 h. Alfalfa pellets and access to water were provided throughout the study.
Experimental Procedures
To test the usefulness of laser-Doppler technology for fetal studies, a simple protocol of fetal hypoxic exposure was followed. Fetal cerebral perfusion was recorded continuously with laser-Doppler flowmetry throughout the experiment. During an initial 0.5-h control period, arterial blood samples were taken at 0, 15, and 30 min, and blood pressure was monitored continuously. This was followed by a 30-min period of fetal hypoxia induced by having the ewe breathe 10% oxygen in balance nitrogen. Arterial samples were collected at 5, 10, 20, and 30 min. The hypoxic exposure was followed by a 0.5-h recovery period. During this time interval, arterial blood samples were taken at 10, 20, and 30 min.After completion of the experiment, the fetus was humanely killed with an overdose of T-61 (Hoechst-Roussel), a proprietary euthanasia solution. Flow signals were monitored for 1 h after fetal death to assess the importance of fetal movement artifact in perfusion readings. The ewe was then killed with the same agent, and any remaining flow signal was monitored for 1 additional hour. Thus the fraction of total flow signal attributable to movement artifact could be estimated. The fetal body was towel dried and weighed to the nearest 10 g. The locations of the laser probe and all catheters were verified.
Laser-Doppler Flowmetry
Measurement of cerebral perfusion was performed with a Biopac LDF100A laser-Doppler flowmeter (Biopac Systems, Santa Barbara, CA). The lasers in the LDF100A were semiconductor laser diode devices with a nominal operating wavelength of 780 nm and a maximum output power of 1.5 mW at the probe face. The LDF100A module produced a backscattered signal simultaneously with the perfusion signal. The backscattered signal, which is a measurement of the total amount of light reflected, was used to determine whether the probe was working correctly and had remained in contact with the tissue. The perfusion signal is an index of relative blood perfusion at the distal tip of the probe as calculated by the LDF100A by using an algorithm that analyzes the Doppler shift of the backscattered light. The backscattered signal and perfusion signal were recorded and plotted on separate channels. The MP100 system (Biopac Systems), a modular analog-to-digital converter system, was used for data acquisition. All of the laser-Doppler flowmetry probes used in the study were calibrated with the same motility standard in an aseptically prepared, colloidal solution of suspended latex spheres undergoing Brownian motion, as supplied by the manufacturer.Analytic Procedures
Blood sampling. Fetal arterial blood samples (0.3 ml) were collected anaerobically and analyzed promptly for blood gases. These measurements were made at 39°C by using microelectrodes (model ABL3, Radiometer, Copenhagen, Denmark). Observed values were corrected to the body temperature of the fetus as determined by the thermocouple. Oxyhemoglobin saturation and hemoglobin concentration were measured by using an OSM2 Hemoximeter (Radiometer).
Data handling. We elected to collect raw data and perform all calculations and analyses postacquisition to preserve the raw data. Laser-Doppler flowmetry, backscatter, fetal blood pressure, and temperature were all recorded by using the data acquisition software Acqknowledge (Biopac Systems). The data were collected continuously, and averages during 3-min time spans were calculated. Before averaging, spikes in apparent flow signal, often associated with changes in maternal or fetal position, were removed. The criterion for rejection was abrupt increases of >100% above baseline lasting <2 s, which were thus outside the physiological range.
Average values were exported to a spreadsheet program for further analysis. Mean values of arterial blood pressure and heart rate during the 3-min intervals were calculated by using the waveform analysis functions of the Acqknowledge software program.Statistical analysis. Results are expressed as means ± SE. Data are from 12 experiments conducted in 5 sheep: 4 experiments in 2 sheep, 2 experiments in 1 sheep, and 1 experiment in 2 sheep. The significance of changes during an experiment was evaluated by analysis of variance with repeated measures by using Fisher's least significant difference for multiple-comparisons test. For comparisons between two groups, t-tests were used. The statistical software was DATAMSTR (courtesy of Robert Brace, Univ. of California, San Diego). Significant differences were accepted at the 0.05 level.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Biological Zero
One might suppose that laser-Doppler flow signals would fall to near zero after fetal death. Other investigators have found in the adult animals, however, that signals do not immediately fall to zero after death, even when the head is fixed in a stereotactic frame (23, 29). Indeed, even after total occlusion of all large vessels supplying the brain, there is often some slight residual motion of blood cells remaining in the tissues, as well as some slight muscle and tissue movement in the volume being measured that contribute to an apparent flow signal (23, 29). After surgical removal of tissue from the body, localized cell movement and Brownian motion may still occur in the severed blood vessels. These signals eventually decline to a low stable level after death, which is termed "biological zero" (23, 29).In the present experiments, biological zero was in the range of 30-40% of total baseline signal during early development of the probe holder. With improvements in probe-holder design, biological zero averaged 3% of total flow signal 1 h after maternal death. Subtraction of this signal from flow measurements has been shown to be essential for accurate prediction of percent changes in flow measured, and this was done in the data handling from these experiments.
