- Email: [email protected]
EARLY DETECTION AND PREVENTION OF FŒTAL ACIDOSIS
290
0-06 pH units, which favours elimination of the hydrogen ion in the foetus. In the present study two ways of influencing the metabolic component of the acid-base balance were tried: in a preliminary series, mothers were given one of the modern diuretics; and in the main series sodium bicarbonate was administered. Earlier observations (Rooth 1963) had shown that when mothers were given some of the modern oral diuretics known to induce metabolic alkalosis the infant might be born with a slight alkalosis instead of the usual acidosis. In the preliminary work, 30 women in labour were alternatively given polythiazide or made to serve as controls. The selection was random. Owing to the small number in the series, more mothers had inertia and there were more primigravidæ in the polythiazide group than among the controls. Both these factors would make the polythiazide group more acid than the controls (Rooth and Nilsson 1964), Base excess was measured in the blood of the antecubital vein and in the umbilical venous blood of the mothers as soon as possible after delivery. The mean base excess in 14 women receiving polythiazide was - 7 -mEq. per litre in venous blood and -4-9 mEq. per litre in the umbilical venous blood. In the 16 women who were controls, the mean base excess was - 5,5 mEq. per litre both in venous blood and in umbilical venous blood. Thus, the mothers in the polythiazide group were slightly more acidotic than the controls. This, as stated, could have been due to the differences in labour. Nevertheless, the results showed that polythiazide given to the mother after she had arrived in the labour room did not make her alkalotic enough to reduce her acidosis. This was doubtless because there was not enough time for polythiazide to produce alkalosis, since it took seven to ten days before alkalosis reached its height (Rooth and Fiirst 1963).
period was also studied. 4 of 212 male babies were chromatin-positive, but no chromosome studies were possible. 1 of 185 female babies was chromatin-negative and had
an
XO sex-chromosome constitution.
The survey was made possible by a grant from the Medical Research Council for technical assistance and expenses to one of us (N. M.), and by the cooperation of the nursing staffs of the maternity units who were responsible for taking the buccal smears. For this essential assistance we are most grateful. We are indebted to Miss S. Brunton, Miss M. Brunton, and Mrs. C. Cowen for their technical assistance with the chromosome studies, and to Miss M. Luff and Miss H. MacFarlane for other technical assistance. Laboratory facilities and administrative help were provided by the board of management of the Edinburgh Northern Group of Hospitals, and we are indebted to Dr. A. J. M. Drennan for making the laboratory facilities available at the Western General Hospital. We would like to thank Dr. J. W. Farquhar, Dr. J. 0. Forfar, Dr. A. Keay, Dr. J. A. McBride, Dr. D. T. D. Nicholson, Dr. D. M. Douglas, Dr. J. W. Worling, Dr. J. Y. MacDougall, Dr. M. D. Black, and Dr. J. 0. Craig for their interest and their help in many ways in furthering the investigation. For allowing us to carry out the survey we are grateful to Dr. A. F. Anderson, Dr. W. D. A. Callam, Prof. R. W. B. Ellis, Dr. W. F. Flint, Dr. D. J. M. Irvine, Prof. R. J. Kellar, Dr. C. D. Kennedy, Dr. E. Little, Dr. J. D. 0. Loudon, Dr. J. E. W. Mackie, Dr. T. N. MacGregor, Dr. G. D. Matthew, Dr. P. R. Myerscough, Dr. S. J. Patterson, Dr. M. G. Pearson, Dr. J. Sturrock, and Dr. R. A. Tennent. REFERENCES
Bergeman, E. (1961) Schweiz. med. Wschr. 10, 292. Carr, D. H. (1963) Lancet, ii, 603. de la Chapelle, A. (1962) Acta endocr., Copenhagen, 40, suppl. 65. Gartler, S. M., Waxman, S. H., Giblett, E. (1962) Proc. nat. Acad. Sci. 48, 332. Harnden, D. G. (1960) Brit. J. exp. Path. 41, 31. Jacobs, P. A., Harnden, D. G., Court Brown, W. M., Goldstein, J., Close, H. G., MacGregor, T. N., Maclean, N., Strong, J. A. (1960) Lancet, i, 1213.
Buckton, K. E., Court Brown, W. M., King, M. J., McBride, J. A., MacGregor, T. N., Maclean, N. (1961) ibid. i, 1183. Maclean, N., Harnden, D. G., Court Brown, W. M. (1961) ibid. ii, 406. Moore, K. L. (1959) ibid. i, 217. Barr, M. L. (1955) ibid. ii, 57. Moorhead, P. S., Nowell, P. C., Mellman, W. J., Battips, D. M., Hungerford, D. A. (1960) Exp. Cell. Res. 20, 613. Naik, S. H., Shah, P. N. (1962) Science, 136, 1116. Ross, A. (1960) J. med. Lab. Tech. 17, 178. —
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EARLY DETECTION AND PREVENTION OF FŒTAL ACIDOSIS
Material and Methods in labour were studied. 12 served as controls and 11 were given sodium bicarbonate; after the first blood-sample was obtained the standard solution of the hospital, containing 155 mEq. per litre, was used. Between 100 and 1900 ml. was administered intravenously in the course of half an hour to twenty-five hours. The mean rate of infusion was 2.5 ml, per min. and the fastest rate was 6 ml. per min. The women selected were those who were expected to remain in labour for some hours so that there would be time enough to study them, There were 7 primigravidae in each group. All were vertex deliveries, except 1 breech delivery in the control group, In each group there were 2 cases of inertia corrected by oxytocin in the form of ’Partoten ’ sniffs. For analgesia trichloroethylene (’ Trilene ’) or nitrous oxide was used with equal frequency in both groups. In most cases a small dose of chloroform was given at the moment of delivery, Repeated blood-samples were taken from the antecubital vein of the mother during labour, and as soon as possible after delivery and always within three minutes. Samples were also taken from clamped sections of the umbilical vessels. The blood was analysed for base excess and lactic acid, and (when the samples were secured anaerobically) pH as well. From this Pc02 could be calculated. Standard corrections were made for calculating Pco,. The maternal blood was assumed to be 50% unsaturated, the umbilical venous blood 35%, and the arterial 23
GÖSTA ROOTH M.D.
