Scherer1995.pdf

European Journal of Obstetrics & Gynecology and Reproductive Biology 59 Suppl. (1995) S17-S29

Influence of epidural analgesia on fetal and neonatal well-being R. Scherer*a, W. Holzgreve b 'CheJarzt der K/inik jUr Anasthesio[ogie und operative /ntensivmedizin. Clemenshospi/a/ GmbH, Duesbergweg 124. 48153 Munster, Germany bGeschaJtsjUhrender Oberarzt des Zen/rums jUr Frauenheilkunde. Westfiilische Wilhe/ms-Universitiit, A/bert-Schwei/zer-Str. 33, 48/29 Munster. Germany

Abstract Epidural analgesia is a frequently used method to reduce the pain of child-bearing. Concerns regarding the safety and potential hazards still persist in the medical community. This review intends to examine how epidural analgesia determines the various factors of fetal and neonatal well-being. Placental drug transfer of opiates like morphine, pethidine and fentanyl is rapid and can lead to neonatal depression. Sufentanil seems to be the safest opiate to administer epidurally. Local anaesthetics are transferred to the fetus in substantial amounts, but the reported effects are subtle and are probably inconsequential. Utero- and fetoplacental blood flow seems to be improved by epidural analgesia with local anaesthetics. Even when using stronger solutions for more extensive blockade in patients for caesarean section, no adverse effects could be demonstrated using pulsed Doppler technique as long as prolonged hypotension (> 2 min) is avoided. Hypotension is best prevented with 20-25 ml/kg crystalloid preload and prompt treatment with ephedrine or etilephrine. Addition of adrenaline to local anaesthetics is considered to be safe for the healthy mother and fetus but it should best be avoided in mothers with pregnancy induced hypertension. Fetal and neonatal acid-base balance and gas-exchange are not adversely affected by epidural analgesia. Many studies show that epidural analgesia can indeed protect the fetus if hypotension is prevented. Neonatal well-being evaluated by APGAR, BRAZELTON, SCANLON and NACS scores is not significantly influenced by local anaesthetics. Neonatal depression can occur however with epidural use of morphine, fentanyl and alfentanil. Sufentanil, again in doses up to 30 p.g in association with bupivacaine seems to be devoid of depressive effects on the neonate. In summary, the anaesthetist has good arguments to reassure his obstetrical colleagues that providing epidural analgesia for pregnant women in labour is a justifiable intervention to support the natural process of child-bearing. Keywords: Epidural analgesia; Local anaesthetics; Epidural opioids; Epidural adrenaline; Fetal well-being; Neonatal well-being

1. Introduction Epidural analgesia during labour enjoys increasing popularity among obstetricians and pregnant women. However, pain relief during child birth is still considered by many to be optional. In particular epidural analgesia, the most invasive form of pain relief, may be assumed to be potentially harmful for the baby. Harmful effects of epidural analgesia could originate directly from the drugs used to induce analgesia (local anaesthetics and opioids), or from epidurals conducted in a less than professional manner, allowing hypotension to occur. In this article the authors intend to review the influence of epidural analgesia on the various factors determining fetal and neonatal well-being: placental drug • Corresponding author.

transfer, uteroplacental blood-flow, acid-base balance and gas-exchange and their impact on the clinical assessment of neonatal outcome. 2. Factors determining placental transfer The haemomonochorial structure of the human placenta allows rapid diffusion of liposoluble substances up to a molecular weight of 600-1000 [I]. Hydrophilic substances and ions depend on diffusion through transcellular aqueous pathways and therefore cross the placenta much more slowly, the surface area available for their diffusion being 10- 5 fold smaller [2]. Local anaesthestics are weak bases that can cross the placenta in the non-ionised form only. Placental drug transfer depends on membrane thickness, surface available and concentration gradient. As fetal blood pH is

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R. Scherer, W Holzgreve / European Journal of Obstetrics & Gynecology and Reproductive Biology 59 (1995) 517-529

