J. Physiol. (1977), 270, pp. 719-731 With 3 text-figures Printed in Great Britain
719
DAILY CHANGES IN THE BLOOD OF CONSCIOUS PIGS WITH CATHETERS IN FOETAL AND UTERINE VESSELS DURING LATE GESTATION
By G. C. B. RANDALL From the Animal Diseases Research Institute, 801 Fallowfield Road, P.O. Box 11300, Station H, Ottawa, Ontario, Canada, K2H 8P9
(Received 4 January 1977) SUMMARY
1. Catheters were inserted into the foetal carotid artery and maternal middle uterine artery and vein in twenty foetuses from fifteen sows, 91-105 days pregnant. Blood samples were collected from foetal and maternal circulations for periods of 7-21 days after surgery. 2. Blood gas tensions, pH, packed cell volume (PCV) and the levels of glucose, fructose and lactic acid in conscious pigs were followed in foetal and maternal bloods during late pregnancy. 3. Foetal blood gas tensions, pH, PCV, lactic acid and glucose levels did not change markedly during the last 20-25 days of gestation. Bloodfructose concentration fell during this period with the greatest change occurring after 100 days gestation. Foetal and maternal blood pH values were higher than those reported in the sheep, cow, mare and rhesus monkey. 4. Small changes in Pco, and pH in foetal carotid blood were associated with similar changes in maternal uterine venous blood, so that gradients between sow and foetus remained relatively constant. 5. Daily changes in maternal blood glucose levels were associated with smaller changes in foetal blood glucose and fructose levels. Blood glucose concentrations in foetal blood were generally 40-70 % of maternal concentrations. Over-all relationships between maternal blood glucose and foetal blood fructose concentrations were masked by the independent fall in foetal fructose levels with age. 6. The present findings have been compared with previous observations on acute, anaesthetized preparations in pigs, and chronic preparations in other domestic animals. INTRODUCTION
Since Meschia, Cotter, Breathnach & Barron (1965) developed a technique for obtaining samples of umbilical blood from conscious sheep and goats, numerous workers have used these or similar techniques to study
G. C. B. RANDALL 720 widely differing aspects of foetal physiology in the sheep (Bassett & Thorburn, 1969; Comline & Silver, 1970a; Comline & Silver, 1972; Rudolph & Heymann, 1973). While a limited number of studies have been made on the horse and cow (Comline & Silver, 1970b; Silver, Steven & Comline, 1973; Comline, Hall, Lavelle, Nathanielsz & Silver, 1974) there is generally little information on species other than the sheep and goat. A study of the physiology of pregnancy in the pig is of importance for several reasons. The pig is polytocous and has a diffuse epitheliochorial placenta which is simpler than that found in the horse, where microcotyledons are present (Tsutsumi, 1962; Steven, 1968). As in the horse, no ductus venosus is present, and there is no distinct foetal haemoglobin in late foetal life (Novy, Hoversland, Dhindsa & Metcalfe, 1973). Some parameters of foetal pig blood have been measured in samples taken under general anaesthesia (Cummings & Kaiser, 1959; Comline & Silver, 1974; Hanka, Lawn, Mills, Prior & Tweeddale, 1975; Randall & L'Ecuyer, 1976); however, discrepancies between acute and chronic preparations in the sheep indicate that values obtained under anaesthesia may be different from those of the unstressed foetus. Therefore, a series of daily observations on foetal and maternal blood, taken by means of indwelling catheters was made. Blood gas tensions, pH, haematocrit, and glucose, fructose and lactic acid concentrations in the blood of the foetus and sow were measured, and have been compared with those obtained from anaesthetized pigs and with other species. METHODS
Animal. Yorkshire or Yorkshire x Landrace sows (123-309 kg) 90-105 days pregnant were used, and were kept tethered or in a farrowing crate during the study. Sows received 2 x 10' i.u. procaine penicillin with 2-5 g streptomycin (Pen-di-strep, Rogar S.T.B.) or 750 mg lincomycin hydrochloride (Lincocin, Rogar S.T.B.) I.M. 2 days before and 5 days after surgery. Catheter&. In six foetuses, a double catheter as described by Dawes, Fox, Leduc Liggins & Richards (1972) was used with a polyethylene vascular insert (0.58 mm i.d. x 0-96 mm o.d. Portex Ltd). In five foetuses, a single polyvinyl catheter (0.58 mm i.d. x 0 97 mm o.d. Bolab Inc., Derry, New Hampshire) was used, and in nine the intravascular portion was stretched so that the o.d. was approx. 0-6 mm. Maternal catheters were made of polyvinyl tubing (0.72 mm i.d. x 1-22 mm o.d. Bolab Inc.). A Dacron delt cuff was bonded to the catheters at the point of exit from the sow's abdomen. Anae&themia. Following induction with a 12-5 % solution of sodium thiopental (Pentothal, Abbott) given i.v. to effect (2-3 g) and intubation with a cuffed endotracheal tube (Magill No. 1 1), anaesthesia was maintained with halothane (Fluothane, Ayerst) in oxygen. The sow was placed supine and the ventral abdomen and one flank shaved, washed and sterilized using standard surgical techniques. Catheterization procedure. Following laparotomy in the mid line, the cannulae were inserted through the flank approx. 5 cm above the mammary glands so that the Dacron felt lay in the subcutaneous tissue. A foetus, within the uterus, was lifted
FOETAL BLOOD LEVELS IN THE SOW
721