From the Aid of Crippled Children Laboratory, Department of Internal Medicine, and Department of Obstetrics and Gynæcology, University Hospital, Lund, Sweden
THE clinical signs of foetal asphyxia-i.e., slow or irregular foetal heart-sounds-appear late, and there is real need for its early diagnosis and prevention. Weisbrot et al. (1958) were the first to emphasise that foetal metabolic acidosis is more pronounced when there are signs of asphyxia. Thus, if foetal metabolic acidosis could be determined before delivery, asphyxia might be anticipated and prevented. Since foetal acidosis is mainly caused by maternal metabolic acidosis (Vedra 1959, 1960, Rooth and Nilsson 1964) it should be detectable by measurements of the maternal acidosis before delivery, and if maternal acidosis could be reduced foetal acidosis, too, should be reduced. Goodlin and Kaiser (1957) showed that the fcetal acidosis was increased if the mother was rendered acidotic by ammonium chloride; hence there is reason to believe that if the maternal pH were moved in the alkaline direction the foetal acidosis would be reduced. This is, in fact, what happens normally in pregnancy when the respiratory component (Pc02) of the acid-base balance comes into play. Pco2 is about 32 mm. Hg in the pregnantv woman, compared with 40 mmm. Hg in non-pregnant subjects. This gives a pH increase in the mother of’ ’
women
blood 65%. Base excess is the metabolic component in the acid-base balance and gives in mEq. per litre the addition of base or aod to the whole blood. Negative figures denote a metabolic acidosis. pH, Pc02, and base excess were measured according to the technique of Astrup et al. (1960). Lactic acid was measured by means of the lactic-acid-dehydrogenase method, the commercial reagents Biochemica Boehringer being used.
I
291
Fig. 3-Metabolic acidosis in maternal venous blood during labour and after delivery in mothers receiving sodium bicarbonate intravenously. Sodium bicarbonate was given as soon as the first sample was obtained. The interrupted line indicates discontinuation of the drip.
Fig. I-Metabolic acidosis in maternal venous blood during labour and after delivery in untreated mothers (controls). Results
Fig. 1 shows that the maternal metabolic acidosis usually appears during the last two hours of labour. The onset of the acidosis was also related to clinical signs. The intensity of the pains was graded 1=slight, 2 = medium, and 3=strong; and this figure was divided by the interval in minutes between the onset of the pains. This gave a numerical index of the amount of work done per unit of time by the mother during labour. As is shown in fig. 2, the acidosis usually began at an index of about 1.
Mdosis, therefore, only began when the pains were of at least medium intensity. When the mothers were given sodium bicarbonate their metabolic acidosis
was
reduced.
Figs. 3 and 4, which
correspond to figs. 1 and 2 in the
untreated
group,
bring
out these differences.
Pairing
the controls and the treated women and testing the values at two hours and one hour before delivery and after delivery with sequence analyses, the Fig. 2-Relation between metabolic acidosis treated group in maternal venous blood and " labour is significantly index " in untreated mothers (controls). less acidotic at a 1% level. The mean base excess two hours before delivery was -4-7 mEq. per litre against --21 in the treated group. One hour before delivery the corresponding values were -5-7 and -3-6 mEq. per litre and after delivery —10-0;, against -4-5 mEq. per litre. The mean base excess at index 1-0 in the untreated group was - 4-5 mEq. per litre against -2,4 in the group receiving sodium bicarbonate. Using sequence analyses the paired differences were significant at the 1% level. 2 of the women on bicarbonate had a labour index of about 1-0 for almost twenty-four hours, and despite this they showed no increase in acidosis. The effect of the bicarbonate may also be calculated from the amount of bicarbonate given; had none been administered the 11 treated women would have had somewhat more acidosis than the 12 control women.
The base excess in the cord blood is shown in table I. The mean base excess value in the umbilical veins is - 10-0 in the control series against - 5-5 mEq. per litre in the treated group. Corresponding values for the umbilical artery are -13-7 and -6-7 mEq. per litre. These differences are also
statistically significant. Table
II
gives the values for pH and Pc02 after delivery in the women receiving bicarbonate as well as in the controls. The mean
Pc02s was higher in the group receiv-
in maternal venous blood and "labour index" in mothers receiving sodium bicarbonate
Fig. 4-Relation between metabolic acidosis intravenously.