lower than that of maternal plasma, weak bases are more ionised in fetal plasma. In fetal acidosis ionisation of weak bases maintains a concentration gradient for the non-ionised drug form, therefore increasing fetal transfer rates for basic drugs. Thus, the compromised fetus is at increased risk from local anaesthetics. However, this ion-trapping effect is masked by the effect of protein binding. Protein binding is an important factor determining the free fraction of a drug and the resulting equilibrium fetal/maternal (F/M) ratio. A rise in fetal plasma protein binding would increase maternal-to-fetal drug transfer rate. Fetal albumin concentration at term slightly exceeds maternal [3], thus the F/M ratio of albumin-bound drugs such as fentanyl may exceed unity at equilibrium. The other important drug binding protein is aI-acid glycoprotein, which rises in fetal plasma much more slowly [3]. Therefore, F/M ratio of drugs bound to this protein, like local anaesthetics, could be less than unity at equilibrium, despite the ion-trapping effect. High fetal protein binding increases fetal transfer of drugs given in multiple doses [4]; the protein-bound drug component may act as a store that prolongs the effect of the drug well into to the neonatal period. Placental blood flow has a more marked effect on transfer of highly diffusable drugs, than on transfer of poorly diffusable drugs. Gaylard et al. [5] showed that bupivacaine highly bound to maternal protein may still be transfered to the fetus in spite of a substantial fall in maternal flow in the rabbit. F/M ratios should be interpreted with caution. On brief exposures they may give a measure of transplacental transfer rate, on prolonged exposure however F/M ratios reflect the equilibrium distribution of a freely diffusable drug [6]. F/M ratio may be particularly misleading when considering bolus administration of a highly liposoluble drug compared to a more hydrophilic one. Maternal plasma concentration of the former drug falls rapidly, while placental transfer is also rapid and the F/M ratio will rapidly exceed unity. Maternal plasma concentration of the latter drug falls less rapidly, placental transfer is slower and the F/M ratio rises slowly. Fetal exposure, however, to the more hydrophilic drug may actually be greater, because of the more sustained maternal plasma load [7].

2.1. Placental transfer of opioids Morphine is very poorly liposoluble and weakly bound to aI-acid glycoprotein. Epidural injection of 4-6 mg morphine to the mother was rapidly transferred in a significant amount to the fetus [8]. The pharmacokinetics of epidurally administered morphine are similar to those by intramuscular route [9]. Pethidine is 20-30 times more liposoluble than mor-

Table I Maternal artery and fetal artery levels after epidural injection of 50 J.l.g sufentanil and 50 J.l.g fentanyl. Modified from Kumar [18] Time (min)

I 10 45 60 90 120

Sufentanil (50 J.l.g)a

Fentanyl (50 J.l.g)b

Maternal (pglml)

Fetal (pglml)

Maternal (pglml)

Fetal (pglml)

32 48 54 48 52 38

ND ND ND ND ND ND

20 20 30 50 40 30

ND 10 ± 20 ± 10 ± 10 ± 3 ±

± 29 ± 25 ± ± ± ±

34 52 44 29

± ± ± ± ± ±

30 20 30 50 60 60

30 30 20 10 3

aData from Vertommen et al. [17]. bData from Craft et al. [14]. ND. not detectable.

phine [10], and 30-65% bound mainly to at-acid glycoprotein. Pethidine rapidly crosses the placenta in humans [11] so that F/M ratios rise quickly, exceeding unity as maternal levels fall. Fentanyl is highly liposoluble and bound principally to albumin. Free fentanyl crosses the rabbit placenta more rapidly than free pethidine [12]. Following epidural administration F/M ratios rose to 0.7 after the third dose [13]; it has therefore a potential for producing neonatal depression. Placental transfer of 50-100 p,g epidural fentanyl was shown to occur within 15-45 min in chronically instrumented pregnant sheep [14], with no adverse effect, however, on mother or fetus. There is also a redistribution of fentanyl from neonatal tissues back into the maternal blood [15]. Sufentanil has an equally high lipophilicity. Following epidural administration of 0.125% bupivacaine with adrenaline 1:800 000 and sufentanil up to 30 p,g, plasma levels in mother and neonate were measured. No sufentanil was detected in the plasma of 88% of the neonates and in the remaining 12% the sufentanil plasma levels was at the limit of detectability (0.02 ng/ml) [16]. In the chronically instrumented pregnant sheep model, fentanyl was detected in the fetal arterial blood within 10 min of epidural administration of 50 p,g of fentanyl to the mother [14]. In the same model Vertommen et al. [17] showed that no sufentanil could be detected following an epidural injection of 50 p,g sufentanil (Table I). These studies appear to suggest that epidural sufentanil is the safest opiate to administer epidurally [18].

2.2. Placental transfer of local anaesthetics Bupivacaine is the most widely used local anaesthetic in obstetrical analgesia because of its low incidence of maternal and fetal side effects. Bupivacaine crosses the placenta, its F/M ratios varies between 0.2-0.4 [19-21].

R. Scherer. W. Holzgreve / European Journal of Obstetrics & Gynecology and Reproductive Biology 59 (1995) 517-529

Bupivacaine is highly (90%) bound to maternal ai-acid glycoprotein, while only moderately (50%) bound to fetal plasma [22]. The differential protein binding between mother and fetus largely explains bupivacaine's low F/M ratio. However, more recent and sensitive analytical techniques have shown that substantial amounts of bupivacaine are transferred across the placenta and taken up in fetal tissues following epidural administration [23], and fetal dose clearly rises with duration of maternal administration [24]. Fletcher et at. [25] suggested an association between altered protein binding and increased F/M ratios when adrenaline is added to bupivacaine. Adrenaline may enhance overall fetal equilibration but does not reduce fetal exposure. However, in spite of clear evidence for considerable placental transfer of bupivacaine, any reported effects have been subtle and are probably not clinically significant. Lignocaine is often chosen by anaesthetists for epidural anaesthesia for caesarean section because of its more rapid onset of action compared to bupivacaine. Lignocaine's F/M ratios are reported as 0.5-0.7 [26,27J. It is metabolized by hepatic enzymes to two active metabolites, monoethylglycinexylidide and glycinexylidide. The neonate is able to metabolize lignocaine [28]; a relationship between the active metabolites and neonatal outcome has not been demonstrated. Chloroprocaine has gained some popularity in the United States, but has never been approved for use in Europe. Rapid hydrolysis by plasma cholinesterase in the mother and neonate with normal plasma cholinesterase limits its potential for toxicity. Active drug levels can be measured following epidural analgesia; these levels are very low and probably inconsequential to mother an fetus [29].