from the abdomen and rotated so as to bring its ventral surface to the anti-mesometrial surface of the uterus. A 3-4 cm incision was made through the uterus, membranes and foetal skin to the right of mid line running cranially from the sternum. The uterus, foetal membranes and skin were joined with tissue forceps to minimize loss of amniotic fluid. Following exposure of the carotid, a 2-5-3-5 cm catheter was inserted, and tied into the vessel in eleven piglets, but in nine others the vessel was not ligatured. Soluble penicillin-G powder (Connaught) was sprinkled into the foetal incision before it was closed. An amniotic fluid catheter (i.d. 1.0 mm, o.d. 2-0 mm) was stitched to the piglet's chest, and in some foetuses a polyvinyl catheter (i.d. 0-58 mm, o.d. 0-97 mm) was placed in the trachea to monitor pressure changes. The uterine incision was closed with two rows of 310 chromic catgut sutures, the first of which contained both uterus and membranes. Maternal catheters were inserted into small branches of the middle uterine artery and uterine vein at another foetal implantation site. Aseptic precautions. Stringent precautions were maintained both during and after surgery. Sterile heparinized saline (100 i.u. heparin, 1000 i.u. penicillin/ml in 0-92 % saline w/v) was prepared from dry heparin. Capped hypodermic needles were bonded into the external ends of the catheters and stored, either in a pouch on the sow's flank or in a plastic box attached to the farrowing crate. Sample collection. Samples were collected daily (09.00-10.00) although in younger foetuses occasional samples were missed to avoid over-bleeding. Collection into heparinized capillary tubes (Radiometer, Copenhagen) joined with polyvinyl tubing allowed the small sample (0.4-0.5 ml.) to be divided with minimal wastage. Samples were mixed and placed in iced water until analysed. The mixture of blood and saline removed prior to sampling was returned to the foetus, and the catheters were filled with heparinized saline. Measurement . Measurements of pH, PCO2 and P02 were made within 30 min of collection at 38. 5 C using a BMS 3 microsystem and a PHM 71 blood gas analyzer (Radiometer, Copenhagen). Packed cell volune (PCV) was determined on a microhaematocrit centrifuge (TEC, Needham Hts., Mass.). Glucose, fructose and lactic acid levels were estimated in whole blood following deproteinization of 50 (or 25) #1. samples in ice-cold uranyl acetate or perchloric acid. Glucose was estimated by the glucose oxidase-peroxidase method using a commercial kit (Boehringer, Mannheim); fructose by the method of Chinard, Danesino, Hartmann, Huggett, Paul & Reynolds (1956) and lactic acid using the method of Harrower & Brown (1972). Selection of foetuses and data. The study was restricted to piglets which were followed for 7 days or longer without evidence of deterioration. They were within the wt. range of their litter-mates and, with one exception, were alive at Caesarian section or on the day of delivery. One foetus died 17 days after surgery; until the fourteenth day, tracheal pressure recordings had shown patterns similar to those attributed to foetal breathing in the sheep (Dawes et al. 1972). Samples taken from this foetus until the fourteenth day were included in this study. Samples taken during the first 2 days following surgery, and on the day of parturition, were excluded from calculations of mean values. RESULTS
Catheters placed in the foetal carotid artery remained patent for more than 7 days without signs of deterioration in twenty foetuses from fifteen sows, and samples were collected from 7-21 days after surgery. Catheters remained patent for more than 7 days in the maternal uterine artery in four sows and in the maternal uterine vein in five sows. Ten additional foetuses
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FOETAL BLOOD LEVELS IN THE SOW 723 (not included in the data) underwent rapid deterioration characterized by a doubling of the PCV over a period of 24-48 h and this consistently occurred 7 days after surgery. Blood gas and pH values in such piglets were similar to those of other cannulated piglets during the first 6 days following surgery. Blood pH, PFo, Pc0 and PCV level Maternal arterial and venous pH, Po, and P6O, values remained relatively stable during the later stages of gestation (Table 1) although the numbers of maternal samples were small. Maternal and foetal pH values were frequently higher on the day following surgery than on subsequent days. The pH of foetal carotid blood remained stable throughout the TABLE 2. Mean differences in Pol, Pco2 and pH values (± S.E. of mean) between maternal uterine venous and foetal carotid arterial blood Maternal uterine vein Foetal carotid artery* Mean difference
pH 7-459 ± 0.002 7-431 + 0.003 0.028 + 0003
(61)
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51-9 + 0 440 22.8 ± 0.258 29-1 ± 0*433
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* Comparisons were restricted to animals in which both foetal and maternal catheters were patent.
portion of the gestation period under study and, as is discussed later, variations in foetal values were generally related to changes in maternal values. Occasionally, however, transient falls in foetal pH values unassociatedwith maternal changes and lasting 1-2 days were observed. Where more than one foetus was cannulated in a sow, the pattern of daily variations was generally similar in both foetuses, suggesting that both were subject to external changes. There were no significant changes in foetal PO, or PCO2 values during the gestational ages studied. Since foetal and maternal pH and blood gas values remained stable during late gestation, data were combined for comparison of foetal and maternal values. The differences between maternal uterine vein and foetal carotid are listed in Table 2, and the similar pattern of changes in maternal and foetal pH and Pco, for one foetus is illustrated in Fig. 1. Changes in maternal Pco, were closely followed by changes in foetal values whereas changes in foetal PO, levels associated with maternal changes were much less marked (Fig. 2). PCGV, glucose, fructose and lactic acid levels There were no significant changes in maternal or foetal blood glucose levels with advancing gestational age. Mean values for PCV, blood glucose
G. C. B. RANDALL 724 and lactic acid are given m Table 3. Foetal PCV values were more variable on the first and second days after surgery, and were lower than maternal levels. There were no significant changes with advancing gestational age. Frequently, sows ate less on the second and third day following surgery, and this was reflected in lower blood glucose levels on those days. Although foetal blood glucose levels changed little in the period 90-1 14 days gestation, 7*50
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Fig. 1. Daily changes in foetal and maternal blood pH, PCO and Po, in one sow, 100 days pregnant on day of surgery. A, maternal artery; A, maternal vein; *, foetalcarotidartery. Thepiglet was born alive 14 days after surgery.