Sodium bicarbonate was given as soon as the first sample was obtained. The interrupted line
indicates discontinuation of the drip.
ing bicarbonate, though the differences are not significant. The data also confirm the strong correlation between the levels of maternal and fcetal metabolic acidosis as measured in the umbilical vein (fig. 5). The series is obviously too small for assessing the clinical effect of bicarbonate administration on the foetus. Still, there were 4 instances of meconium-stained amniotic fluid in the control group against only 1 in the bicarbonate group. (This does not include the breech delivery in the control group.) The relation between base excess and lactic acid in the maternal blood and in the cord blood is shown in figs. 6
(mEq. per litre) IN UMBILICAL VENOUS AND ARTERIAL BLOOD OF MOTHERS AFTER BICARBONATE ADMINISTRATION TABLE I-BASE EXCESS
*
On chlorthalidone 25 mg.
daily during
the last
two
weeks of pregnancy.
t On hydrochlorthiazide 50 mg. daily duringthe last tv
292
sis and its presence can be gauged by the intensity and the frequency of the pains. Maternal and fcetal acidosis, therefore, predominantly results from labour at a time when the maternal muscular effort becomes so great that the oxygen demand by her working tissues cannot be met. This is in agreement with the absence of foetal acidosis after elective cxsarean section (Engstrom et al. 1963) and increased acidosis in the foetus when the mother has been made hypoxic by the administration of nitrous oxide
and 7. Both in the maternal blood and in the cord blood the acidosis is seen to be due only to a
small extent to lactic acid.
Moreover, there is no obvious difference in the ratio of base excess to lactic acid between those receiv-
(Rooth 1963). On
Fig. 5-Relation between metabolic acidosis foetal umbilical venous blood.
ing bicarbon-
*
and the control group. The mean
x
ate
venous
in
blood and maternal
Untreated mothers (controls). Mothers receiving sodium bicarbonate intra-
venously. Base excess in umbilical vein= 1-3+0-9 base in maternal vein. r=0-81. n=21. p<0-001.
excess
lactic-acid concentration after delivery in the mother and in the cord blood is shown in table II. Discussion
In the maternal blood there is no metabolic acidosis before the onset of labour. Rooth et al. (1961) found a mean base excess of + 0-3 mEq. per litre in the blood of the intervillous space before the onset of labour, and Rooth and Sjostedt (1962) found a mean of +0-2 mEq. per litre in capillary blood. Similar results were obtained by Rossier and Hotz (1953) in arterial blood. The work of Bell et al. (1928), Eastman and McLane (1931), and Hendricks (1957) on lactic acid in foetal metabolism, as well as the measurements of pH and bicarbonate by Vedra (1959,
1960), pointed to increase in metabolic acidosis after delivery. Rooth and Nilsson (1964) found a mean base excess of - 63 mEq. per litre in the antecubital vein of the mothers after delivery. The individual variations revealed little acidosis in un-
an
complicated
these
findings,
therefore, acidosis is not a normal state for the foetus and is not without potential danger. Not only is there clinical evidence, as already suggested, to correlate acidosis and asphyxia but also on chemical grounds acidosis leads to asphyxia, if asphyxia is defined as a state of low pH, highPC02, and decreased oxygen supply to the tissues. The effect of acidosis on pH is obvious, and, if the foetus cannot per unit of time eliminate more carbon dioxide to the mother, the pH decrease will increase Pco2, as can be calculated from the Henderson- Hasselbalch
equation. The close correlation between the fcetal and Fig. 7-Relation between level of metabolic acidosis and lacdc the maternal metabolic acid concentration in umbilical acidosis shows that, in blood (arterial and venous). order to evaluate foetal Untreated mothers (controls), x Mothers receiving sodium bi. acidosis, it is enough carbonate. to measure maternal acidosis. This is now (particularly with the Astrup technique) a simple procedure. The biochemical evidence warrants the statement that measurements of base excess in women in labour will give early information about foetal asphyxia and can have practical applications in the prevention of asphyxia. This may be undertaken either obstetrically or biochemically or by a combination of the two. The obstetrical procedures will, of course, vary from case to case. Because of the time factor the only biochemical
deliveries in
multigravidx but more pronounced acidosis
in primigravidas Fig. 6-Relation between level of metabolic acidosis and lactic acid concentration in maternal venous blood during labour and after delivery. *
x
Untreated mothers (controls). Mothers receiving sodium bicarbonate.