3. Effect of epidural analgesia on utero-and fetoplacental blood flow Uterine blood flow at term is estimated to reach 500-700 ml/min, while only 350-550 ml/min perfuse the intervillous space and are available for metabolicexchange with the fetus. Uterine perfusion is pressure dependent, therefore maternal hypotension always results in a decrease of intervillous blood flow. Uterine and spiral arteries are capable of vasoconstriction due to stimulation of sympathathetic a-adrenoreceptors, either as a reflex to maternal hypotension or by direct stimulation of receptors via vasoactive drugs. Pregnancyinduced hypertension (PIH) is associated with increased sensitivity of uterine vessels to catecholamines [30]. Umbilical blood flow is estimated to reach 250 mVmin, accounting for about 50% of fetal cardiac output. Umbilical vessels possess both a- and {3-

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adrenoreceptors but are devoid of autoregulation. Apart from direct receptor stimulation, isolated human umbili· cal vessels have been shown to contract in response to bupivacaine but not to chloroprocaine [3IJ. Therefore, intervillous blood flow may be reduced in response to maternal hypotension or uterine vasoconstriction and hence become an important factor in the development of fetal asphyxia. Measurement of uterine and intervillous blood flow initially was attempted using radionuclide methods. After intravenous injection of 99Tc or inhalation of 133Xe, disappearance of accumulation of radioactivity was used as a semiquantitative estimation of intervillous blood flow per unit volume. A Finish group, headed by Hollmen and Jouppila, systematically studied the effect of regional anaesthesia on intervillous blood flow using the intravenous 133Xe technique, giving a semiquantitative estimate of intervillous blood flow in the central part of the placenta. Even though the radiation dose to mother and fetus is small, serious reservations persist among obstetricians and their patients regarding routine use of radionuclide methods. With the development of pulsed Doppler techniques, obstetricians have focused on this noninvasive method to study changes in blood flow during epidural analgesia on both sides of the placenta, the uterine artery or arcuate artery on the maternal side, and the umbilical artery and aorta on the fetal side. Measurement of blood flow is difficult due to variations in vessel diameter and insonation angle, but the examination of blood velocity waveforms such as resistance index (RI), pulsatility index (PI), or systolic/diastolic ratio (SID) give valuable information that is independent of insonation angle. Radionuclide studies by Hollmen and his group [32,33J had shown that epidural analgesia during normal labour improved intervillous blood flow significantly; the more extensive the sympathetic blockade, the more marked was the observed increase in intervillous blood flow. Using pulsed Doppler, Marx et at. [34] found a decrease in resistance in the umbilical artery following epidural analgesia in 13 of 16 fetuses during labour. Patton et at. [35] in 1991 examined the hemodynamic changes associated with fluid preload and epidural anaesthesia, using umbilical artery Doppler velocimetry in 12 normally labouring gravidas at term. Although on the maternal side, fluid preload was associated with significant increases in heart rate, stroke volume and cardiac output, as well as with a decrease in vascular resistance, there were no changes in uterine or umbilical artery SID ratios during any stage of the study. Other authors reported no change in pulsatility index, fetal aortic and umbilical flow [36] following epidural analgesia. However, when comparing effects of epidural analgesia on blood flow velocity waveforms, preload,