725 FOETAL BLOOD LEVELS IN THE SOW quite large daily variations occurred in some foetuses (Fig. 3). Foetal blood fructose levels, however, fell over the period studied with the largest decrease occurring after 100 days. Mean foetal blood fructose levels at < 99 days, 100-106 days and > 107days gestation were 6 7 + 0 33 (s.E. of mean); 5 70 + 0-20 and 4-57 + 0-16 mmol/l, respectively. There was marked individual variation in both initial levels and the gestational age at which the decline in blood fructose began. Lactic acid levels in the foetus were frequently elevated (4.44-7.77 mmol/l) on the day following surgery, but fell to a resting level on the second or third day. There was no significant increase in foetal blood lactic acid during late pregnancy.
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In general, daily variations in maternal blood glucose were reflected by similar (but smaller) changes in foetal glucose levels. The relationship between maternal and foetal glucose levels in one foetus over a 13 days period is illustrated in Fig. 3. There was a significant correlation (r = 0-410, P < 0.005) between foetal and maternal levels, and foetal levels were
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FOETAL BLOOD LEVELS IN THE SOW 727 usually 40-70 % of maternal levels. Fluctuations in maternal glucose levels were generally associated with changes in foetal fructose levels. The existence of a closer relationship between foetal fructose levels and maternal blood glucose levels was, however, masked by the independent fall in foetal fructose levels which occurred during this period, and by the variation in foetal age at which this fall occurred.
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Fig. 3. Daily changes in foetal blood glucose and fructose levels and maternal blood glucose levels in one sow, 100-day pregnant on day of surgery: A, maternal artery; A, maternal vein; *, foetal carotid glucose; 0, foetal carotid fructose. The piglet was born alive 14 days after surgery. DISCUSSION
This study was restricted to piglets which had survived for 7 days without signs of deterioration since a rapid increase in PCV occurred 7-8 days after surgery in a proportion of the prepared foetuses. The relationship to time of surgery has been constant, irrespective of foetal age at surgery, but no satisfactory determination of the cause has yet been made. Some died in utero 3-8 d after the increase in PCV, but many were born alive and,
G. C. B. RANDALL 728 although they remained plethoric, were fully viable until killed several days after birth. There was no evidence of growth retardation and the changes were not preceded by any consistent changes in blood gases, pH, glucose, fructose or lactate in the first 6 days following surgery. In some earlier preparations which died following elevation of the PCV, areas of necrosis were seen in the cerebral hemispheres and appeared to have resulted from reduced cerebral blood flow, since fibrin deposits had built up on the catheter which lay in the bicarotid trunk. No microscopic lesions have been found in piglets cannulated with the shorter catheter placed in one carotid. The pig foetus, with its smaller vessels, may be more susceptible to the impediment to blood flow due to the presence of a catheter than the larger species, and the increase in PCV in some foetuses may result from individual variations. Other foetuses, however, in which the jugular vein alone was cannulated, have shown similar changes in PCV, suggesting that factors other than cerebral blood supply might be implicated. The interval between surgery and deterioration does, however, caution against the use of foetuses in the immediate post-surgical period. The pH values of both foetal and maternal blood were higher than those reported for the sheep, horse and cow (Comline & Silver, 1970a; Dawes et al. 1972; Silver et al. 1973) while PCO2 values were similar or somewhat higher than in those species. Elevated blood pH levels in maternal and foetal blood of anaesthetized sows have been reported by other workers (Cummings & Kaiser, 1959; Comline & Silver, 1974; Hanka et al. 1975). In the present study, maternal pH values in conscious sows were lower than those given for anaesthetized sows by Comline & Silver (1974), who reported an unexplained alkalosis during anaesthesia. However, uterine venous values were similar to those of 7-45-7-48, given by Comline & Silver (1974) for jugular vein blood in conscious sows. McMurtry, Frith & Will (1973) gave arterial pH values of 7-48 and 7-47 for 5-month-old male and female miniature-pigs, and the high pH, therefore, may be a species characteristic rather than an effect of pregnancy. Foetal Pco, values were slightly lower in conscious foetuses than in anaesthetized foetuses (Cummings & Kaiser, 1959; Comline & Silver, 1974) and it seems probable that, in spite of good anaesthesia and minimal disturbance, some interference with placental function is present in acute preparations. Foetal arterial and maternal Po0 values were remarkably similar to those of anaesthetized sows given by Comline & Silver (1974), although maternal values differed slightly from those of Hanka et al. (1975). Values for pH, PCV and blood gases remained remarkably stable over the gestational period studied (91-115 d) and would suggest that, as in the sheep (Meschia et al. 1965; Comline & Silver, 1970a), there is little change in the oxygen-carrying capacity of foetal blood in late gestation.
729 FOETAL BLOOD LEVELS IN THE SOW Comparisons between maternal and foetal blood must be qualified by the fact that the maternal vessels were catheterized at separate foetal implantation sites. This should not have influenced arterial values, but minor differences in venous values, due to local blood flow patterns, may have existed from site to site. In general, fluctuations in maternal pH and Pco, values were reflected by similar changes in foetal values, so that maternal-foetal differences remained relatively constant. Foetal carotid arterial blood might be expected to have slightly higher Po. values than umbilical arterial blood (Born, Dawes, Mott & Widdicombe, 1954), thus giving a smaller maternal-foetal difference. Foetal arterial PO, values were less influenced by changes in maternal values than were other parameters, and it has been demonstrated previously in anaesthetized sows that changes in foetal PO, are associated with factors influencing uterine blood flow, rather than with maternal Po, (Comline & Silver, 1974; Hanka et al. 1975). Fluctuations in foetal arterial Po0 might also be reduced by the passage of the umbilical venous blood through the liver, since the pig has no ductus venosus. Blood glucose levels were slightly lower than those described previously for anaesthetized sows and foetuses (Aherne, Hays, Ewan & Speer, 1969; Randall & L'Ecuyer, 1976) where levels in both foetal and maternal circulations may have been elevated by anaesthesia. Day-to-day changes in maternal and foetal blood have confirmed earlier findings that foetal glucose levels are more closely associated with maternal levels than with gestational age (Aherne et al. 1969; Randall & L'Ecuyer, 1976). In contrast, foetal fructose levels fell during the gestational period studied with the most rapid rate of fall occurring after 100 days. Most ofthe foetuses were within this age range and this, together with individual variations in the time of onset of the rapid fall in foetal fructose levels, masked any over-all relationship between foetal fructose and maternal glucose levels. However, within individuals, some association was observed and investigations earlier in gestation might show a more definite relationship. The fall in fructose was not associated with increased lactate or falling glucose levels. There is little evidence for utilization of fructose by the foetal or newborn pig (Aherne et al. 1969) and declining levels might indicate a decline in the rate of synthesis relative to loss to the foetal fluids. If the placenta is the sole source of foetal fructose in the pig, then the fall might indicate disturbances in placental function brought about by change in either foetal or maternal endocrine levels. The constructive comments of Dr R. S. Comline of the University of Cambridge during the preparation of the manuscript were much appreciated. I am particularly grateful to Dr C. L.'Ecuyer for his help and encouragement during the early development of the surgical technique and to Dr K. J. Betteridge for his helpful discussion.
