Plasma nonesterified fatty acid and blood glucose levels in healthy and hypoxemic newborn infants

Transcription

1 FETAL AND MEDICINE NEONATAL Richard E. Behrman, Editor Plasma nonesterified fatty acid and blood glucose levels in healthy and hypoxemic newborn infants BIood glucose and plasma NEFA levels were determined during the first 72 hours of life in 240 healthy and hypoxemic babies of varying birth weight and gestation. In the healthy babies, an initial fall in blood glucose during the first hours of life coincided with a rise in plasma NEFA levels. Thereafter the levels of both substances gradually rose. In term babies the rise of plasma NEFA was greater than in the two group of low-birth-weight babies. The effects of hypoxemia were different in the three groups of babies studied. There appeared to be a defect in fatty acm mobilization and~or metabolism in the hypoxemic term infant. This defect appeared to be already present in both AGA and SGA neonates, and hypoxemia did not further compromise glucose or NEFA homeostasis. The effect was to cause lower blood glucose and plasma NEFA levels in hypoxemic term infants when compared with healthy control infants. The clinical implication is that term babies who suffer from birth asphyxia are at risk of developing significant hypoglycemia and should be managed by early and frequent feeding. Roger J. Harris, M.D., M.R.C.P. (U.K.), D.C.H., Bristol England THE RELATIONSHIP between the blood levels of glucose and NEFA, at least in the newborn period, is incompletely understood. It has been shown that there is a rise in plasma NEFA levels immediately after birth, 1 coinciding with a fall in blood glucose levels. 2-4 In adults NEFA may exert a glucose-sparing action. 5 It is not clear whether this relationship applies to the newborn infant. It is the purpose of the present communication to show the trend of blood glucose and plasma NEFA levels in term, AGA preterm, and SGA babies, and the effect of hypoxemia on this trend. METHODS Babies studied. Table I gives details of the 240 babies studied. They were born at Southmead General Hospital or the Bristol Maternity Hospital, and nursed in the respective special care baby units and neonatal nuts- From the Department of Child Health, Southmead General Hospital, Bristol, and the United Bristol Hospitals. Reprint address: Department of Child Health, King's College Hospital London, S.E.S, England eries. A few babies were born at home and transferred to one of the units. All the babies studied had rectal temperatures between 35 ~ and 37.5 ~ C. at the time of sampling. All procedures were performed on babies just prior to a feed. Table II gives the feeding schedules of the different groups of babies studied. At the time of the survey SGA babies were fed within 2 hours of birth with 5 or 10 per cent dextrose and subsequently at two or Abbreviations used NEFA: nonesterified fatty acids AGA: appropriate for gestational age SGA: small for gestational age IRDS: idopathic respiratory distress syndrome three hourly intervals, depending on birth weight or gestational age, for three feeds, and subsequently with breast milk, to a minimum volume of 70 ml. per kilogram per 24 hours on Day 1,110 ml. per kilogram per 24 hours on Day 2, and 150 ml. per kilogram per 24 hours on Day 3. AGA preterm babies were fed by a similar regimen, but smaller volumes were used after the VoL 84, No. 4, pp

2 Volume 84 Fatty acid and blood glucose levels Number 4 Table I. Details of babies in the three groups studied Mean birth Group Healthy weight (grn.) 1 S.E. Hypoxemw Mean birth weight (gm.) 1 S.E. Term: Infants born after 60 the 37th week of gestation, appropriate weight for dates Preterm (AGA): Infants 40 born before the 37th week of gestation, appropriate weight for dates SGA: Term infants whose 80 birth weight was below the 10th percentile for gestation on the data of the British Perinatal Mortality Survey 6 3, " 3, , t 2, ,840 17" 1,630 *Babies who had suffered birth asphyxia, requiring intubation and intermittent positive pressure ventilation for resuscitation. ~'Babies suffering from IRDS, requiring oxygen to maintain PAo2 ) 60 ram. Hg (see text). Table II. Daily fluid and calorie intake of the babies studied who were normoglycemic Day 1 Day 2 Day3 CalorieslKg./ 24 hr. ml/kg./ 24 hr. Calories/Kg./ ml./kg./ 24 hr. 24 hr. CalorieslKg./ mlikg./ 24 hr. 24 hr. Healthy term 26 60* Hypoxemic term 36 70* Healthy AGA 26 60* Hypoxemic AGA 36 70* Healthy SGA 45 70* Hypoxemic SGA *Extra fluid, either dextrose or breast milk, was given to any baby with a low recording Dextrostix measurement. The calories and fluid volumes on the first day are accordingly minimum values, first day of life in order to reach 150 ml. per kilogram per 24 hours by Day 5. Babies of birth weight below 1,250 grams were fed at two hourly intervals. The decision to feed SGA babies at two hourly intervals was guided by the Dextrostix test. If this recorded 20 to 40 mg. per cent, then two hourly feeding was instituted, increasing the fluid volume by 15 ml. per kilogram per 24 hours. In the series no babies were fed hourly or by continuous intragastric infusion. Healthy term babies were all fed within 6 hours of birth 60 ml. per kilogram per 24 hours on Day 1, 90 ml. per kilogram per 24 hours on Day 2, and 120 ml. per kilogram per 24 hours on Day 3. Hypoxemic babies of all three groups were fed immediately after birth, if SGA similar volumes to their healthy conterparts and if term or AGA more. (See Table II.) All AGA and hypoxemic babies, as well as any baby showing a disinclination to suck, were fed via and indwelling nasogastric catheter. No babies in this series received intravenous feed. For the purposes of this series, a baby was considered hypoxemic if the Po 2 was ( 60 mm. Hg. in umbilical or radial artery blood. All of the hypoxemic AGA babies required oxygen at varying concentrations to maintain adequate arterial oxygen saturation (PA02)60 mm. Hg) for 48 hours in 14 and 72 hours in 11. Twelve of the hypoxemic term babies and thirteen of the SGA babies re-