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position of the patient and extension of the sympathetic block may affect the results [37J. When considering epidural analgesia for labour, radionuclide studies and Doppler studies seem to indicate that there are no major changes in, or detrimental effects on, uteroplacental and intervillous blood flow. Epidural analgesia for labour using local anaesthetics in low concentrations differs in many aspects, however, from epidural anaesthesia for caesarean section. Stronger anaesthetic solutions in larger doses are necessary and therefore potentially dangerous side effects of major regional anaesthesia are reported more frequently. Nonlaboring mothers had significantly higher incidence of hypotension than laboring mothers, 36% vs. 24% in a study by Brizgys et al. [38] during epidural anaesthesia for caesarean section. Already in 1988 Veille et al. [39] tried to evaluate the umbilical artery flow velocity waveform before and during epidural anaesthesia for elective caesarean section in 18 patients, using range garted pulsed Doppler. They found that the waveform analysis of the umbilical artery close to its placental insertion did not change significantly. The perinatal research group at the Department of Obstetrics and Gynecology in Zurich [40] also performed pulsed Doppler evaluations in 13 women undergoing elective caesarean section. They found no changes in the resistance and pulsatility indices of the umbilical artery velocity waveforms, even though there were changes in the maternal femoral arterial and venous flow pattern indicating an increase in leg blood flow after epidural anaesthesia. A study using combined spinal-epidural anaesthesia for caesarean section enrolled II women from the obstetrics service of the center for Women's Diseases at the University of Munster. They all had single intrauterine pregnancies, no maternal medical problems or maternal drug intake and no signs of threatening fetal asphyxia or fetal malformations. The combined spinalepidural anaesthesia was applied with an ultrathin spinal needle (29,27 G) and the local anaesthetics were first applied spinally and later epidurally for an extension of the effect. The dosage for the combined spinal and epidural anaesthesia was 1.5-2 ml and 5-10 ml 0.5% bupivacaine, respectively. The Doppler evaluation consisted of a baseline measurement taken before fluid preload, with further measurements after intravenous fluid preload and 3-5 min and finally 15-20 min after achieving adequate anaesthesia. We measured the SID ratio, the resistance and pulsatility indices of the umbilical artery, the fetal aorta and arcuate (uterine) artery and surveyed the maternal blood pressure and heart-rate continuously as well as the fetal well-being by continuous CTGmonitoring. A more detailed description of the patients and methods will be given elsewhere. Table 2a-c summarizes the pulsatility indices for the

Table 2a Doppler flow profile (pulsatility indices) of the arcuate artery in 11 patients before and following combined spinal epidural anaesthesia for caesarean section Patient (gestational age in weeks)

Pre-prim.

Post-prim.

3-5 min

15-20 min

E.K. (38) R.S. (38) A.S. (41) RM. (36) J.J. (36) M.K. (33) S.O. (35)' G.O. (31) C.H. (36) S.B. (38) R.E. (39)

0.75 0.73 0.8

0.75 0.38

0.79 0.66 0.69

1.28 0.84

0.79 0.57 0.74 1.26 0.91 1.29 1.39

I 0.73 0.57

0.72 0.92 0.55

1.07 1.05 0.72

0.92 1.14 0.82 1.02 0.66 1.07 0.57

aRR (syst): 120 - 90 mmHg; 2 mg vasoconstr. -

1.53 1.22 1.62

130 mmHg.

Table 2b Doppler flow profile (pulsatility indices) of the umbilical artery in II patients before and following combined spinal epidural anaesthesia for caesarean section Patient (gestational age in weeks)

Pre-prim.

Post-prim.

3-5 min

15-20 min

E.K. (38) RS. (38) A.S. (41) P.M. (36) J.1. (36) M.K. (33) S.O. (35)a G.O. (31) C.H. (36) S.B. (38) R.E. (39)

1.14 1.47 I 0.78 0.74 0.9 1.16 0.75 1.11 1.25 0.78

1.1 1.02

1.12 1.61 0.73 0.6 0.7 0.86 1.03 1.18 1.02 0.94 1.07

1.08 1.42 0.82

0.67 0.84 0.86 1.23 1.11 0.88

aRR (syst): 120 - 90 mmHg; 2 mg vasoconstr. -

0.65 0.85 0.96 0.97 0.98 1 0.93 130 mmHg.

Table 2c Doppler flow profile (pulsatility indices) of the fetal aorta in II patients before and following combined spinal epidural anaesthesia for caesarean section Patient (gestational age in weeks)

Pre-prim.

Post-prim.

3-5 min

15-20 min

E.K. (38) R.S. (38) A.S. (41) P.M. (36) J.J. (36) M.K. (33) S.O. (35)' G.O. (31) C.H. (36) S.B. (38) RE. (39)

2.09 1.81 2 2.02 2.21 1.68 1.41 2.05 2.12 2.14 1.66

1.7 1.94

1.89 1.53 2.1 1.71 1.68

1.6 2.43 2.24

1.56 1.81 1.16 2.32 2.1 1.55

1.98 2.06 1.86 1.87

aRR (syst): 120 - 90 mmHg; 2 mg vasoconstr. -

1.3 1.35 1.62 1.79 1.95 1.84 1.71 130 mmHg.

R. Scherer. W. Holzgreve / European Journal of Obstetrics & Gynecology and Reproductive Biology 59 (/995) SJ7-S29

three vessels, and Fig. la-c shows, as a graphical depiction, the changes of the resistance index of the three vessels at the four measurement points. It can clearly be seen that there were no significant changes, not even in the one case where the systolic blood pressure fell from 120 to 90 mmHg, but recovered quickly after 2 mg of etilefrin had been given. Table 3 summarizes data of an additional case where the measurements were performed

in a patient with combined aortic stenosis/insufficiency, who had a pressure gradient of 40 mmHg at 39 weeks of pregnancy. She received an epidural anaesthesia with 75 mg bupivacaine injected in 40 min. Also in this case there were no significant changes either in blood pressure, maternal heart rates or in the umbilical and arcuate artery resistance and pulsatility indices. Our study therefore showed no significant changes in the Doppler

-- E.K. (38.)