and in complicated deliveries. This study suggests that the onset of maternal metabolic acido-
TABLE
II-MEAN
PH,
CARBON-DIOXIDE
TENSION, AND LACTIC-9Cb
CONCENTRATION AFTER DELIVERY AND IN CORD BLOOD
293
is to give a base intravenously. This was tried HIGH PENICILLINASE PRODUCTION in 11 women. No complications were observed, and the CORRELATED WITH MULTIPLE ANTIBIOTIC effect of bicarbonate on maternal acidosis turned out to be RESISTANCE IN STAPHYLOCOCCUS AUREUS as expected from the calculations. Moreover, the effect M. H. RICHMOND on foetal acidosis was as great as the effect on maternal B.A., Ph.D. acidosis. Maternal and foetal acidosis were reduced by OF THE NATIONAL INSTITUTE FOR MEDICAL RESEARCH, half after the administration of a mean of 60 mEq. of THE RIDGEWAY, MILL HILL, LONDON, N.W.7 bicarbonate. These results also confirm that the fcetal M. T. PARKER acidosis is dominated by maternal acidosis, because the M.D. Cantab., Dip. Bact. foetus must eliminate its hydrogen ions through the mother. M. PATRICIA JEVONS MADELEINE JOHN If the concentration increases in the mother the fcetal level M.D. Lond., Dip. Bact. B.Sc. must obviously increase even more. OF THE CROSS-INFECTION REFERENCE LABORATORY, Although pH is the important reading the discussion COLINDALE, LONDON, N.W.9 has centred on base excess-the metabolic component of IT is widely recognised that the amount of penicillinase the acid-base balance. This seems justified since the Pc02 readings in the venous blood of the mother and in produced by Staphylococcus aureus varies greatly from strain to strain, but little work has been reported in which the umbilical vein are very similar (Rooth et al. 1961, Wulf 1962). Differences in pH will therefore be dominated this variation has been studied by strictly quantitative methods in cultures induced under standard conditions. by base excess differences. The values for PC02 in the group of mothers receiving Ayliffe and Barber (1963), who used a semiquantitative bicarbonate tended to be higher than in the control group, test (Foley and Perret 1962), showed that strains which although it was still lower than in non-pregnant women. were also resistant to other antibiotics were on the whole This indicates that pronounced acidosis stimulates a more active producers of penicillinase than those resistant to penicillin. hyperventilation over and above the " normal " hyper- only The quantity of penicillinase formed (defined here as ventilation of pregnancy. the of enzyme activity per unit mass of culture amount Both maternal and fcetal acidosis depend only to a small at a fixed time after induction) was measured in 181 extent upon lactic acid (Rooth and Nilsson 1963). The traditional opinion that the acidosis of hypoxia is due to epidemiologically independent penicillin-resistant strains lactic acid cannot be upheld. Margaria et al. (1933) seem of Staph. aureus. It ranged from 6 units enzyme per mg. dry weight of organisms to 460 units per mg. Correlation to have come to a similar conclusion from their finding that the disappearance-rate of the acidosis and lactic acid of these results with the phage pattern, and with resistance to other antibiotics and to mercury salts, suggested that were different. The addition of sodium bicarbonate could be expected the"ability to produce much penicillinase was a character only to affect base excess and not the lactic-acid content. of hospital staphylococci ". Materials and Methods In 3 of the women there was relatively much lactic acid after delivery, but, on the whole, the lactic acid decreased Cultures of Staph. aureus The 181 cultures included 162 selected from those examined as well as base excess when bicarbonate was given. This in the Staphylococcus Reference Laboratory during the past suggests that the formation of lactic acid depends more In addition, 8 cultures were obtained from Dr. two years. on pH than on the amount of anaerobic work done by the treatment
tissues. Conclusions
The metabolic acidosis in women after delivery usually begins during the last hours of labour, when the pains are of medium intensity and come at intervals of not more than three minutes. The very strong correlation between fcetal and maternal acidosis implies that fcetal asphyxia can be diagnosed early by measuring maternal metabolic acidosis during labour. Maternal and fcetal acidosis may be reduced by giving sodium bicarbonate intravenously to the mother. One important cause of foetal asphyxia can thus be obviated. The patients investigated were from the department of obstetrics and gynaecology in the University Hospital, and I am grateful to Prof. Alf Sj6vall for the facilities The assistance of the midwives, particularly Miss Anna Greta S-ensson, R.N., is very much appreciated. Finally, my thanks are due to Miss Vivi Ann Nilsson for technical assistance. The study was supported by a grant from the Association for the Aid of Crippled Children, New York. Polythiazide (’ Renese’)was supplied by Pfizer A.B., Stockholm.
Mary Barber, Postgraduate Medical School, Ducane Road, Hammersmith, London; 8 cultures (nos. 95, 107, 118, 147, 171, 172, 177, 178) from Dr. M. Bergdoll, University of Chicago; 1 (strain U9) from Dr. P. A. Pattee, Department of Bacteriology, Ohio State University (see Pattee and Baldwin 1961); 1 from Prof. K. Eriksen, Universitetets Institut for Almindelig Pathologi, Copenhagen; and 1 from Dr. J. Harding, Central Middlesex Hospital, London. The standard " strain came from the collection of organisms in the bacterial (524/SC)
division of the National Institdte for Medical Research at Mill Hill (Rogers 1953, Novick 1962, NI 524 in Ayliffe and Barber 1963). They were all phage-typed by the method of Blair and Williams (1961). All the strains were epidemiologically " independent ": that is to say, no two cultures from one hospital or geographical district had the same phage-typing pattern. They were not, however, selected at random, and do not necessarily reflect the characters of penicillin-resistant strains found in the general population. Rather, they consisted of a series of separate collections of cultures with common characters, which were
physiology
REFERENCES
Astrup, P., Jorgensen, K., Siggaard Andersen, O., Engel, K. (1960) Lancet, i, 1035. Bell, W. B. Cunningham, L., Jowett, M., Millet, H., Brooks, J. (1928) Brit. med. J. i, 126. Eastman, N. J., McLane, C. M. (1931) Bull. Johns Hopk. Hosp. 48, 261. Engstrom, L., Karlberg, P., Rooth, G., Tynell, R. (1963) Acta pædiat., Stockh. (in the press). Goodlin, R. C., Kaiser, J. H. (1957) Amer. J. med. Sci. 233, 662. Hendricks, C. H. (1957) Amer. J. Obstet. Gynec. 73, 492. Margaria, R., Edwards, H. T., Dill, D. B. (1933) Amer. J. Physiol. 106, 689.
