Does placental lactate production have a role in ephedrine-induced fetal metabolic acidosis?
Middlesborough, UK
* E-mail: drdavidcooper{at}aol.com
Editor—Maternal ephedrine administration can cause fetal respiratory acidosis during spinal anaesthesia for caesarean section. We consider this to be secondary to a beta-adrenergic-mediated increase in fetal carbon dioxide production.1 Ephedrine can also cause fetal metabolic acidosis. We have previously considered this to be secondary to ephedrine increasing fetal metabolic rate to the extent that oxygen demand exceeds its limited supply, thereby increasing anaerobic metabolism. However, observations from an unpublished retrospective study of urgent Caesarean deliveries under spinal anaesthesia have raised the possibility that ephedrine may increase placental lactate production. This has led us to further analyse data from a recent study2 to investigate whether the placenta had a role in the ephedrine-induced fetal metabolic acidosis encountered.
In our unpublished retrospective study, whether the first-line vasopressor was ephedrine (n=86) (92% by intermittent bolus) or phenylephrine (n=118) (70% by prophylactic infusion), the umbilical artery base excess (UABE) was similar [mean –3.1 mEq litre–1 (SE 0.4) and –3.4 mEq litre–1 (SE 0.3), respectively (P=0.49) (t-test)]. However, the umbilical arterio-venous base excess difference at delivery was more likely to be positive with ephedrine than with phenylephrine [OR 2.1, 95% CI 1.2–3.7 (P=0.009)]. The mean umbilical arterio-venous base excess difference with ephedrine was 0.4 mEq litre–1 (SE 0.2), compared with –0.4 mEq litre–1 (SE 0.2) with phenylephrine (P=0.005) (t-test). Ephedrine was, therefore, more likely to be associated with a net addition of metabolic acid from the placenta to the fetal circulation, which was balanced by a net removal of metabolic acid by the fetus.
This observation could be explained if ephedrine increased placental lactate production, which was then metabolized by the fetus. Maternal ephedrine administration increases fetal catecholamine levels compared with phenylephrine.3 It is normal for the placenta to produce lactate under aerobic conditions4 and there is in vitro evidence that epinephrine increases human placental lactate production.5 The placenta converts up to one-third of glucose to lactate, which is a major source of metabolic fuel and a carbon source for growth.4 Placental conversion of glucose to lactate increases the transfer of glucose from the mother to the fetus by increasing the maternal–fetal concentration gradient of glucose. Hydrogen ions are released during the production of lactate, increasing acidity. Subsequent fetal metabolism of lactate by gluconeogenesis, or oxidation, removes hydrogen ions, indirectly increasing bicarbonate concentration.
In the recent prospective study of low-risk caesarean sections, where prophylactic ephedrine or phenylephrine was given to maintain maternal arterial pressure, ephedrine was associated with fetal metabolic acidosis.2 The mean UABE was –4.4 mEq litre–1 (SE 0.8, IQR –1.4 to –6.5) with ephedrine, compared with –0.7 mEq litre–1 (SE 0.4, IQR 0.5 to –1.9) with phenylephrine (P<0.001) (t-test). To assess the net effect of ephedrine on metabolic acid addition to/removal from the fetal circulation by the fetus, we have further analysed the data, using a regression model to predict UABE from umbilical venous base excess and patient group. There was a strong association between UABE and umbilical venous base excess, but this was not affected by patient group: UABE (mEq litre–1)=0.66+(1.13 times umbilical venous base excess) (r2=0.87, t=17.3, F=301, P<0.0001). To assess the net effect of ephedrine on metabolic acid addition to/removal from the fetal circulation by the placenta, we used a regression model to predict umbilical venous base excess from UABE and patient group. There was a strong association between umbilical venous base excess and UABE. Interestingly, this was affected by patient group, with umbilical venous base excess being lower in the ephedrine group (Table 1).
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To explain our observations, we suggest that ephedrine may increase placental lactate production: if a proportion of the additional lactate produced by the placenta is not metabolized by the fetus, hydrogen ions could accumulate within the fetal circulation, causing fetal metabolic acidosis. The possible influence of ephedrine on placental lactate production warrants further investigation.
References
1 Cooper DW, Carpenter M, Mowbray P, Desira WR, Ryall DM, Kokri MS. Fetal and maternal effects of phenylephrine and ephedrine during spinal anesthesia for cesarean delivery. Anesthesiology (2002) 97:1582–90.[CrossRef][Web of Science][Medline]
2 Cooper DW, Gibb SC, Meek T, et al. Effect of intravenous vasopressor on spread of spinal anaesthesia and fetal acid–base equilibrium. Br J Anaesth (2007) 98:649–56.
3 LaPorta RF, Arthur GR, Datta S. Phenylephrine in treating maternal hypotension due to spinal anaesthesia for caesarean delivery: effects on neonatal catecholamine concentrations, acid base status and Apgar scores. Acta Anaesthesiol Scand (1995) 39:901–5.[Web of Science][Medline]
4 Dicke JM. Placental transport, metabolism and perinatal nutrition. In: Clinical Maternal–Fetal Medicine—Winn HN, Hobbins JC, eds. (2000) New York, London: The Parthenon Publishing Group. 926.
5 Ginsburg J. The effect of adrenaline on placental metabolism. Proc R Soc Med (1966) 59:748–50.[Web of Science][Medline]
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