3 58 0 Harris The Journal of Pediatrics April 1974 Table III. Blood glucose and plasma NEFA values in term, preterm, and small-for-dates neonates during the first 72 Type of baby 7 Cord 3 hr. 6 hr. 12 hr. 24 hr. 48 hr. Term: a. Healthy , b. Hypoxemic _ Statistical analysis a. v b. P = ( (0.01 (0.01 (0.001 Preterm: c, Healthy * d. Hypoxemic l Statistical analysis c. v d. P = N,S. Small for dates: e. Healthy " ~ 3.2* * f. Hypoxemic Statistical analysis e. v f. P = ( 0.01 ( 0.01 (0.05 Statistical analysis: P values obtained using student t test, = not significant. (P).0,05.) Level of statistical significance for comparison of healthy term babies and healthy pre-term and small for dates babies: *P ~ ( 0.05; ~P = ( 0,01; *P = ( If no indication, the difference was not significant. quired a low oxygen concentration in the inspired air (( 40 per cent) to prevent the continuing hypoxemia or hypercapnia (PAc02) 60 ram. Hg) for varying periods up to 48 hours after birth. Babies requiring ventilation have not been included in the series. Sampling and chemical methods. Cord blood samples were obtained from all babies, and a further 1.5 ml. venous blood was taken at 3, 6, and 12 hours of age in all. Two hundred and thirty nine babies were venesected at 24 hours, 236 at 48 hours, and 234 at 72 hours. The other babies not included had died (see result section). All samples were placed in bottles containing fluoride with oxalate. Blood glucose estimations were performed within 2 hours of sampling by using a modified glucose oxidase method7; the remainder of the blood was centrifuged and the plasma stored at --20 ~ C. NEFA estimations were performed in duplicate within one week of separation by the Duncombe colorimetric micromethod.8 RESULTS Table IIl shows the changes of blood glucose and plasma NEFA 1 S.E. in the six groups of babies during the first 3 days of life. Healthy babies. Blood glucose fell initially in all babies for 3 to 6 hours before a rise occurred. At 3 hours the levels were significantly lower in both groups of low-birth-weight babies compared with term babies, but thereafter the blood glucose in AGA babies rose to similar levels to those of term infants. The levels in SGA babies remained lower, the difference being significant at 48 and 72 hours of age. Plasma NEFA rose immediately after birth in all of the babies, but the rise in the low-birth-weight babies was less than in the term ones, the difference being significant at all ages except 24 hours in AGA babies. Hypoxemic babies. The effects of hypoxemia were different in the three groups of babies. Compared with healthy term infants, the hypoxemic ones had significantly lower levels of both blood glucose and plasma NEFA throughout the first three days of life. The results in hypoxemic AGA babies, however, were similar to those in healthy AGA ones. In hypoxemic SGA babies there was a significantly greater fall in blood glucose at 3 hours, but thereafter both blood glucose and plasma NEFA were higher than in the healthy SGA babies, the difference being significant at 24 hours for blood glucose and plasma NEFA and at 48 hours for blood glucose. Mortality. Of the babies included in the series, six died. All were in the hypoxemic group. None of the deaths could be attributed to early feeding or to the volumes used. Table IV shows the details of the six babies who died. In addition, one baby died at 11 days with an E. colisepticemia. This baby had not had umbilical catheters inserted and had given no cause for concern until the ninth day. Her gestation period was 32 weeks; her weight 1,350 grams.