Rooth, G. (1963) Amer. J. Obstet. Gynec. 85, 78. (1963) Unpublished. Caligara, F. (1961) ibid. 36, 278. Furst, C. (1963) Unpublished. Nilsson, I. (1964) Clin. Sci. (in the press). Sjostedt, S. (1962) Arch. Dis. Childh. 37, 366. Rossier, P. H., Hotz, M. (1953) Schweiz. med. Wschr. 83, 897. Vedra, B. (1959) Acta Pædiat., Stockh. 48, 60. (1960) Biol. Neonat., Basle, 2, 121. Weisbrot, I. M., James, L. S., Prince, C. E., Holaday, D. A., Apgar, V. (1958) J. Pediat. 52, 395. Wulf, H. (1962) Z. Geburtsh. Gynk. 158, 117. —
—
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—
—
—
0-06 pH units, which favours elimination of the hydrogen ion in the foetus. In the present study two ways of influencing the metabolic component of the acid-base balance were tried: in a preliminary series, mothers were given one of the modern diuretics; and in the main series sodium bicarbonate was administered. Earlier observations (Rooth 1963) had shown that when mothers were given some of the modern oral diuretics known to induce metabolic alkalosis the infant might be born with a slight alkalosis instead of the usual acidosis. In the preliminary work, 30 women in labour were alternatively given polythiazide or made to serve as controls. The selection was random. Owing to the small number in the series, more mothers had inertia and there were more primigravidæ in the polythiazide group than among the controls. Both these factors would make the polythiazide group more acid than the controls (Rooth and Nilsson 1964), Base excess was measured in the blood of the antecubital vein and in the umbilical venous blood of the mothers as soon as possible after delivery. The mean base excess in 14 women receiving polythiazide was - 7 -mEq. per litre in venous blood and -4-9 mEq. per litre in the umbilical venous blood. In the 16 women who were controls, the mean base excess was - 5,5 mEq. per litre both in venous blood and in umbilical venous blood. Thus, the mothers in the polythiazide group were slightly more acidotic than the controls. This, as stated, could have been due to the differences in labour. Nevertheless, the results showed that polythiazide given to the mother after she had arrived in the labour room did not make her alkalotic enough to reduce her acidosis. This was doubtless because there was not enough time for polythiazide to produce alkalosis, since it took seven to ten days before alkalosis reached its height (Rooth and Fiirst 1963).
period was also studied. 4 of 212 male babies were chromatin-positive, but no chromosome studies were possible. 1 of 185 female babies was chromatin-negative and had
an
XO sex-chromosome constitution.
The survey was made possible by a grant from the Medical Research Council for technical assistance and expenses to one of us (N. M.), and by the cooperation of the nursing staffs of the maternity units who were responsible for taking the buccal smears. For this essential assistance we are most grateful. We are indebted to Miss S. Brunton, Miss M. Brunton, and Mrs. C. Cowen for their technical assistance with the chromosome studies, and to Miss M. Luff and Miss H. MacFarlane for other technical assistance. Laboratory facilities and administrative help were provided by the board of management of the Edinburgh Northern Group of Hospitals, and we are indebted to Dr. A. J. M. Drennan for making the laboratory facilities available at the Western General Hospital. We would like to thank Dr. J. W. Farquhar, Dr. J. 0. Forfar, Dr. A. Keay, Dr. J. A. McBride, Dr. D. T. D. Nicholson, Dr. D. M. Douglas, Dr. J. W. Worling, Dr. J. Y. MacDougall, Dr. M. D. Black, and Dr. J. 0. Craig for their interest and their help in many ways in furthering the investigation. For allowing us to carry out the survey we are grateful to Dr. A. F. Anderson, Dr. W. D. A. Callam, Prof. R. W. B. Ellis, Dr. W. F. Flint, Dr. D. J. M. Irvine, Prof. R. J. Kellar, Dr. C. D. Kennedy, Dr. E. Little, Dr. J. D. 0. Loudon, Dr. J. E. W. Mackie, Dr. T. N. MacGregor, Dr. G. D. Matthew, Dr. P. R. Myerscough, Dr. S. J. Patterson, Dr. M. G. Pearson, Dr. J. Sturrock, and Dr. R. A. Tennent. REFERENCES
Bergeman, E. (1961) Schweiz. med. Wschr. 10, 292. Carr, D. H. (1963) Lancet, ii, 603. de la Chapelle, A. (1962) Acta endocr., Copenhagen, 40, suppl. 65. Gartler, S. M., Waxman, S. H., Giblett, E. (1962) Proc. nat. Acad. Sci. 48, 332. Harnden, D. G. (1960) Brit. J. exp. Path. 41, 31. Jacobs, P. A., Harnden, D. G., Court Brown, W. M., Goldstein, J., Close, H. G., MacGregor, T. N., Maclean, N., Strong, J. A. (1960) Lancet, i, 1213.