730
730
G. C. B. RANDALL C .B ADL
It is a pleasure to acknowledge the skilled technical assistance of Mrs J. Hierlihy and Messrs Y. Barbeau, G. Raby and R. Marenger during this study and the careful handling of the sows by Mr S. Shearer and Miss E. Cathcart. REFERENCES AHERNE, F. X., HAYS, V. M., EwAN, R. C. & SPEER, V. C. (1969). Glucose and fructose in the foetal and newborn pig. J. Anim. Sci. 29, 906-911. BASSETT, J. M. & THORBURN, G. D. (1969). Foetal plasma cortico-steroids and the initiation of parturition in the sheep. J. Endocr. 44, 285-286. BORN, G. V. R., DAWES, G. S., MOTT, J. C. & WIDDICOMBE, J. G. (1954). Changes in the heart and lungs at birth. Cold Spring Harb. Symp. quant. Biol. 19, 102-108. CHINARD, F. P., DANESINO, V., HARTMANN, W. L., HUGGETT, A. ST. G., PAUL, W. & REYNOLDS, S. R. M. (1956). The transmission of hexoses across the placenta in the human and the rhesus monkey (Macaca mulatta). J. Physiol. 132, 289-303. COMLINE, R. S. & SILVER, M. (1970a). Daily changes in foetal and maternal blood of conscious pregnant ewes, with catheters in umbilical and uterine vessels. J. Physiol. 209, 567-586. COmLINE, R. S. & SILVER, M. (1970b). P02, PC02, and pH levels in the umbilical and uterine blood of the mare and ewe. J. Physiol. 209, 587-608. CoNLINE, R. S. & SILVER, M. (1972). The composition of foetal and maternal blood during parturition in the ewe. J. Phy8iol. 222, 233-256. CoMLInm, R. S. & SILVER, M. (1974). A comparative study of blood gas tensions, oxygen affinity and red cell 2, 3 DPG concentrations in foetal and maternal blood in the mare, cow and sow. J. Phy8iol. 242, 805-826. COMLINE, R. S., HALL, L. W., LAVELLE, R., NATHANIELSZ, P. W. & SILVER, M. (1974). Parturition in the cow. Endocrine changes in animals with chronically implanted catheters in the foetal and maternal circulations. J. Endoer. 63, 451-472. CUMMINGS, J. N. & KAISER, I. H. (1959). The blood gases, pH and plasma electrolytes of the sow and foetal pig at 106 days of pregnancy. Am. J. Ob8tet. Gynec. 77, 10-17. DAWES, G. S., Fox, H. E., LEDUC, B. M., LIGGINS, G. C. & RICHARDS, R. T. (1972). Respiratory movements and rapid eye movement sleep in the foetal lamb. J. Physiol. 220, 119-143. HAmu, R., LAWN, L., MILLS, I. H., PRIOR, D. C. & TWEEDDALE, P. M. (1975). The effects of maternal hypercapnia on foetal oxygenation and uterine blood flow in the pig. J. Phy8iol. 247, 447-460. HARROWER, J. R. & BROWN, C. H. (1972). Blood lactic acid - a micromethod adapted to field collection of microliter samples. J. apple. Phy8iol. 33, 709-711. MCMURTRY, I. F., FRITH, C. H. & WILL, D. A. (1973). Cardiopulmonary responses of male and female swine to simulated high altitude. J. apple. Phy8iol. 35, 459-462. MESCHIA, G., COTTER, J. R., BREATHNACH, C. S. & BARRON, D. H. (1965). The haemoglobin, oxygen, carbon dioxide and hydrogen ion concentrations in the umbilical bloods of sheep and goats as sampled via indwelling plastic catheters. Q. Ji exp. Phy8iol. 50, 185-195. NovY, M. J., HOVERSLAND, A. S., DHINDSA, D. S. & METCALFE, J. (1973). Blood oxygen affinity and haemoglobin type in adult, newborn and foetal pigs. Resp. Phy8iol. 19, 1-11. RANDALL, G. C. B. & L'EcuvER, C. (1976). Tissue glycogen and glood glucose and fructose levels in the pig foetus during the second half of gestation. Biologia Neonat. 28, 74-82.
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RUDOLPH, A. M. & HEYMANN, N. A. (1973). Control of the foetal circulation. In Foetal and Neonatal Physiology, Barcroft Centenary Symposium, ed. CommNE, R. S., CROSS, K. W., DAWES, G. S. & NATHANIELSZ, P. W., pp. 89-111. London: Cambridge University Press. SILVER, M., STEVEN, D. H. & COMLINE, R. S. (1973). Placental exchange and morphology in ruminants and the mare. In Foetal and Neonatal Physiology, Barcroft Centenary Symposium, ed. COMLINE, R. S., CROSS, K. W., DAWEs, G. S. & NATEANIELSZ, P. W., pp. 243-271. London: Cambridge University Press. STEVEN, D. H. (1968). Structural differences between exchange units in the sheep and horse placenta. J. Physiol. 196, 24-26P. TSUTSUMI, Y. (1962). The vascular pattern of the placenta in farm animals. J. Fac. Agric. Hokkaido (imp) Univ. 52, 372-482.