The effects of maternal hypoxia on fetal arterial hemoglobin, arterial
PO2, arterial PCO2,
oxyhemoglobin saturation, arterial pH, mean arterial blood pressure,
and heart rate in the 12 experiments are summarized in Table
1. Maternal hypoxia led to declines of fetal preductal arterial PO2 from 21.1 ± 0.5 to 10.7 ± 0.4 Torr with little change in arterial pH or
PCO2. The fetal hypoxemia was
reversible, and, after 30 min of recovery, fetal
PO2 was indistinguishable from initial control
values. These results are similar to many earlier experiments with
sheep, conducted by our laboratory and others, in which maternal
hypoxia has been induced by the administration of 10-12% oxygen
in balance nitrogen to the ewe (2, 16).
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An unedited flow tracing from a representative fetus is shown in Fig.
2. Cerebral perfusion may be seen to
increase progressively during a 30-min interval of hypoxemia and to
return to initial baseline levels during a 30-min period of recovery.
Perfusion is given in arbitrary units. Relative changes in flow were
calculated by assuming that the average during the initial control
period is 100%. The relative nature of laser-Doppler flowmetry is a
characteristic limitation of the methodology discussed in more detail
in Limitations of the Methodology. The coefficient
of variation of the perfusion signal for this experiment averaged 5.5%
in the initial control period, 3.0% during the last 10 min of the
hypoxic period, and 3.1% during the last 10 min of the recovery
period.
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The changes in cerebral perfusion as an average of all experiments are
shown in Fig. 3. Results are plotted as
percentage of initial control period. Cerebral perfusion is seen to
promptly increase with the onset of hypoxia and by 6 min had become
significantly elevated above baseline values. By the end of the 30-min
hypoxic exposure, fetal cerebral perfusion had increased 56 ± 8%
above control levels. After the hypoxic period was ended, flow did not immediately return to baseline, but it declined slowly and, after 15 min, had declined to levels indistinguishable from baseline readings.
Table 2 was prepared to assess the
variability of flow recordings among animals studied. Average results
are shown for animals studied on more than one occasion.
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Biological Zero and Movement Artifacts
Typically, the flow signal fell to near zero within 60 s of fetal death. These results are shown for one fetus in Fig. 4. One hour later, when the ewe was killed, further declines in the flow signal were not detectable, although the amount of movement artifact in the signal was reduced. Note that others consistently find that biological zero is above electrical zero (23, 29).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Since its first application for measurement of blood flow of the skin by Stern and co-workers (26), laser-Doppler flowmetry has been used to measure blood flow in various organs and has found clinical application in neurosurgical intensive care units (1, 5). It has not been adapted for fetal use, principally because of movement artifacts caused by movement of the probe relative to the tissue, which is caused by maternal and/or fetal movement. We report here the first successful adaptation of laser-Doppler methodology for use in the chronically prepared fetus. Motion artifacts have been largely overcome by using a custom-molded probe holder that is fixed rigidly to the skull of the fetus, thereby securing the distal tip of the laser-Doppler flow probe relative to the brain tissue being studied.
The essential elements of the methodology are twofold. The first is the embedding of the fiber-optic cable in the holder with a 90° bend, as shown in Fig. 1. By this means, external pressure from the uterine wall, which varies from time to time, will not change the location of the probe within the brain. The second is the molding of the probe holder to the shape of the skull by using a calvarium as a template and then the fixation of the holder at surgery with tissue glue across the entire surface that contacts the skull. This procedure minimizes movement of the fiber-optic cable. The technique should be readily feasible in fetal physiology laboratories.
Need for and Advantages of the Method
Measurement of fetal cerebral perfusion in the chronically instrumented animal fetus is a central parameter in the study of fetal physiology. The use of radioactive-labeled microspheres to measure fetal blood flow was introduced by Rudolph and Heymann in 1967 (24). This technique has been widely used and more recently adapted to include fluorescent microspheres (11). The advantage of the microsphere method is that absolute flow in an organ may be calculated, providing the investigator with important information. However, the disadvantages of the method are many: the technique is labor intensive and slow, hemodynamic variability may lead to large errors, and there are appreciable costs (13-15). However, the most significant drawback of the method is the limited number of measurements that can be made per experiment. Eight microsphere injections per experiment are the maximum number feasible with current technology, and four injections are more typical. This severely limits the investigator who is interested in chronic studies or in performing multiple experiments on one animal. Another important limitation stems from fetal physiology. Physiological adjustments may change with time, and regulatory plateaus may be very small. The microsphere "snapshot" method leaves room for different conclusions depending on the time selected for observations to be made. Figure 3 illustrates the point well; apparent hypoxic responses would differ markedly with spheres given at times ranging from 5 to 30 min after the onset of acute hypoxia. Until now, there has been no feasible alternative to the use of microspheres for study of fetal blood flow. Ideally, a method for measuring microcirculatory blood flow in the fetal brain should provide a continuous measurement in absolute units, with a simple technique. Methods such as hydrogen or xenon clearance, iodoantipyrine autoradiography, and microspheres do not fulfill these criteria.Extensive validation and testing of laser-Doppler flowmetry have shown that changes in signal intensity correlate tightly with proportional changes in microcirculatory blood flow. A detailed discussion of such validation in adults of several species is available (10, 12, 17, 18, 21). Validation studies have dealt with questions concerning linearity of signal, correlation of laser-Doppler measurements with standard measures of blood flow, placement and type of probe, probe location in tissue, and determination of biological zero. These studies have provided support for the method, and a good correlation between laser-Doppler and microsphere results is observed (12, 17). As a result of these studies, the method is now well established as reliable in the adult for measuring blood perfusion in microvascular beds in both research and clinical settings (1, 6, 8, 9, 20, 22, 28).