Buckton, K. E., Court Brown, W. M., King, M. J., McBride, J. A., MacGregor, T. N., Maclean, N. (1961) ibid. i, 1183. Maclean, N., Harnden, D. G., Court Brown, W. M. (1961) ibid. ii, 406. Moore, K. L. (1959) ibid. i, 217. Barr, M. L. (1955) ibid. ii, 57. Moorhead, P. S., Nowell, P. C., Mellman, W. J., Battips, D. M., Hungerford, D. A. (1960) Exp. Cell. Res. 20, 613. Naik, S. H., Shah, P. N. (1962) Science, 136, 1116. Ross, A. (1960) J. med. Lab. Tech. 17, 178. —
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—
EARLY DETECTION AND PREVENTION OF FŒTAL ACIDOSIS
Material and Methods in labour were studied. 12 served as controls and 11 were given sodium bicarbonate; after the first blood-sample was obtained the standard solution of the hospital, containing 155 mEq. per litre, was used. Between 100 and 1900 ml. was administered intravenously in the course of half an hour to twenty-five hours. The mean rate of infusion was 2.5 ml, per min. and the fastest rate was 6 ml. per min. The women selected were those who were expected to remain in labour for some hours so that there would be time enough to study them, There were 7 primigravidae in each group. All were vertex deliveries, except 1 breech delivery in the control group, In each group there were 2 cases of inertia corrected by oxytocin in the form of ’Partoten ’ sniffs. For analgesia trichloroethylene (’ Trilene ’) or nitrous oxide was used with equal frequency in both groups. In most cases a small dose of chloroform was given at the moment of delivery, Repeated blood-samples were taken from the antecubital vein of the mother during labour, and as soon as possible after delivery and always within three minutes. Samples were also taken from clamped sections of the umbilical vessels. The blood was analysed for base excess and lactic acid, and (when the samples were secured anaerobically) pH as well. From this Pc02 could be calculated. Standard corrections were made for calculating Pco,. The maternal blood was assumed to be 50% unsaturated, the umbilical venous blood 35%, and the arterial 23
GÖSTA ROOTH M.D.
From the Aid of Crippled Children Laboratory, Department of Internal Medicine, and Department of Obstetrics and Gynæcology, University Hospital, Lund, Sweden
THE clinical signs of foetal asphyxia-i.e., slow or irregular foetal heart-sounds-appear late, and there is real need for its early diagnosis and prevention. Weisbrot et al. (1958) were the first to emphasise that foetal metabolic acidosis is more pronounced when there are signs of asphyxia. Thus, if foetal metabolic acidosis could be determined before delivery, asphyxia might be anticipated and prevented. Since foetal acidosis is mainly caused by maternal metabolic acidosis (Vedra 1959, 1960, Rooth and Nilsson 1964) it should be detectable by measurements of the maternal acidosis before delivery, and if maternal acidosis could be reduced foetal acidosis, too, should be reduced. Goodlin and Kaiser (1957) showed that the fcetal acidosis was increased if the mother was rendered acidotic by ammonium chloride; hence there is reason to believe that if the maternal pH were moved in the alkaline direction the foetal acidosis would be reduced. This is, in fact, what happens normally in pregnancy when the respiratory component (Pc02) of the acid-base balance comes into play. Pco2 is about 32 mm. Hg in the pregnantv woman, compared with 40 mmm. Hg in non-pregnant subjects. This gives a pH increase in the mother of’ ’
women
blood 65%. Base excess is the metabolic component in the acid-base balance and gives in mEq. per litre the addition of base or aod to the whole blood. Negative figures denote a metabolic acidosis. pH, Pc02, and base excess were measured according to the technique of Astrup et al. (1960). Lactic acid was measured by means of the lactic-acid-dehydrogenase method, the commercial reagents Biochemica Boehringer being used.
I
291
Fig. 3-Metabolic acidosis in maternal venous blood during labour and after delivery in mothers receiving sodium bicarbonate intravenously. Sodium bicarbonate was given as soon as the first sample was obtained. The interrupted line indicates discontinuation of the drip.
Fig. I-Metabolic acidosis in maternal venous blood during labour and after delivery in untreated mothers (controls). Results
Fig. 1 shows that the maternal metabolic acidosis usually appears during the last two hours of labour. The onset of the acidosis was also related to clinical signs. The intensity of the pains was graded 1=slight, 2 = medium, and 3=strong; and this figure was divided by the interval in minutes between the onset of the pains. This gave a numerical index of the amount of work done per unit of time by the mother during labour. As is shown in fig. 2, the acidosis usually began at an index of about 1.
Mdosis, therefore, only began when the pains were of at least medium intensity. When the mothers were given sodium bicarbonate their metabolic acidosis
was
reduced.
Figs. 3 and 4, which
correspond to figs. 1 and 2 in the
untreated
group,
bring
out these differences.
Pairing
the controls and the treated women and testing the values at two hours and one hour before delivery and after delivery with sequence analyses, the Fig. 2-Relation between metabolic acidosis treated group in maternal venous blood and " labour is significantly index " in untreated mothers (controls). less acidotic at a 1% level. The mean base excess two hours before delivery was -4-7 mEq. per litre against --21 in the treated group. One hour before delivery the corresponding values were -5-7 and -3-6 mEq. per litre and after delivery —10-0;, against -4-5 mEq. per litre. The mean base excess at index 1-0 in the untreated group was - 4-5 mEq. per litre against -2,4 in the group receiving sodium bicarbonate. Using sequence analyses the paired differences were significant at the 1% level. 2 of the women on bicarbonate had a labour index of about 1-0 for almost twenty-four hours, and despite this they showed no increase in acidosis. The effect of the bicarbonate may also be calculated from the amount of bicarbonate given; had none been administered the 11 treated women would have had somewhat more acidosis than the 12 control women.
The base excess in the cord blood is shown in table I. The mean base excess value in the umbilical veins is - 10-0 in the control series against - 5-5 mEq. per litre in the treated group. Corresponding values for the umbilical artery are -13-7 and -6-7 mEq. per litre. These differences are also
statistically significant. Table
II
gives the values for pH and Pc02 after delivery in the women receiving bicarbonate as well as in the controls. The mean
Pc02s was higher in the group receiv-
in maternal venous blood and "labour index" in mothers receiving sodium bicarbonate
Fig. 4-Relation between metabolic acidosis intravenously.