719
DAILY CHANGES IN THE BLOOD OF CONSCIOUS PIGS WITH CATHETERS IN FOETAL AND UTERINE VESSELS DURING LATE GESTATION
By G. C. B. RANDALL From the Animal Diseases Research Institute, 801 Fallowfield Road, P.O. Box 11300, Station H, Ottawa, Ontario, Canada, K2H 8P9
(Received 4 January 1977) SUMMARY
1. Catheters were inserted into the foetal carotid artery and maternal middle uterine artery and vein in twenty foetuses from fifteen sows, 91-105 days pregnant. Blood samples were collected from foetal and maternal circulations for periods of 7-21 days after surgery. 2. Blood gas tensions, pH, packed cell volume (PCV) and the levels of glucose, fructose and lactic acid in conscious pigs were followed in foetal and maternal bloods during late pregnancy. 3. Foetal blood gas tensions, pH, PCV, lactic acid and glucose levels did not change markedly during the last 20-25 days of gestation. Bloodfructose concentration fell during this period with the greatest change occurring after 100 days gestation. Foetal and maternal blood pH values were higher than those reported in the sheep, cow, mare and rhesus monkey. 4. Small changes in Pco, and pH in foetal carotid blood were associated with similar changes in maternal uterine venous blood, so that gradients between sow and foetus remained relatively constant. 5. Daily changes in maternal blood glucose levels were associated with smaller changes in foetal blood glucose and fructose levels. Blood glucose concentrations in foetal blood were generally 40-70 % of maternal concentrations. Over-all relationships between maternal blood glucose and foetal blood fructose concentrations were masked by the independent fall in foetal fructose levels with age. 6. The present findings have been compared with previous observations on acute, anaesthetized preparations in pigs, and chronic preparations in other domestic animals. INTRODUCTION
Since Meschia, Cotter, Breathnach & Barron (1965) developed a technique for obtaining samples of umbilical blood from conscious sheep and goats, numerous workers have used these or similar techniques to study
G. C. B. RANDALL 720 widely differing aspects of foetal physiology in the sheep (Bassett & Thorburn, 1969; Comline & Silver, 1970a; Comline & Silver, 1972; Rudolph & Heymann, 1973). While a limited number of studies have been made on the horse and cow (Comline & Silver, 1970b; Silver, Steven & Comline, 1973; Comline, Hall, Lavelle, Nathanielsz & Silver, 1974) there is generally little information on species other than the sheep and goat. A study of the physiology of pregnancy in the pig is of importance for several reasons. The pig is polytocous and has a diffuse epitheliochorial placenta which is simpler than that found in the horse, where microcotyledons are present (Tsutsumi, 1962; Steven, 1968). As in the horse, no ductus venosus is present, and there is no distinct foetal haemoglobin in late foetal life (Novy, Hoversland, Dhindsa & Metcalfe, 1973). Some parameters of foetal pig blood have been measured in samples taken under general anaesthesia (Cummings & Kaiser, 1959; Comline & Silver, 1974; Hanka, Lawn, Mills, Prior & Tweeddale, 1975; Randall & L'Ecuyer, 1976); however, discrepancies between acute and chronic preparations in the sheep indicate that values obtained under anaesthesia may be different from those of the unstressed foetus. Therefore, a series of daily observations on foetal and maternal blood, taken by means of indwelling catheters was made. Blood gas tensions, pH, haematocrit, and glucose, fructose and lactic acid concentrations in the blood of the foetus and sow were measured, and have been compared with those obtained from anaesthetized pigs and with other species. METHODS
Animal. Yorkshire or Yorkshire x Landrace sows (123-309 kg) 90-105 days pregnant were used, and were kept tethered or in a farrowing crate during the study. Sows received 2 x 10' i.u. procaine penicillin with 2-5 g streptomycin (Pen-di-strep, Rogar S.T.B.) or 750 mg lincomycin hydrochloride (Lincocin, Rogar S.T.B.) I.M. 2 days before and 5 days after surgery. Catheter&. In six foetuses, a double catheter as described by Dawes, Fox, Leduc Liggins & Richards (1972) was used with a polyethylene vascular insert (0.58 mm i.d. x 0-96 mm o.d. Portex Ltd). In five foetuses, a single polyvinyl catheter (0.58 mm i.d. x 0 97 mm o.d. Bolab Inc., Derry, New Hampshire) was used, and in nine the intravascular portion was stretched so that the o.d. was approx. 0-6 mm. Maternal catheters were made of polyvinyl tubing (0.72 mm i.d. x 1-22 mm o.d. Bolab Inc.). A Dacron delt cuff was bonded to the catheters at the point of exit from the sow's abdomen. Anae&themia. Following induction with a 12-5 % solution of sodium thiopental (Pentothal, Abbott) given i.v. to effect (2-3 g) and intubation with a cuffed endotracheal tube (Magill No. 1 1), anaesthesia was maintained with halothane (Fluothane, Ayerst) in oxygen. The sow was placed supine and the ventral abdomen and one flank shaved, washed and sterilized using standard surgical techniques. Catheterization procedure. Following laparotomy in the mid line, the cannulae were inserted through the flank approx. 5 cm above the mammary glands so that the Dacron felt lay in the subcutaneous tissue. A foetus, within the uterus, was lifted
FOETAL BLOOD LEVELS IN THE SOW
721
from the abdomen and rotated so as to bring its ventral surface to the anti-mesometrial surface of the uterus. A 3-4 cm incision was made through the uterus, membranes and foetal skin to the right of mid line running cranially from the sternum. The uterus, foetal membranes and skin were joined with tissue forceps to minimize loss of amniotic fluid. Following exposure of the carotid, a 2-5-3-5 cm catheter was inserted, and tied into the vessel in eleven piglets, but in nine others the vessel was not ligatured. Soluble penicillin-G powder (Connaught) was sprinkled into the foetal incision before it was closed. An amniotic fluid catheter (i.d. 1.0 mm, o.d. 2-0 mm) was stitched to the piglet's chest, and in some foetuses a polyvinyl catheter (i.d. 0-58 mm, o.d. 0-97 mm) was placed in the trachea to monitor pressure changes. The uterine incision was closed with two rows of 310 chromic catgut sutures, the first of which contained both uterus and membranes. Maternal catheters were inserted into small branches of the middle uterine artery and uterine vein at another foetal implantation site. Aseptic precautions. Stringent precautions were maintained both during and after surgery. Sterile heparinized saline (100 i.u. heparin, 1000 i.u. penicillin/ml in 0-92 % saline w/v) was prepared from dry heparin. Capped hypodermic needles were bonded into the external ends of the catheters and stored, either in a pouch on the sow's flank or in a plastic box attached to the farrowing crate. Sample collection. Samples were collected daily (09.00-10.00) although in younger foetuses occasional samples were missed to avoid over-bleeding. Collection into heparinized capillary tubes (Radiometer, Copenhagen) joined with polyvinyl tubing allowed the small sample (0.4-0.5 ml.) to be divided with minimal wastage. Samples were mixed and placed in iced water until analysed. The mixture of blood and saline removed prior to sampling was returned to the foetus, and the catheters were filled with heparinized saline. Measurement . Measurements of pH, PCO2 and P02 were made within 30 min of collection at 38. 