°1,-----------------------, 0,8

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+ A.S.

'*

A.S. (41.)

-D-

P.M. (36.)

* J.J.

L----+-----____:=:~

(38.)

(36.)

.. M.K. (33.)

... 5.0. (35.)

*

%G.O. (31.)

0,4

.C.H. (36.) 5\l- 5.8. (38.)

'*

0,2

ol.----------------------!

Pre-prim.

®1

Post-prim.

3·5 min

A.E. (39.)

* AA (syst): 120 •• > 90 --> (2 mg vasoconstr.) --> 130

15·20 min -- E.K. (38.)

r--------------------,

-

A.S. (38.)

*

A.S. (41.)

-0-

P.M. (36.)

*J.J. (36.) .. M.K. (33.)

... S.O. (35.)

% G.O.

0,4

*

(31.)

.C.H. (36.)

s;;- 5.8. (38.)

'*

0,2

*

oLPre-prim.

~

Post-prim.

3-5 min Fig. 1. A and B. (continued next page).

A.E. (39.)

AA (syst): 120 --> 90

--> (2 mg vasoconstr.) -- > 130

15·20 min

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R. Scherer. W. Holzgreve / European Journal of Obstetrics & Gynecology and Reproductive Biology 59 (1995) S17-S29

--- E.K. (38.)

+ R.S.

(38.)

*

A.S. (41.)

-G-

P.M. (36.)

* J.J. -+- M.K.

(36.) (33.)

* S.O. (35.) * % G.O. (31.)

0,7

• C.H. (36.) ~

*"

0,6

*

0,5 Pre-prim. L...-

_

Post-prim.

3-5 min

S.B. (38.) R.E. (39.)

RR (syst): 120 --> 90 --> (2 mg vasoconstr.)

--> 130

15-20 min

Fig. I. Doppler flow profile (resistance indices) of (a) the arcuate artery, (b) the umbilical artery and (c) the fetal aorta.

flow profile after epidural and spinal anaesthesia on the maternal (arcuate artery) or the fetal side (umbilical artery/fetal aorta). These studies support the conclusion that epidural analgesia for labouring mothers, or a major epidural or spinal-epidural block for caesarean section, has not shown a negative effect on the fetus, as long as prolonged hypotension is avoided. 3.1. Maternal hypotension and aortocaval compression Maternal hypotension is the most frequent complication of epidural blockade; it is mostly mild with epidural analgesia for labour but can be severe when a major epidural blockade is attempted for caesarean section. Hypotension is usually defined as a fall of blood pressure greater than 20-30% froIJl the preanaesthetic level. Hypotension is caused by vasodilatation induced by epidural blockade and exacerbated by aortocaval compression if the parturient adopts the supine position.

Vena cavae compression is an important cause of decrease in intervillous blood flow resulting in fetal hypoxaemia [41,42]. In the supine position intervillous blood flow may fall by 20-30% [43]. It has been shown with 133Xe washout, that a change from the lateral to the supine position can induce a significant decrease in intervillous blood flow [43]. Doppler studies have shown that resistance in uterine and umbilical artery increased significantly in mothers passing from full lateral to supine position without any change in maternal blood pressure [44,45]. Hence, supine position should be avoided during labour whenever possible. In situations where supine position cannot be avoided, it is essential to remember that left lateral tilt will only relieve aortic compression, but to avoid compression of vena cava left uterine displacement is just as important. 3.2. Prevention and treatment of maternal hypotension Only very short periods of maternal hypotension (not

Table 3 Doppler flow profile of 24-year-old gravida (39 weeks) with combined aortic stenosis insufficiency

After volume priming After prophyl. vasoconstr. i. v. 5 min after 50 mg bupivacaine 5 min after 75 mg bupivacaine

Blood pressure (mmHg)

Maternal heartrate (beats/min)

