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Canadian Journal of Anesthesia 49:701-705 (2002)
© Canadian Anesthesiologists' Society, 2002
Obstetrical and Pediatric Anesthesia

Plasma lidocaine concentrations are higher in twin compared to singleton newborns following epidural anesthesia for Cesarean delivery

[Les concentrations plasmatiques de lidocaïne sont plus élevées chez les nouveau-nés jumeaux, comparés au nouveau-né unique, à la suite d’une anesthésie épidurale pour césarienne]

Manuel C. Vallejo, MD and Sivam Ramanathan, MD

From the Department of Anesthesiology, Magee-Womens Hospital, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Address correspondence to: Dr. Manuel C. Vallejo, Department of Anesthesiology, Magee-Womens Hospital, University of Pittsburgh, 300 Halket Street, Pittsburgh, PA 15213, USA. Phone: 412-641-4260; Fax: 412-641-4766; E-mail: vallejomc{at}anes.upmc.edu


   Abstract
TOP
 Abstract
Introduction
 Methods
 Statistical analysis
 Results
 Discussion
 References
 
Purpose: This study compares plasma lidocaine concentrations in 16-sets of twin neonates to 16-singleton neonates all of whom were delivered by Cesarean section under lumbar epidural anesthesia (LEA).

Methods: Lidocaine 1.5% with epinephrine 5 µg•mL-1 was used for activation of LEA. Upon delivery plasma lidocaine concentrations were measured from the maternal vein (MV), neonatal umbilical vein (UV) and umbilical artery (UA) using TDx fluorescence polarization immunoassay.

Results: MV lidocaine concentrations were similar in both twin and singleton mothers. Both mean lidocaine UV and UA levels were 35% higher in twin A (first-delivered) compared to the singleton neonate, (P < 0.01, t test). Similarly, twin B mean UV and UA lidocaine levels were 35% and 53% higher than the singleton value (P < 0.01). Mean UV and UA lidocaine fetal/maternal ratios in both twins were at least 18% higher than the singleton value (P < 0.05).

Conclusion: Even though there were no differences in neonatal outcome, a potential does exist for high plasma lidocaine concentrations in twin fetuses, suggesting that the total maternal dose of lidocaine must be regulated carefully.


   Introduction
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 Abstract
 Introduction
Methods
 Statistical analysis
 Results
 Discussion
 References
 
LOCAL anesthetics are rapidly absorbed from the epidural space into the maternal systemic circulation and transferred to the fetus via the uteroplacental circulation.1 Uteroplacental transfer of local anesthetics depends on multiple factors including: maternal drug concentration, volume of distribution, maternal cardiac output and uterine blood flow, amount of placental surface available for drug transfer, pKa, protein binding, maternal and fetal blood pH, and the ratio of ionized and unionized drug fractions.1,2

Multiple gestation causes additional changes in maternal cardiac output and blood volume compared to singleton gestation. The purpose of this study is to determine the effect of twin pregnancy on maternal and fetal lidocaine levels compared to a singleton pregnancy.


   Methods
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 Abstract
 Introduction
 Methods
Statistical analysis
 Results
 Discussion
 References
 
The local Institutional Review Board approved the study protocol and patients gave informed written and verbal consent. Sixteen parturients with a twin pregnancy and 16 control parturients with a singleton pregnancy who agreed to participate in the study were sequentially included over a six-month time period. All patients were scheduled for elective Cesarean delivery and were free from preexisting medical or pregnancy-induced complications. Patients received 1000 mL of Ringer’s lactate intravenously prior to induction of epidural anesthesia. At the L3 –L4 vertebral interspace, an epidural catheter was inserted 4 cm into the epidural space using a loss of resistance technique. Following a test dose of 3 mL of lidocaine 1.5% with 1:200, 000 epinephrine to rule out intrathecal or venous catheter placement, 5-mL incremental injections of the same anesthetic were given to reach a T4 dermatome level. All patients received 6 L•min-1 of oxygen via a disposable oxygen mask with left uterine displacement. The Nellcor pulse oximeter (Nellcor Inc., Hayward CA, USA) was used to measure continuous maternal oxygen saturation (SaO2). External upper extremity maternal blood pressure was measured and recorded every two minutes using DinamapTM (Critikon Inc., Tampa, FL, USA). Hypotension (systolic blood pressure < 100 mmHg) was treated with 5-mg increments of ephedrine intravenously.