5 C using a BMS 3 microsystem and a PHM 71 blood gas analyzer (Radiometer, Copenhagen). Packed cell volune (PCV) was determined on a microhaematocrit centrifuge (TEC, Needham Hts., Mass.). Glucose, fructose and lactic acid levels were estimated in whole blood following deproteinization of 50 (or 25) #1. samples in ice-cold uranyl acetate or perchloric acid. Glucose was estimated by the glucose oxidase-peroxidase method using a commercial kit (Boehringer, Mannheim); fructose by the method of Chinard, Danesino, Hartmann, Huggett, Paul & Reynolds (1956) and lactic acid using the method of Harrower & Brown (1972). Selection of foetuses and data. The study was restricted to piglets which were followed for 7 days or longer without evidence of deterioration. They were within the wt. range of their litter-mates and, with one exception, were alive at Caesarian section or on the day of delivery. One foetus died 17 days after surgery; until the fourteenth day, tracheal pressure recordings had shown patterns similar to those attributed to foetal breathing in the sheep (Dawes et al. 1972). Samples taken from this foetus until the fourteenth day were included in this study. Samples taken during the first 2 days following surgery, and on the day of parturition, were excluded from calculations of mean values. RESULTS
Catheters placed in the foetal carotid artery remained patent for more than 7 days without signs of deterioration in twenty foetuses from fifteen sows, and samples were collected from 7-21 days after surgery. Catheters remained patent for more than 7 days in the maternal uterine artery in four sows and in the maternal uterine vein in five sows. Ten additional foetuses
C. C. B. RANDALL
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FOETAL BLOOD LEVELS IN THE SOW 723 (not included in the data) underwent rapid deterioration characterized by a doubling of the PCV over a period of 24-48 h and this consistently occurred 7 days after surgery. Blood gas and pH values in such piglets were similar to those of other cannulated piglets during the first 6 days following surgery. Blood pH, PFo, Pc0 and PCV level Maternal arterial and venous pH, Po, and P6O, values remained relatively stable during the later stages of gestation (Table 1) although the numbers of maternal samples were small. Maternal and foetal pH values were frequently higher on the day following surgery than on subsequent days. The pH of foetal carotid blood remained stable throughout the TABLE 2. Mean differences in Pol, Pco2 and pH values (± S.E. of mean) between maternal uterine venous and foetal carotid arterial blood Maternal uterine vein Foetal carotid artery* Mean difference
pH 7-459 ± 0.002 7-431 + 0.003 0.028 + 0003
(61)
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* Comparisons were restricted to animals in which both foetal and maternal catheters were patent.
portion of the gestation period under study and, as is discussed later, variations in foetal values were generally related to changes in maternal values. Occasionally, however, transient falls in foetal pH values unassociatedwith maternal changes and lasting 1-2 days were observed. Where more than one foetus was cannulated in a sow, the pattern of daily variations was generally similar in both foetuses, suggesting that both were subject to external changes. There were no significant changes in foetal PO, or PCO2 values during the gestational ages studied. Since foetal and maternal pH and blood gas values remained stable during late gestation, data were combined for comparison of foetal and maternal values. The differences between maternal uterine vein and foetal carotid are listed in Table 2, and the similar pattern of changes in maternal and foetal pH and Pco, for one foetus is illustrated in Fig. 1. Changes in maternal Pco, were closely followed by changes in foetal values whereas changes in foetal PO, levels associated with maternal changes were much less marked (Fig. 2). PCGV, glucose, fructose and lactic acid levels There were no significant changes in maternal or foetal blood glucose levels with advancing gestational age. Mean values for PCV, blood glucose
G. C. B. RANDALL 724 and lactic acid are given m Table 3. Foetal PCV values were more variable on the first and second days after surgery, and were lower than maternal levels. There were no significant changes with advancing gestational age. Frequently, sows ate less on the second and third day following surgery, and this was reflected in lower blood glucose levels on those days. Although foetal blood glucose levels changed little in the period 90-1 14 days gestation, 7*50
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Fig. 1. Daily changes in foetal and maternal blood pH, PCO and Po, in one sow, 100 days pregnant on day of surgery. A, maternal artery; A, maternal vein; *, foetalcarotidartery. Thepiglet was born alive 14 days after surgery.
725 FOETAL BLOOD LEVELS IN THE SOW quite large daily variations occurred in some foetuses (Fig. 3). Foetal blood fructose levels, however, fell over the period studied with the largest decrease occurring after 100 days. Mean foetal blood fructose levels at < 99 days, 100-106 days and > 107days gestation were 6 7 + 0 33 (s.E. of mean); 5 70 + 0-20 and 4-57 + 0-16 mmol/l, respectively. There was marked individual variation in both initial levels and the gestational age at which the decline in blood fructose began. Lactic acid levels in the foetus were frequently elevated (4.44-7.77 mmol/l) on the day following surgery, but fell to a resting level on the second or third day. There was no significant increase in foetal blood lactic acid during late pregnancy.