Umbilical artery RI

Umbilical artery PI

Arcuate artery RI

Arcuate artery PI

126/66 131/61 120/65 118/63

72 73 89 91

0.7 0.57 0.60 0.62

1.15 0.82 0.97 1.03

0.48 0.55 0.48 0.59

0.66 0.89 0.69 0.89

R. Scherer. W. Hol;greve / European Journal of Obstetrics & Gynecology and Reproductive Biology 59 (1995) S17-S29

exceeding 2 min and corrected rapidly) do not result in impaired neonatal status [46]. Therefore, effective prevention, early detection and prompt treatment of maternal hypotensive episodes are mandatory. As discussed in the previous chapter, if hypotension is prevented, neither epidural nor spinal anaesthesia decrease intervillous blood flow or umbilical artery flow velocity [35,36,39,40,47-49]. Preloading maternal circulation with either crystalloid or colloid solutions is considered an important measure to prevent hypotension. Most authorities advocate the infusion of at least 500 ml of lactated Ringer's solution prior to administering epidural analgesia; much larger fluid volumes may be required with epidural anaesthesia for caesarean section. Using 25 ml/kg crystalloid preload, Alahutha et al. [50] found no increase in uteroplacental resistance. Based on these results Hollmen [37] recommends preloading with 20-25 ml/kg crystalloid solution to prevent maternal hypotension. For early detection of maternal hypotension most anaesthetists and obstetricians rely on frequent noninvasive measurement of blood pressure in the arm. However, maternal hypotension was detected at least I min earlier when blood pressure was taken in the leg instead of the arm [51]. Despite preventive measures such as full lateral position and preloading with crystalloid solutions, hypotension does occur and a vasopressor may be needed. Ephedrine, an indirect acting smypathomimetic drug stimulating a- and f)-receptors in doses up to 15 mg given slowly, has been shown to produce no significant change in intervillous blood flow [52]. ]n a more recent study using Doppler technique, Rasanen et al. [53] compared the effects of ephedrine to etilephrine, a mixed aand f)-stimulant with more a-adrenergic dominance than ephedrine. Both drugs significantly increased pulsatility index in the uterine artery after bolus administration. In a more dilute form, however, ephedrine did not increase uterine and arcuate artery pulsatility index, which could be well demonstrated with phenylephrine, a pure a-stimulant [54]. Neither ephedrine, etilephrine nor phenylephrine were able to increase resistance in the umbilical artery; therefore these vasopressors may be considered safe for the healthy fetus at least [53,54].

3.3. Effect of adrenaline with local anaesthetics Adrenaline is frequently added to local anaesthetic solutions as a test dose to detect unintentional, intravascular placement of the epidural catheter or to improve the quality and duration of an epidural blockade. Can adrenaline absorbed from the epidural space effect uteroplacental perfusion? Neither 20 IJ-g of adrenaline with bupivacaine nor 100 IJ-g of adrenaline with lignocaine induced any change in intervillous blood flow in two studies by Jouppila et al. [32,55]. Adding 100 IJ-g of adrenaline to bupivacaine or lignocaine in studies using

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Doppler technique produced no change in uterine artery resistance or umbilical flow velocities [56,57]. Therefore, the unintentional i. v. injection of 15 IJ-g adrenaline with a test dose of local anaesthetic, or the basic addition of a concentration of adrenaline not exceeding 1:200 000, is considered to have no lasting and harmful effect on healthy mother or healthy fetus [37]. ]n contrast to normal pregnancy, parturients with chronic or pregnancy-induced hypertension may tolerate sympathetic drugs obviously less well. Pregnancyinduced hypertension is associated with a significantly decreased intervillous blood flow [58] and increased sensitivity of uteroplacental vessels to cathecholamines [30]. ]n this situation epidural analgesia using 10 ml bupivacaine 0.25%, without a vasoconstricting agent, has been shown to improve intervillous blood flow significantly [59]. Ramos-Santos et al. [61] performed Doppler velocimetry of the uterine and umbilical arteries before and after intravenous fluid loading and at 30 and 60 min after epidural blockade, while monitoring the maternal vital signs and fetal heart rate continuously in small groups of patients with preeclampsia (n 7), chronic hypertension (n 8) and no complications (n 10). Although mean maternal blood pressure fell significantly in all groups, no maternal hypotension or change in mean maternal and fetal heart rates were observed. Similar to our findings, they did not notice any changes in the umbilical artery SID ratios in any of the three groups after epidural block. However, because the mean uterine artery SID ratio fell significantly in the preeclamptic group to values similar to those of the normal group, the authors concluded that in these patients, epidural anaesthesia may even help to reduce uterine artery vasospasm and therefore may prevent intrapartum fetal asphyxia. By contrast, on the basis of preliminary evidence, addition of adrenaline to a local anaesthetic should be avoided in the compromised fetus [60] as increases in uterine and umbilical resistance have been observed [37,44].

=

=

=

4. Effects of epidural analgesia on fetal and neonatal acidbase balance and gas-exchange cord blood-gas and acid-base Umbilical measurements, together with fetal heart rate (FHR) monitoring and APGAR scores, are the most frequently used parameters to predict and evaluate fetal outcome. Umbilical venous (UV) pH, evaluating placenta function, and umbilical artery (UA) pH, reflecting fetal status, make umbilical cord blood pH a sensitive indicator of birth asphyxia [62]. Fetal hypoxaemia and acidaemia are closely related to reductions in intervillous blood flow. Before discussing effects of epidural analgesia on fetal acid-base balance, the normal blood gas/acid-base values should be known.