At delivery, the maternal radial artery was sampled for blood gas analysis with a single stick using a #25 G needle. Maternal venous (MV) blood was collected from the antecubital vein and heparin was added as an anticoagulant. The specimen was centrifuged, plasma isolated and frozen at -20°C until analyzed for total plasma lidocaine concentration. Additionally, neonatal umbilical vein (UV) and umbilical artery (UA) samples were collected in heparin from the segment of a doubly clamped umbilical cord for measurement of blood pH, gas tensions and lidocaine levels. The umbilical cord of the first born (twin A) and the second born (twin B) were identified by placing one and two clamps on the respective umbilical cord. Neonatal Apgar scores and birth weights were also recorded.

Plasma lidocaine levels were measured using the TDx automated immunoassay method (Abbot Diagnostic, Eden Prairie, MN, USA) with a lower detection limit of 0.1 µg•mL-1 and a cross-reactivity of < 0.05% to lidocaine metabolites.3–5 Compared to high pressure liquid chromatography, TDx immunoassay shows excellent correlation, with a reported correlation coefficient of 0.944, a slope of 0.975 and an intercept of 0.096.5 Fetal/maternal (F/M) lidocaine concentration ratios were calculated by dividing neonatal UV or UA lidocaine values by MV values for lidocaine.


   Statistical analysis
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 Abstract
 Introduction
 Methods
 Statistical analysis
Results
 Discussion
 References
 
Results were expressed as mean ± SD. Values from twin A and/or twin B were compared with corresponding values from the singleton fetus using unpaired t test. Values from twins were compared with each other using paired t test. Data were analyzed using Statistica for Windows, version 5.1. (Statsoft, Tulsa, Oklahoma, USA). A P < 0.05 was considered significant.


   Results
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 Abstract
 Introduction
 Methods
 Statistical analysis
 Results
Discussion
 References
 
Sixteen parturients with a twin pregnancy at 37 ± 3 weeks gestation and 16 parturients with a singleton pregnancy at 38 ± 4 weeks gestation were studied. No parturient who agreed to participate failed to complete the study. Table IGo presents demographic information, neonatal birth weight and Apgar scores. No significant differences existed in age, height, and gestational age between parturients carrying singleton and multiple gestations (Table IGo). However, compared to singleton parturients, twin parturients weighed more (Table IGo). Mean total dose of epidural lidocaine used to establish anesthesia for Cesarean section was not significantly different between the singleton and twin groups. Uterine incision to delivery time was shortest in the singleton delivery and longest in twin B (Table IGo). Both twin A and twin B had a smaller birth weight than the singleton newborn and twin B was significantly smaller than twin A (Table IGo). Both one-and five-minute Apgar scores were similar in singleton and twin newborns (Table IGo). All babies from both groups had a normal postnatal course.


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  		TABLE I Demographic data, total lidocaine dose, gestational age, and neonatal data
 
Six parturients with a twin pregnancy (37.5%) and five parturients with a singleton pregnancy (31.3%) were treated for maternal hypotension (systolic blood pressure < 100 mmHg) with ephedrine (P = NS). All twin gestations had a single placenta with two umbilical cords. Fourteen of the twin placentas were dichorionic and diaminiotic. Information as to the number of amnions and chorions in the remaining two twin placentas were not available.

MV plasma lidocaine concentrations were not significantly different from each other in both the twin and singleton groups (Figure 1Go). However, both UV and UA plasma lidocaine concentrations were significantly higher in both twins compared to the singleton neonate (P < 0.01, Figure 1Go). Additionally, UA lidocaine concentration in twin B was significantly higher than in twin A (P < 0.01, Figure 1Go). Regression analysis did not reveal correlation with respect to body mass index (BMI), UA and UV lidocaine concentrations.



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  		FIGURE 1 Plasma lidocaine concentration in singleton and twin neonates. MV = maternal vein; UV = neonatal umbilical vein; UA = neonatal umbilical artery; *Significantly different from the corresponding value in the singleton subjects; #Significantly different from the corresponding value of twin A. For all statistical comparisons, P values are < 0.01.

 
Both F/M UV and UA ratios were significantly higher in both twins compared to the singleton newborn. The UA blood F/M ratio in twin B was significantly higher than twin A (P < 0.05, Figure 2Go).



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  		FIGURE 2 Fetal/maternal plasma concentration ratio in the umbilical vein (UV) and umbilical artery (UA) in singleton and twin gestations. *Significantly different from the corresponding value in the singleton subjects. #Significantly different from the corresponding value of twin A. For all statistical comparisons, P values are < 0.05.