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In general, daily variations in maternal blood glucose were reflected by similar (but smaller) changes in foetal glucose levels. The relationship between maternal and foetal glucose levels in one foetus over a 13 days period is illustrated in Fig. 3. There was a significant correlation (r = 0-410, P < 0.005) between foetal and maternal levels, and foetal levels were
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FOETAL BLOOD LEVELS IN THE SOW 727 usually 40-70 % of maternal levels. Fluctuations in maternal glucose levels were generally associated with changes in foetal fructose levels. The existence of a closer relationship between foetal fructose levels and maternal blood glucose levels was, however, masked by the independent fall in foetal fructose levels which occurred during this period, and by the variation in foetal age at which this fall occurred.
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Fig. 3. Daily changes in foetal blood glucose and fructose levels and maternal blood glucose levels in one sow, 100-day pregnant on day of surgery: A, maternal artery; A, maternal vein; *, foetal carotid glucose; 0, foetal carotid fructose. The piglet was born alive 14 days after surgery. DISCUSSION
This study was restricted to piglets which had survived for 7 days without signs of deterioration since a rapid increase in PCV occurred 7-8 days after surgery in a proportion of the prepared foetuses. The relationship to time of surgery has been constant, irrespective of foetal age at surgery, but no satisfactory determination of the cause has yet been made. Some died in utero 3-8 d after the increase in PCV, but many were born alive and,
G. C. B. RANDALL 728 although they remained plethoric, were fully viable until killed several days after birth. There was no evidence of growth retardation and the changes were not preceded by any consistent changes in blood gases, pH, glucose, fructose or lactate in the first 6 days following surgery. In some earlier preparations which died following elevation of the PCV, areas of necrosis were seen in the cerebral hemispheres and appeared to have resulted from reduced cerebral blood flow, since fibrin deposits had built up on the catheter which lay in the bicarotid trunk. No microscopic lesions have been found in piglets cannulated with the shorter catheter placed in one carotid. The pig foetus, with its smaller vessels, may be more susceptible to the impediment to blood flow due to the presence of a catheter than the larger species, and the increase in PCV in some foetuses may result from individual variations. Other foetuses, however, in which the jugular vein alone was cannulated, have shown similar changes in PCV, suggesting that factors other than cerebral blood supply might be implicated. The interval between surgery and deterioration does, however, caution against the use of foetuses in the immediate post-surgical period. The pH values of both foetal and maternal blood were higher than those reported for the sheep, horse and cow (Comline & Silver, 1970a; Dawes et al. 1972; Silver et al. 1973) while PCO2 values were similar or somewhat higher than in those species. Elevated blood pH levels in maternal and foetal blood of anaesthetized sows have been reported by other workers (Cummings & Kaiser, 1959; Comline & Silver, 1974; Hanka et al. 1975). In the present study, maternal pH values in conscious sows were lower than those given for anaesthetized sows by Comline & Silver (1974), who reported an unexplained alkalosis during anaesthesia. However, uterine venous values were similar to those of 7-45-7-48, given by Comline & Silver (1974) for jugular vein blood in conscious sows. McMurtry, Frith & Will (1973) gave arterial pH values of 7-48 and 7-47 for 5-month-old male and female miniature-pigs, and the high pH, therefore, may be a species characteristic rather than an effect of pregnancy. Foetal Pco, values were slightly lower in conscious foetuses than in anaesthetized foetuses (Cummings & Kaiser, 1959; Comline & Silver, 1974) and it seems probable that, in spite of good anaesthesia and minimal disturbance, some interference with placental function is present in acute preparations. Foetal arterial and maternal Po0 values were remarkably similar to those of anaesthetized sows given by Comline & Silver (1974), although maternal values differed slightly from those of Hanka et al. (1975). Values for pH, PCV and blood gases remained remarkably stable over the gestational period studied (91-115 d) and would suggest that, as in the sheep (Meschia et al. 1965; Comline & Silver, 1970a), there is little change in the oxygen-carrying capacity of foetal blood in late gestation.
729 FOETAL BLOOD LEVELS IN THE SOW Comparisons between maternal and foetal blood must be qualified by the fact that the maternal vessels were catheterized at separate foetal implantation sites. This should not have influenced arterial values, but minor differences in venous values, due to local blood flow patterns, may have existed from site to site. In general, fluctuations in maternal pH and Pco, values were reflected by similar changes in foetal values, so that maternal-foetal differences remained relatively constant. Foetal carotid arterial blood might be expected to have slightly higher Po. values than umbilical arterial blood (Born, Dawes, Mott & Widdicombe, 1954), thus giving a smaller maternal-foetal difference. Foetal arterial PO, values were less influenced by changes in maternal values than were other parameters, and it has been demonstrated previously in anaesthetized sows that changes in foetal PO, are associated with factors influencing uterine blood flow, rather than with maternal Po, (Comline & Silver, 1974; Hanka et al. 1975). Fluctuations in foetal arterial Po0 might also be reduced by the passage of the umbilical venous blood through the liver, since the pig has no ductus venosus. Blood glucose levels were slightly lower than those described previously for anaesthetized sows and foetuses (Aherne, Hays, Ewan & Speer, 1969; Randall & L'Ecuyer, 1976) where levels in both foetal and maternal circulations may have been elevated by anaesthesia. Day-to-day changes in maternal and foetal blood have confirmed earlier findings that foetal glucose levels are more closely associated with maternal levels than with gestational age (Aherne et al. 1969; Randall & L'Ecuyer, 1976). In contrast, foetal fructose levels fell during the gestational period studied with the most rapid rate of fall occurring after 100 days. Most ofthe foetuses were within this age range and this, together with individual variations in the time of onset of the rapid fall in foetal fructose levels, masked any over-all relationship between foetal fructose and maternal glucose levels. However, within individuals, some association was observed and investigations earlier in gestation might show a more definite relationship. The fall in fructose was not associated with increased lactate or falling glucose levels. There is little evidence for utilization of fructose by the foetal or newborn pig (Aherne et al. 1969) and declining levels might indicate a decline in the rate of synthesis relative to loss to the foetal fluids. If the placenta is the sole source of foetal fructose in the pig, then the fall might indicate disturbances in placental function brought about by change in either foetal or maternal endocrine levels. The constructive comments of Dr R. S. Comline of the University of Cambridge during the preparation of the manuscript were much appreciated. I am particularly grateful to Dr C. L.'Ecuyer for his help and encouragement during the early development of the surgical technique and to Dr K. J. Betteridge for his helpful discussion.