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Umbilical cord blood pH values at birth derived from large series varies are: UV pH, 7.32-7.35; UA pH, 7.24-7.27 [62-64). Analysing blood samples obtained by cordocentesis before labour, Nicolaides et al. (65) found slightly higher pH values in well-grown fetuses than at birth. Fetal acidaemia being the hallmark of fetal asphyxia is best diagnosed using UA pH (66). A UA pH of 7.25 is considered to be the lower limit of normal and values < 7.20 are considered diagnostic of fetal acidaemia [66,67). However, recently an even lower cut-off point of UA pH of 7.00 has been proposed (68). However, even low values of UA pH (:5 7.05) have little prognostic value in cases of neurologic dysfuntion or hypoxic ischaemic encephalopathy [64,66). Only in 8-21% of patients with cerebral palsy can birth asphyxia be determined as the cause of hypoxic or ischaemic encephalopathy [69,70). In order to provide valid evidence of the effect of epidural analgesia on fetal blood gas/acid-base balance, one has to sort out all confounding factors that contribute to peripartum intrauterine asphyxia, such as prematurity, growth retardation, pregnancy-induced hypertension, maternal disease and umbilical cord compression. Umbilical blood data obtained at birth should be related to blood data from samples taken by ultrasonographic cordocentesis before starting an epidural analgesia (71). In the first stage of labour, in the absence of epidural analgesia, a progressive but modest degree of acidaemia can be observed in the blood of the mother and in fetal scalp blood. However, pH and base excess gradients between mother and fetus increased slightly during active labour. With epidural analgesia and mothers adopting full lateral position, maternal and fetal acidaemia almost disappeared [72,73). In the second stage of naturallabour acidaemia worsened more rapidly than during the first stage (74), while mothers receiving epidural analgesia did not develop second stage acidaemia whether they pushed or not. Epidural analgesia had also a positive effect on cumulative fetal acidaemia. Bearing down during the expulsive phase of labour tended to hasten the onset of fetal acidaemia. However, as most mothers were in a supine position, aorto-caval compression may have been a confounding factor (75). Many other studies confirmed the hypothesis that epidural analgesia can protect the fetus [76,77). Epidural analgesia reduces pain-induced maternal hyperventilation during labour, preventing left shift of the haemoglobin dissociations curve in the mother, which can have detrimental effects on fetal haemoglobin saturation (78). There is one study by Shyken et al. [79], however, that seems to contradict all previous studies. These authors compared two groups of vaginally delivered patients with and without epidural analgesia. In the epidural

group mean UA pH was 7.26 ± 0.04 compared to 7.29 ± 0.04 in the nonepidural group; the authors concluded that epidural analgesia does not offer any c1earcut advantage to the normal term fetus. This study has been heavily criticized by Downing et al. (80) on the bases of the study being retrospective, non-randomized and non-matched for age and parity design. Considering the small sample size « 30 patients in each group), neither the statistical power of the study nor the required sample size were defined to avoid type B error. Maternal hypotension following regional anaesthesia (epidural or spinal) may also be a factor promoting fetal acidaemia. In patients with epidural anaesthesia, severe hypotension was associated with significant fetal acidaemia UA pH 7.16 ± 0.07 compared to nonhypotensive patients with UA pH 7.27 ± 0.04 [81). However, umbilical artery acidaemia resulting from hypotension was less severe with epidural than with spinal anaesthesia [82-84). If hypotension following regional blockade was minimized by prehydration and/or prompt treatment with vasopressors, fetal acidaemia was negligible [85,86). 5. Effect of EDA on neonatal well-being In addition to fetal and neonatal blood chemistry, neonatal well-being is routinely assessed by APGAR score and neurobehavioural testing. The APGAR score evaluating colour, heart rate, reflex irritability, muscle tone and respiratory effort, is taken at I, 5 and 10 min after birth. A low I-min APGAR score poorly correlates with late outcome; correlation is slightly better for the 5-min score. Slow improvement of APGAR scores, however, can indicate an increased risk of brain damage. Therefore, neurological evaluation is a much more accurate method to assess CNS function of the newborn. The Brazelton neonatal behavioural assessment scale (BNBAS) consist of 49 items exploring tone, activity, reflexes and responses to stress and social interactive behaviour (87). The test must be performed by a specially trained observer and takes 45 min, which explains the scarce use of this test by anaesthetists and pediatricians in the delivery room. The Scanlon early neonatal neurobehavioural scale (ENNS) [88) is easier and faster to perform, evaluation of the 15 items does not need a specialized observer, but unlike the BNBAS, does not explore the behavioural aspects. The neurologic and adaptive capacity score (NACS) (89) consists of a neurological examination comprising 15 items in four sections (passive tone, active tone, primitive reflexes and general behaviour) and a behavioural evaluation with five items derived from the BNBAS. The normal score range from 35 to a maximum of 40

R. Scherer. W. Holzgreve / European Journal of Obstetrics & Gynecology and Reproductive Biology 59 (/995) S/7-S29

points. The neonates are tested 50 min and 2 h after birth and again after 24 h if the score was < 35. The NACS takes only 4-5 min to perform. Its 15 neurological items help to distinguish between drug effects and brain oedema caused by birth asphyxia or trauma [90]. 5.1. Influence of local anaesthetics