4 Volume 84 Fatty acid and blood glucose levels Number 4 hours of life Mean plasma NEFA level OzM/liter) 1 S.E. 72 hr. Cord 3 hr. 6 hr. 12 hr. 24 hr. 48 hr. 72 hr _ _ (0.05 ( _ <0.05 <0.01 <0.01 ( ' * _ 22.6~ ' _+ 17.7" _ _ " _ ~ ' ~" t * N S. (0.05 DISCUSSION The blood glucose levels of the healthy babies in the present series were in general agreement with previous reports,2-4, 9-11 with the exception that at 6 hours of age low-birth-weight babies had similar blood glucose levels to normally grown infants. There is no clear explanation for this, but it may be a consequence of early feeding; it has been shown 12 that there was no appreciable fall in blood glucose levels postnatally in babies fed from birth, irrespective of birth weight or gestational age. Hypoxemia has the effect of decreasing the blood glucose throughout the first 72 hours of life in term infants with less effect in AGA and SGA infants as compared with their respective control groups. The hypoxemic SGA infants, after an initial rapid fall in blood glucose, had higher levels than healthy control infants. Hypoxemic AGA infants had blood glucose levels similar to healthy control infants. However, in this group, the range of blood glucose at different ages tended to be wide and occasional examples of hypoglycemia were seen. It has been shown ~3,14 that hypoglycemia occurred in infants following birth asphyxia and also in AGA infants suffering from IRDS; other workers have disputed this. Is In the present series, whereas the majority of babies with IRDS remained normoglycemic, an occasional baby developed potentially dangerous blood glucose levels. Thus these babies must be considered "at risk" with regard to developing hypoglycemia. Previously reported plasma NEFA levels in normal babies ~, t6, 17 have shown much greater postnatal rises than in the present series. The explanation of this apparent discrepancy is by no means clear, but three factors may play a part. (1) There is an important methodological difference; the Duncombe colorimetric micromethod used in the present series measures fatty acids of chain length C10-C18, whereas the methods employed in the above series were titrimetric methods, which also measure medium- and short-chained acids. (2) All term babies in the present series were fed by 6 hours of age, whereas in the series referred to above, no baby was fed before 12 hours of age. It has been shown ~8 that the administration of glucose early in life results in a fall of plasma NEFA levels. (3) With more attention being paid to maintaining adequate environmental temperature, fewer babies were exposed to thermal stress. Therefore, there may be a reduction in the amount of lipid mobilized from brown adipose tissue, and this may be reflected by the lower plasma NEFA levels demonstrated. However, it has been reported ~9 that in healthy babies, temperature played little part in influencing plasma NEFA levels, at least during the first 2 hours of life. There are few reports of plasma NEFA levels in healthy low-birth-weight babies. Higher levels than those seen in term babies were reportedj 8, 20, 21 Plasma ketone bodies have also been shown to rise more in