Sodium bicarbonate was given as soon as the first sample was obtained. The interrupted line
indicates discontinuation of the drip.
ing bicarbonate, though the differences are not significant. The data also confirm the strong correlation between the levels of maternal and fcetal metabolic acidosis as measured in the umbilical vein (fig. 5). The series is obviously too small for assessing the clinical effect of bicarbonate administration on the foetus. Still, there were 4 instances of meconium-stained amniotic fluid in the control group against only 1 in the bicarbonate group. (This does not include the breech delivery in the control group.) The relation between base excess and lactic acid in the maternal blood and in the cord blood is shown in figs. 6
(mEq. per litre) IN UMBILICAL VENOUS AND ARTERIAL BLOOD OF MOTHERS AFTER BICARBONATE ADMINISTRATION TABLE I-BASE EXCESS
*
On chlorthalidone 25 mg.
daily during
the last
two
weeks of pregnancy.
t On hydrochlorthiazide 50 mg. daily duringthe last tv
292
sis and its presence can be gauged by the intensity and the frequency of the pains. Maternal and fcetal acidosis, therefore, predominantly results from labour at a time when the maternal muscular effort becomes so great that the oxygen demand by her working tissues cannot be met. This is in agreement with the absence of foetal acidosis after elective cxsarean section (Engstrom et al. 1963) and increased acidosis in the foetus when the mother has been made hypoxic by the administration of nitrous oxide
and 7. Both in the maternal blood and in the cord blood the acidosis is seen to be due only to a
small extent to lactic acid.
Moreover, there is no obvious difference in the ratio of base excess to lactic acid between those receiv-
(Rooth 1963). On
Fig. 5-Relation between metabolic acidosis foetal umbilical venous blood.
ing bicarbon-
*
and the control group. The mean
x
ate
venous
in
blood and maternal
Untreated mothers (controls). Mothers receiving sodium bicarbonate intra-
venously. Base excess in umbilical vein= 1-3+0-9 base in maternal vein. r=0-81. n=21. p<0-001.
excess
lactic-acid concentration after delivery in the mother and in the cord blood is shown in table II. Discussion
In the maternal blood there is no metabolic acidosis before the onset of labour. Rooth et al. (1961) found a mean base excess of + 0-3 mEq. per litre in the blood of the intervillous space before the onset of labour, and Rooth and Sjostedt (1962) found a mean of +0-2 mEq. per litre in capillary blood. Similar results were obtained by Rossier and Hotz (1953) in arterial blood. The work of Bell et al. (1928), Eastman and McLane (1931), and Hendricks (1957) on lactic acid in foetal metabolism, as well as the measurements of pH and bicarbonate by Vedra (1959,
1960), pointed to increase in metabolic acidosis after delivery. Rooth and Nilsson (1964) found a mean base excess of - 63 mEq. per litre in the antecubital vein of the mothers after delivery. The individual variations revealed little acidosis in un-
an
complicated
these
findings,
therefore, acidosis is not a normal state for the foetus and is not without potential danger. Not only is there clinical evidence, as already suggested, to correlate acidosis and asphyxia but also on chemical grounds acidosis leads to asphyxia, if asphyxia is defined as a state of low pH, highPC02, and decreased oxygen supply to the tissues. The effect of acidosis on pH is obvious, and, if the foetus cannot per unit of time eliminate more carbon dioxide to the mother, the pH decrease will increase Pco2, as can be calculated from the Henderson- Hasselbalch
equation. The close correlation between the fcetal and Fig. 7-Relation between level of metabolic acidosis and lacdc the maternal metabolic acid concentration in umbilical acidosis shows that, in blood (arterial and venous). order to evaluate foetal Untreated mothers (controls), x Mothers receiving sodium bi. acidosis, it is enough carbonate. to measure maternal acidosis. This is now (particularly with the Astrup technique) a simple procedure. The biochemical evidence warrants the statement that measurements of base excess in women in labour will give early information about foetal asphyxia and can have practical applications in the prevention of asphyxia. This may be undertaken either obstetrically or biochemically or by a combination of the two. The obstetrical procedures will, of course, vary from case to case. Because of the time factor the only biochemical
deliveries in
multigravidx but more pronounced acidosis
in primigravidas Fig. 6-Relation between level of metabolic acidosis and lactic acid concentration in maternal venous blood during labour and after delivery. *
x
Untreated mothers (controls). Mothers receiving sodium bicarbonate.