730
730
G. C. B. RANDALL C .B ADL
It is a pleasure to acknowledge the skilled technical assistance of Mrs J. Hierlihy and Messrs Y. Barbeau, G. Raby and R. Marenger during this study and the careful handling of the sows by Mr S. Shearer and Miss E. Cathcart. REFERENCES AHERNE, F. X., HAYS, V. M., EwAN, R. C. & SPEER, V. C. (1969). Glucose and fructose in the foetal and newborn pig. J. Anim. Sci. 29, 906-911. BASSETT, J. M. & THORBURN, G. D. (1969). Foetal plasma cortico-steroids and the initiation of parturition in the sheep. J. Endocr. 44, 285-286. BORN, G. V. R., DAWES, G. S., MOTT, J. C. & WIDDICOMBE, J. G. (1954). Changes in the heart and lungs at birth. Cold Spring Harb. Symp. quant. Biol. 19, 102-108. CHINARD, F. P., DANESINO, V., HARTMANN, W. L., HUGGETT, A. ST. G., PAUL, W. & REYNOLDS, S. R. M. (1956). The transmission of hexoses across the placenta in the human and the rhesus monkey (Macaca mulatta). J. Physiol. 132, 289-303. COMLINE, R. S. & SILVER, M. (1970a). Daily changes in foetal and maternal blood of conscious pregnant ewes, with catheters in umbilical and uterine vessels. J. Physiol. 209, 567-586. COmLINE, R. S. & SILVER, M. (1970b). P02, PC02, and pH levels in the umbilical and uterine blood of the mare and ewe. J. Physiol. 209, 587-608. CoNLINE, R. S. & SILVER, M. (1972). The composition of foetal and maternal blood during parturition in the ewe. J. Phy8iol. 222, 233-256. CoMLInm, R. S. & SILVER, M. (1974). A comparative study of blood gas tensions, oxygen affinity and red cell 2, 3 DPG concentrations in foetal and maternal blood in the mare, cow and sow. J. Phy8iol. 242, 805-826. COMLINE, R. S., HALL, L. W., LAVELLE, R., NATHANIELSZ, P. W. & SILVER, M. (1974). Parturition in the cow. Endocrine changes in animals with chronically implanted catheters in the foetal and maternal circulations. J. Endoer. 63, 451-472. CUMMINGS, J. N. & KAISER, I. H. (1959). The blood gases, pH and plasma electrolytes of the sow and foetal pig at 106 days of pregnancy. Am. J. Ob8tet. Gynec. 77, 10-17. DAWES, G. S., Fox, H. E., LEDUC, B. M., LIGGINS, G. C. & RICHARDS, R. T. (1972). Respiratory movements and rapid eye movement sleep in the foetal lamb. J. Physiol. 220, 119-143. HAmu, R., LAWN, L., MILLS, I. H., PRIOR, D. C. & TWEEDDALE, P. M. (1975). The effects of maternal hypercapnia on foetal oxygenation and uterine blood flow in the pig. J. Phy8iol. 247, 447-460. HARROWER, J. R. & BROWN, C. H. (1972). Blood lactic acid - a micromethod adapted to field collection of microliter samples. J. apple. Phy8iol. 33, 709-711. MCMURTRY, I. F., FRITH, C. H. & WILL, D. A. (1973). Cardiopulmonary responses of male and female swine to simulated high altitude. J. apple. Phy8iol. 35, 459-462. MESCHIA, G., COTTER, J. R., BREATHNACH, C. S. & BARRON, D. H. (1965). The haemoglobin, oxygen, carbon dioxide and hydrogen ion concentrations in the umbilical bloods of sheep and goats as sampled via indwelling plastic catheters. Q. Ji exp. Phy8iol. 50, 185-195. NovY, M. J., HOVERSLAND, A. S., DHINDSA, D. S. & METCALFE, J. (1973). Blood oxygen affinity and haemoglobin type in adult, newborn and foetal pigs. Resp. Phy8iol. 19, 1-11. RANDALL, G. C. B. & L'EcuvER, C. (1976). Tissue glycogen and glood glucose and fructose levels in the pig foetus during the second half of gestation. Biologia Neonat. 28, 74-82.
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RUDOLPH, A. M. & HEYMANN, N. A. (1973). Control of the foetal circulation. In Foetal and Neonatal Physiology, Barcroft Centenary Symposium, ed. CommNE, R. S., CROSS, K. W., DAWES, G. S. & NATHANIELSZ, P. W., pp. 89-111. London: Cambridge University Press. SILVER, M., STEVEN, D. H. & COMLINE, R. S. (1973). Placental exchange and morphology in ruminants and the mare. In Foetal and Neonatal Physiology, Barcroft Centenary Symposium, ed. COMLINE, R. S., CROSS, K. W., DAWEs, G. S. & NATEANIELSZ, P. W., pp. 243-271. London: Cambridge University Press. STEVEN, D. H. (1968). Structural differences between exchange units in the sheep and horse placenta. J. Physiol. 196, 24-26P. TSUTSUMI, Y. (1962). The vascular pattern of the placenta in farm animals. J. Fac. Agric. Hokkaido (imp) Univ. 52, 372-482.