5 5 8 2 Harris The Journal of Pediatrics April 1974 Table IV. Summary of babies who died No. Age at death (hr.) Gestation Birth weight (grams) 85O 2, , , , ,300 Autopsy findings Atelectasis and immaturity Hyaline membrane disease and subarachnoid Pulmonary alveolar Hyaline membrane disease and intraventricular Hyaline membrane disease and intraventricular Bilateral tentorial tears and subdural hematoma "dysmature" and preterm AGA babies. 2] However, in the present series lower plasma NEFA levels were reported in both groups of low-birth-weight babies. There do not appear to be any similar findings reported in the literature, although low plasma NEFA levels at 2, 8, and 12 hours of age were reported in babies born of mothers suffering from severe pre-exclampsia17; however, the birth weights of the babies concerned were not indicated. Also, in the present series, there was little further rise in plasma NEFA levels after 12 hours of age in the healthy SGA neonate. It is likely that keeping the babies warm and providing adequate nutrition were the major factors accounting for these results. There are few reports on the effect of hypoxemia on the postnatal elevation of plasma NEFA levels. Low levels were demonstrated in babies at 2 and 12 hours of age who had a delay in breathing of at least 2 minutes after birth. 17 The results obtained in the hypoxemic term infants of the present series would tend to be in agreement with these findings. However, it has been shown 22 that following mild asphyxia, there was a much greater rise in plasma NEFA levels than was seen in four babies who died following severe perinatal asphyxia. It has been shown recently that acidosis and hypercapnia had no appreciable effect on the postnatal elevation of plasma NEFA levels, ]9 at least over the first 2 hours of life. Certainly this appeared to be the case with the hypoxemic AGA babies in the present series; however, in the case of the hypoxemic SGA babies of the present series, there was a slightly greater elevation of the plasma NEFA levels compared with healthy control infants. In early neonatal life, the newborn infant conserves carbohydrate for essential cerebral metabolism. Although it has been suggested that lactate 23 or glycerol and ketone bodies 24 may be utilized by the neonatal brain, definite confirmation is lacking. It, therefore, seems that glucose is the sole metabolic fuel accessible to the brain. Respiratory quotient studies 25, 26 have suggested that the metabolism of the newly born infant rapidly becomes lipid based. This change may be reflected in the rapid postnatal elevation of plasma NEFA levels. Adequate circulating levels of NEFA exert a glucose-sparing action via the glucose-fatty acid cycles; this results in diminished peripheral utilization of glucose, thereby making more glucose available for metabolism in the brain. Immediate availability of NEFA is more essential in the low-birth-weight baby. All have markedly reduced amounts of carbohydrate in the body stores 27 ; in addition, the SGA baby has a relatively large brain:liver ratio, 28 which throws greater demands on the carbohydrate stores; they also have an increased basal metabolic rate when compared with AGA and term babies. 29 It is, perhaps, rather suprising that in the present series there is a relatively poor postnatal rise in plasma NEFA levels. The influence of warmth and early feeding has already been commented on, but a failure of tipolysis or an increased peripheral consumption of circulating NEFA compared with that seen in the term baby cannot be ruled out. The role of sympathetic activity in the newborn period may be important. Increased sympathetic activity has been reported at this time, 3~ more marked following placental insufficiency. An increased activity increases glycogenolysis and lipolysis, and this has the effect of elevating both blood glucose and plasma NEFA levels. The SGA neonate may have a more active sympathetic system as a result of prolonged intrauterine "stress," and this could explain the apparent tolerance of this group of babies to hypoxemia compared with term babies to whom birth and the subsequent hypoxemia may be the first stressful situation encountered. Plasma pressor activity has recently been reported 31 to be elevated in newborn infants suffering from asphyxia neonatorum. This observation requires further elucidation. The main conclusion that can be drawn from the data presented is that there would appear to be a defect in fatty acid mobilization and/or metabolism in the hypoxemic term infant. This defect would appear to be already

6 Volume 84 Fatty acid and blood glucose levels Number 4 present in both AGA and SGA neonates, and additional hypoxemia does not result in further compromise of NEFA and glucose homeostasis. Thus, the term hypoxemic neonate is functionally more like the AGA and SGA baby with regard to glucose and fatty acid metabolism, and may be considered to be as much at risk as these babies for the development of significant hypoglycemia. The clinical implication of these results is that.early and frequent feeding is a safe and effective way of maintaining more physiologic blood glucose levels. It is generally accepted that AGA and SGA neonates are at risk in regard to the development of significant hypoglycemia. The data presented here indicate that hypoxemic term infants are at similar risk and should also be managed on an early feeding regimen. I wish to thank Dr. B. D. Corner, Dr. P. M. Dunn, and Professor N. R. Butler for allowing me to study babies under their care. I also wish to thank Dr. B. D. Corner for her advice and guidance in the preparation of my thesis. Many thanks are due to the biochemistry technicians of the Southmead Hospital Pathology Laboratory for performing the blood glucose estimations and to Dr. F. J. W. Lewis, Director of the Laboratory, for his continuing interest and encouragement. I would also like to thank Dr. David Hull and Dr. B. A. Wharton for advice in the preparation of this paper. Finally, I wish to acknowledge the statistical assistance of Miss E. H. L. Duncan and Mrs. A. Morris of the University of Bristol Department of Public Health. REFERENCES 1. Van Duyne, C. M., and Havel, R. J." Plasma unesterified fatty acid concentration in fetal and neonatal life, Proc. Soc. Exp. Biol. Med. 102: 599, Cornblath, M., Ganzon, A. F., Nicolopoulos, D., Baens, G. S., Hollander, R. J., Gordon, M. H., and Gordon, H. H.: Studies of carbohydrate metabolism in the newborn infant. III. 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7 5 8 4 Harris The Journal of Pediatrics April Shelley, H. J.: Carbohydrate reserves in the newborn infant, Br. Meal. J. 1: 273, Dawkins, M. J. R.: Hypoglycaemia in childhood, Proc. Roy. Soc. Med. 57: 1063, Silverman, W. A. and Sinclair, J. C.: Carbohydrate and energy metabolism in the newborn--an international exploration, Pediatrics 39: 592, Cheek, D. B. Malinek, M_, and Fraillon, J. M.: Plasma adrenaline and noradrenaline in the neonatal period, and infants with respiratory distress syndrome and placental insufficiency, Pediatrics 31: 374, Holden, K. R., Young, R. B., Piland, J. H., and Hurt, W. G.: Plasma pressors in normal and stressed newborns, Pediatrics 49: 495, 1972.