 
Table IIGo presents maternal arterial blood gas tensions, neonatal UV and UA gas tensions and pH at delivery. No differences were noted in continuous maternal SaO2 saturation between groups. Maternal arterial PCO2, pH and base excess were not significantly different between the singleton and twin gestational groups (Table IIGo). However, maternal arterial PO2 was slightly lower in twins compared to singleton parturients.


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  		TABLE II Blood gas tensions in maternal artery, neonatal UV and UA at delivery
 
Compared to the singleton fetus, no differences were noted in twin umbilical arterial, and twin UV pH and base excess (Table IIGo). However, umbilical arterial PO2 in both twins was higher than the singleton value. Likewise, umbilical arterial PCO2 in both twins was lower compared to the singleton (Table IIGo).


   Discussion
TOP
 Abstract
 Introduction
 Methods
 Statistical analysis
 Results
 Discussion
References
 
The degree of drug transfer across the placenta depends on: 1) maternal concentration of lidocaine; 2) maternal cardiac output and uterine blood flow; 3) placental surface available for transfer; 4) physical-chemical properties of the drug (pKa, protein binding); and 5) maternal and fetal blood pH, which determines the ratio between ionized and unionized fractions of lidocaine and blood pH.1,2 Although lidocaine F/M ratios are known for singleton human fetuses,6,7 no data are available for twin fetuses. Our results show there is increased fetal uptake of lidocaine in both twin fetuses compared to the singleton fetus.

The reason for increased fetal UV and umbilical arterial lidocaine uptake in twins in our study was not related to any difference in maternal vein concentration because maternal vein lidocaine levels were not significantly different between the singleton and twin groups. Additionally, there was no difference in mean total dose of epidural lidocaine to establish anesthesia for Cesarean section between both groups. Furthermore, the higher twin maternal body weight could not account for higher fetal lidocaine levels because there was no correlation with respect to BMI and UA and UV lidocaine concentrations using regression analysis.

Why would twin fetuses have higher plasma lidocaine concentrations? It is well known that both heart rate and stroke volume are increased in twin pregnancies, especially during the third trimester, leading to a significant increase in cardiac output and cardiac index compared to singleton pregnancies.8 Additionally, the normal increase in plasma volume is expanded even more so in twin pregnancies.9,10 Likewise, the increase in uterine blood flow is greater than a singleton pregnancy and the uteroplacental unit is larger.9 The two placentas in twin gestations can act as a parallel low-resistance circuit, causing a fall in systemic vascular resistance with increased blood flow.9 Morris et al.11 found the mean clearance time of NaCl from the uterine muscle of twin pregnancies was 50% longer than in singleton pregnancies. The increase in cardiac output, plasma volume, as well as uterine blood flow in twin pregnancy can enhance lidocaine delivery to the larger twin fetoplacental unit. Amide local anesthetics like lidocaine are highly protein bound which limits placental transfer. However, maternal total protein levels drop considerably in twin pregnancy compared to singleton.10 Kennedy et al.12 identified maternal and fetal protein binding and blood pH as fundamental factors controlling fetal lidocaine levels. The drop in total serum protein in twin pregnancy increases the amount of free lidocaine available to the fetus.

Another factor for increased lidocaine levels in twins may be related to birth weight. As noted in this study, twin fetuses are normally smaller than singleton fetuses.13 Smaller body weight is associated with a lower volume of distribution and hence higher plasma fetal drug levels.2 Additionally, differences in oxygenation between twins and singleton are due to fetal weight.14 The transfer of oxygen across the placenta is blood-flow limited and the placenta supplies about 8 mL O2•min-1•kg-1 of fetal weight.14 In our study, mean singleton birth weight is greater than twin birth weight (Table IIGo), which explains the lower singleton UA oxygen tension.

Vascular communications, which are more likely to occur in a monochorionic placenta, can affect the amount of drug reaching either of the twin fetuses and thus affects the plasma concentration of drugs that cross the placenta from the maternal circulation. None of our twin neonates had any evidence of twin-to-twin transfusion such as anemia or vascular overload. In addition, most of our patients with a twin pregnancy had a dichorionic placenta.

Birth order influences the blood-gas status of twins.15,16 Both Fuchi and Young noted substantial differences between twin A and twin B with respect to their oxygenation with conditions consistently favouring twin A.15,16 Young et al.16 attributed the poor outcome in twin B to reduced uterine size following the delivery of twin A with decreased intervillous blood flow, and alteration in the placental volume produced by clamping the umbilical cord of twin A. Our results confirm Young’s results in that twin B had lower UV and UA pH and PO2 and higher PCO2. The decreased blood pH in twin B may also have contributed to higher lidocaine uptake due to decreased protein binding and increased ion trapping.1,17

No differences were noted with respect to uterine incision to delivery times between singleton and twin A deliveries. However, twin B delivery time was significantly longer compared to both singleton and twin A delivery times. The prolonged time interval in delivery of twin B may have accentuated the higher lidocaine F/M ratio in twin B, but this is clearly not the only reason for the increased lidocaine F/M levels in twins.