Bupivacaine, the most widely used local anaesthetic for epidural analgesia during labour, does reach the fetus in substantial amounts (Chapter I). Its relatively long half life of 14 h in the newborn [91], its known cardiotoxicity and its increased placental transfer during fetal acidaemia, could render bupivacaine a potentially troublesome drug in obstetrics. However, apart from transient abnormal fetal heart rate patterns, which occurred more frequently with bupivacaine, no significant differences in APGAR scores or acid-base status has been detected when bupivacaine was compared with lignocaine or chloroprocaine [92,93]. A reduced neonatal muscle tone has been associated with a mean total dose of bupivacaine of 130 mg [94]; other authors found a depressed sucking response 24 h after bupivacaine was used for caesarean section [95]. The vast majority of published studies, however, showed apparently complete absence of neonatal effects of bupivacaine [96,97] with excellent scores with ENNS [88,92] and NACS [93]. Lignocaine is rarely used for pain relief during labour, therefore few studies exist. Scanlon et al. [88] reported neonates whose mothers received lignocaine for epidural analgesia as being 'floppy but alert', compared with neonates born without maternal analgesia. A more recent study by Abboud et al. [98] attested to the relative safety of lignocaine even in high doses. Chloroprocaine, not approved in Europe, has not been related to any deleterious effects with regard to fetal heart rate, APGAR scores or acid-base status [92,93].

5.2. Influence of opioids

The epidural administration of opioids has the greatest potential of neonatal adverse effects. Morphine 2-4 mg given epidurally resulted in slight changes in alertness and general behaviour in six of eight neonates evaluated with ENNS [99]. In one of 20 neonates, a single epidural dose of 5 mg morphine to the mother was associated with repeated episodes of apnoea in the immediate post natal period [8]. Doses of up to 7.5 mg of morphine had no effect on APGAR score and NACS in 30 neonates [100]. Fentanyl in repeated doses of 150 p.g up to a total dose of 600 p.g induced respiratory depression in one out of

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38 neonates reported by Carrie et al. [101]. Small doses of fentanyl 100-150 p.g may produce respiratory depression in the mother [102] eventhough some authors claim that small doses of fentanyl seem devoid of depressant effects in mother and baby [103,104]. Alfentanil in a dose of about 200 p.g/kg given by continuous epidural infusion resulted in hypotonic infants with low NACS scores, though APGAR scores and umbilical pH were normal [105]. Pethidine, 100 mg given epidurally to mothers may be associated with normal APGAR scores or ENNS [106], but neonatal depression in three of 10 babies was also reported [107]. Sufentanil in a dose of < 50 p.g had no effect on APGAR scores [108]. However, epidural opioids are seldom given as the sole analgesic agent. More and more frequently, opioids are combined with local anaesthetics in low concentrations. The claimed advantages of this combination are reduction of total dose of both drugs, avoidance of major sympathetic and motor blockade, decreased incidence of instrumental delivery and an improvement of the analgesic quality [109]. Fentanyl has been the most widely studied drug in combination with lignocaine and bupivacaine. In general fentanyl seems to have little effect; normal fetal heart rate pattern and APGAR scores were associated with 100 p.g of fentanyl [110,111]. Even a mean total dose of 350 /log did not cause neonatal depression [112]. Alfentanil 0.05-1.0 mg did not cause fetal heart rate abnormalities or depressed APGAR, ENNS or NACS [113,114].

Sulfentanil seems to be the most promising opioid in obstetrical practice. As already mentioned above, to date sulfentanil could not be detected in fetal blood following an epidural dose of up to 30 /log [16,115]. In doses up to 30 /log sulfentanil in association with bupivacaine did not depress NACS or ENNS tests [109,116,117]. Higher doses, however, exceeding 50 /log resulted in neonatal depression with low NACS scores [116].

There is an increasing body of evidence that the addition of opioids to local anaesthetics decreases the incidence of instrumental delivery. Chestnut [118], adding 2 /log/ml of fentanyl to a continuous infusion of 0.0625% bupivacaine in the second stage of labour did not increase the instrumental delivery rate. Likewise Vertommen [109] showed that adding sulfentanil to a 0.125% bupivacaine solution led to a lower forceps rate than a larger dose of 0.125% bupivacaine. In summary, epidural analgesia definitively seems to have more beneficial than detrimental effects on fetal and neonatal well-being in normal and high-risk pregnancies. Possible deleterious effects mainly result from maternal hypotension and administration of large doses of local anaesthetics to the mother. Incremental doses of

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dilute local anaesthetic solutions and possibly the addition of opioids will improve the quality of analgesia during labour and increase fetal and neonatal safety. Even sophisticated monitoring techniques, such as the pulsed Doppler technique, were so far unable to detect previously unknown risks of epidural analgesia regarding blood flow to the fetus. Elaborate neurobehavioural tests could only describe subtle and transient alterations. Therefore, the anaesthetist has good arguments to reassure his obstetrical colleagues that providing epidural analgesia for pregnant women in labour is a justifiable intervention to support the natural process of child-bearing.

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