and in complicated deliveries. This study suggests that the onset of maternal metabolic acido-
TABLE
II-MEAN
PH,
CARBON-DIOXIDE
TENSION, AND LACTIC-9Cb
CONCENTRATION AFTER DELIVERY AND IN CORD BLOOD
293
is to give a base intravenously. This was tried HIGH PENICILLINASE PRODUCTION in 11 women. No complications were observed, and the CORRELATED WITH MULTIPLE ANTIBIOTIC effect of bicarbonate on maternal acidosis turned out to be RESISTANCE IN STAPHYLOCOCCUS AUREUS as expected from the calculations. Moreover, the effect M. H. RICHMOND on foetal acidosis was as great as the effect on maternal B.A., Ph.D. acidosis. Maternal and foetal acidosis were reduced by OF THE NATIONAL INSTITUTE FOR MEDICAL RESEARCH, half after the administration of a mean of 60 mEq. of THE RIDGEWAY, MILL HILL, LONDON, N.W.7 bicarbonate. These results also confirm that the fcetal M. T. PARKER acidosis is dominated by maternal acidosis, because the M.D. Cantab., Dip. Bact. foetus must eliminate its hydrogen ions through the mother. M. PATRICIA JEVONS MADELEINE JOHN If the concentration increases in the mother the fcetal level M.D. Lond., Dip. Bact. B.Sc. must obviously increase even more. OF THE CROSS-INFECTION REFERENCE LABORATORY, Although pH is the important reading the discussion COLINDALE, LONDON, N.W.9 has centred on base excess-the metabolic component of IT is widely recognised that the amount of penicillinase the acid-base balance. This seems justified since the Pc02 readings in the venous blood of the mother and in produced by Staphylococcus aureus varies greatly from strain to strain, but little work has been reported in which the umbilical vein are very similar (Rooth et al. 1961, Wulf 1962). Differences in pH will therefore be dominated this variation has been studied by strictly quantitative methods in cultures induced under standard conditions. by base excess differences. The values for PC02 in the group of mothers receiving Ayliffe and Barber (1963), who used a semiquantitative bicarbonate tended to be higher than in the control group, test (Foley and Perret 1962), showed that strains which although it was still lower than in non-pregnant women. were also resistant to other antibiotics were on the whole This indicates that pronounced acidosis stimulates a more active producers of penicillinase than those resistant to penicillin. hyperventilation over and above the " normal " hyper- only The quantity of penicillinase formed (defined here as ventilation of pregnancy. the of enzyme activity per unit mass of culture amount Both maternal and fcetal acidosis depend only to a small at a fixed time after induction) was measured in 181 extent upon lactic acid (Rooth and Nilsson 1963). The traditional opinion that the acidosis of hypoxia is due to epidemiologically independent penicillin-resistant strains lactic acid cannot be upheld. Margaria et al. (1933) seem of Staph. aureus. It ranged from 6 units enzyme per mg. dry weight of organisms to 460 units per mg. Correlation to have come to a similar conclusion from their finding that the disappearance-rate of the acidosis and lactic acid of these results with the phage pattern, and with resistance to other antibiotics and to mercury salts, suggested that were different. The addition of sodium bicarbonate could be expected the"ability to produce much penicillinase was a character only to affect base excess and not the lactic-acid content. of hospital staphylococci ". Materials and Methods In 3 of the women there was relatively much lactic acid after delivery, but, on the whole, the lactic acid decreased Cultures of Staph. aureus The 181 cultures included 162 selected from those examined as well as base excess when bicarbonate was given. This in the Staphylococcus Reference Laboratory during the past suggests that the formation of lactic acid depends more In addition, 8 cultures were obtained from Dr. two years. on pH than on the amount of anaerobic work done by the treatment
tissues. Conclusions
The metabolic acidosis in women after delivery usually begins during the last hours of labour, when the pains are of medium intensity and come at intervals of not more than three minutes. The very strong correlation between fcetal and maternal acidosis implies that fcetal asphyxia can be diagnosed early by measuring maternal metabolic acidosis during labour. Maternal and fcetal acidosis may be reduced by giving sodium bicarbonate intravenously to the mother. One important cause of foetal asphyxia can thus be obviated. The patients investigated were from the department of obstetrics and gynaecology in the University Hospital, and I am grateful to Prof. Alf Sj6vall for the facilities The assistance of the midwives, particularly Miss Anna Greta S-ensson, R.N., is very much appreciated. Finally, my thanks are due to Miss Vivi Ann Nilsson for technical assistance. The study was supported by a grant from the Association for the Aid of Crippled Children, New York. Polythiazide (’ Renese’)was supplied by Pfizer A.B., Stockholm.
Mary Barber, Postgraduate Medical School, Ducane Road, Hammersmith, London; 8 cultures (nos. 95, 107, 118, 147, 171, 172, 177, 178) from Dr. M. Bergdoll, University of Chicago; 1 (strain U9) from Dr. P. A. Pattee, Department of Bacteriology, Ohio State University (see Pattee and Baldwin 1961); 1 from Prof. K. Eriksen, Universitetets Institut for Almindelig Pathologi, Copenhagen; and 1 from Dr. J. Harding, Central Middlesex Hospital, London. The standard " strain came from the collection of organisms in the bacterial (524/SC)
division of the National Institdte for Medical Research at Mill Hill (Rogers 1953, Novick 1962, NI 524 in Ayliffe and Barber 1963). They were all phage-typed by the method of Blair and Williams (1961). All the strains were epidemiologically " independent ": that is to say, no two cultures from one hospital or geographical district had the same phage-typing pattern. They were not, however, selected at random, and do not necessarily reflect the characters of penicillin-resistant strains found in the general population. Rather, they consisted of a series of separate collections of cultures with common characters, which were
physiology
REFERENCES
Astrup, P., Jorgensen, K., Siggaard Andersen, O., Engel, K. (1960) Lancet, i, 1035. Bell, W. B. Cunningham, L., Jowett, M., Millet, H., Brooks, J. (1928) Brit. med. J. i, 126. Eastman, N. J., McLane, C. M. (1931) Bull. Johns Hopk. Hosp. 48, 261. Engstrom, L., Karlberg, P., Rooth, G., Tynell, R. (1963) Acta pædiat., Stockh. (in the press). Goodlin, R. C., Kaiser, J. H. (1957) Amer. J. med. Sci. 233, 662. Hendricks, C. H. (1957) Amer. J. Obstet. Gynec. 73, 492. Margaria, R., Edwards, H. T., Dill, D. B. (1933) Amer. J. Physiol. 106, 689.
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