The average response recorded in these experiments was an increase of 56 ± 8% after 30 min of hypoxia. This may be compared with the ~75% increase observed by Cohn and co-workers (7) using radioactive microspheres. It may also be compared with the ~60% increases in flow found by Ashwal and co-workers (3) also using microspheres in near-term fetal sheep.
Limitations of the Methodology
As with any method, laser-Doppler flowmetry also has significant limitations. First, the measurements are relative in nature. Hence, laser-Doppler flowmetry does not provide absolute values for blood flow but rather provides only relative measurements of tissue perfusion. Additionally, probes implanted in the brain may damage tissue and alter perfusion, but this concern seems of lesser importance because others find no significant histopathological damage with chronic implants of similar size (4, 27). The technology is also limited in that it provides information from only a small, localized volume of tissue (~1-2 mm3).Despite these problems, the continuous and real-time measurements provide the investigator with extensive information about both changes in blood flow and the time profile of these changes that would otherwise not be available. The reported adaptation of the method has provided results that agree with previous reports of changes in cerebral blood flow during hypoxia. We conclude that the advantages of laser-Doppler flowmetry make it a useful tool for the study of the fetal cerebral circulation.
Future Possibilities and Perspectives
A period of inadequate oxygenation, either before or during birth, can be identified in many infants born with signs of cerebral injury. A major compensation to hypoxic stress in the fetus is an increase of blood flow to the brain that directs the remaining oxygen stores to this critical organ. This redirection may be mediated by specific molecular messengers, including adenosine, nitric oxide, and prostacyclin, rather than mere oxygen starvation, but the details are poorly understood. Laser-Doppler flowmetry is a method that allows on-line, continuous measurement of fetal cerebral blood flow, and the results are likely to contribute to better understanding of fetal cerebral regulation and the testing of drugs and procedures that might be of use therapeutically.| |
ACKNOWLEDGEMENTS |
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We thank Shannon Bragg for expert technical assistance and Arlin B. Blood for helpful suggestions and editing.
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FOOTNOTES |
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Address for reprint requests and other correspondence: G. Power, Center for Perinatal Biology, Loma Linda Univ. School of Medicine, Loma Linda, CA 92350 (E-mail: gpowerjr{at}aol.com).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Received 10 January 2000; accepted in final form 27 April 2000.
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TOP
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METHODS
RESULTS
DISCUSSION
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C. J Hunter, A. B Blood, C. R White, W. J Pearce, and G. G Power Role of nitric oxide in hypoxic cerebral vasodilatation in the ovine fetus J. Physiol., June 1, 2003; 549(2): 625 - 633. [Abstract] [Full Text] [PDF]
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J. M Bishai, A. B Blood, C. J Hunter, L. D Longo, and G. G Power Fetal lamb cerebral blood flow (CBF) and oxygen tensions during hypoxia: a comparison of laser Doppler and microsphere measurements of CBF J. Physiol., February 1, 2003; 546(3): 869 - 878. [Abstract] [Full Text] [PDF]
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A. B Blood, C. J Hunter, and G. G Power The role of adenosine in regulation of cerebral blood flow during hypoxia in the near-term fetal sheep J. Physiol., September 15, 2002; 543(3): 1015 - 1023. [Abstract] [Full Text] [PDF]
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T. Muller, M. Lohle, H. Schubert, R. Bauer, C. Wicher, I. Antonow-Schlorke, U. Sliwka, P. W Nathanielsz, and M. Schwab Developmental changes in cerebral autoregulatory capacity in the fetal sheep parietal cortex J. Physiol., March 15, 2002; 539(3): 957 - 967. [Abstract] [Full Text] [PDF]
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T. Muller, M. Lohle, H. Schubert, R. Bauer, C. Wicher, I. Antonow-Schlorke, U. Sliwka, P. W Nathanielsz, and M. Schwab Developmental changes in cerebral autoregulatory capacity in the fetal sheep parietal cortex J. Physiol., March 15, 2002; 539(3): 957 - 967. [Abstract] [Full Text] [PDF]
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