In conclusion, even though there were no clinical differences in neonatal outcome, it is important to realize that a potential does exist for high plasma lidocaine concentrations in twin fetuses and, therefore the total maternal dose of lidocaine must be carefully regulated. Further research is needed to assess local anesthetic concentrations in twin fetuses whose mothers receive continuous epidural infusion for prolonged periods of time for labour analgesia.

Revision received May 27, 2002. Accepted for publication March 7, 2002.


   References
TOP
 Abstract
 Introduction
 Methods
 Statistical analysis
 Results
 Discussion
 References
 
1 Biehl D, Shnider SM, Levinson G, Callender K. Placental transfer of lidocaine: effects of fetal acidosis. Anesthesiology 1978; 48: 409–12.[Medline]

2 Wilkinson GR. Pharmacokinetics: the dynamics of drug absorption, distribution, and elimination. In: Hardman JG, Limbird LE, Gilman AG (Eds.). The Pharmacological Basis of Therapeutics, 10th ed. New York: McGraw-Hill, 2001: 3–29.

3 Caplan YH, Levine B. Application of the Abbott TDx lidocaine, phenytoin, and phenobarbital assays to postmortem blood specimens. J Anal Toxicol 1988; 12: 265–7.[Medline]

4 Sedman AJ, Molitoris BA, Nakata LM, Gal J. Therapeutic drug monitoring in patients with chronic renal failure: evaluation of the Abbott TDxTM drug assay system. Am J Nephrol 1986; 6: 132–34.[Medline]

5 Ramanathan J, Bottorff M, Jeter JN, Khalil M, Sibai BM. The pharmacokinetics and maternal and neonatal effects of epidural lidocaine in preeclampsia. Anesth Analg 1986; 65: 120–6.[Medline]

6 Abboud TK, David S, Nagappala S, et al. Maternal, fetal, and neonatal effects of lidocaine with and without epinephrine for epidural anesthesia in obstetrics. Anesth Analg 1984; 63: 973–9.[Abstract/Free Full Text]

7 Abboud TK, Sarkis F, Blikian A, Varakian L, Earl S, Henriksen E. Lack of adverse neonatal neurobehavioral effects of lidocaine. Anesth Analg 1983; 62: 473–5.[Abstract/Free Full Text]

8 Veille JC, Morton MJ, Burry KJ. Maternal cardiovascular adaptations to twin pregnancy. Am J Obstet Gynecol 1985; 153: 261–3.[Medline]

9 Gardner MO, Wenstrom KD. Maternal adaptation. In: Gall SA (Ed). Multiple Pregnancy and Delivery. St. Louis: Mosby-Year Book, Inc., 1996: 99–109.

10 MacGillivray I, Campbell D, Duffus GM. Maternal metabolic response to twin pregnancy in primigravidae. J Obstet Gynaecol Br Commonw 1971; 78: 530–4.[Medline]

11 Morris N, Osborn SB, Wright HP. Effective circulation of the uterine wall in late pregnancy. Measured with NaCl. Lancet 1955; 265: 323–5.

12 Kennedy RL, Bell JU, Miller RP, et al. Uptake and distribution of lidocaine in fetal lambs. Anesthesiology 1990; 72: 483–9.[Medline]

13 Grothe W, Ruttgers H. Twin pregnancies: an 11-year review. Acta Genet Med Gemellol (Roma) 1985; 34: 49–58.[Medline]

14 Longo LD. Respiration in the fetal-placental unit. In: Cowett RM (Ed.): Principles of Perinatal-Neonatal Metabolism. New York: Springer-Verlag, 1991: 304.

15 Fuchi I, Noda K. Twin umbilical cord blood gas values. Acta Genet Med Gemellol 1992; 41: 137–42.[Medline]

16 Young BK, Suidan J, Antoine C, Silverman F, Lustig I, Wasserman J. Differences in twins: the importance of birth order. Am J Obstet Gynecol 1985; 151: 915–21.[Medline]

17 Nancarrow C, Runciman WB, Mather LE, Upton RN, Plummer JL. The influence of acidosis on the distribution of lidocaine and bupivacaine into the myocardium and brain of the sheep. Anesth Analg 1987; 66: 925–35.[Abstract/Free Full Text]





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