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Neonatal effects of adding epidural fentanyl to 0.5% bupivacaine for caesarean section
t,
1991
I.ongman
Group
llK
Ltd
International Journal of Obst tric Anest Resia
-
7
Neonatal effects of adding epidural fentanyl to 0.5% bupivacaine for caesarean section H. S. Helbo-Hansen, Department
U. Bang, P. Lindholm, N. A. Klitgaard
ofAnaesthesia and Department of Clinical Chemistry, Odense University Hospital. Denmark
S U M MA R Y. Epidural injection of opioids has been introduced to improve analgesia during labour and caesarean section. This study was designed to quantify placental transfer of fentanyl and to evaluate neonatal effects of adding fentanyl to 0.5% bupivacaine for epidural anaesthesia in women undergoing elective caesarean section at term. The parturients were randomly allocated to one of four groups of 20, who received either saline (control) or SO,75 or 100 pg of fentanyl added to 20 ml of 0.5% bupivacaine. Apgar scores, time to sustained respiration and umbilical acid-base values did not differ among the groups. The median (interquartile range) umbilical artery to maternal vein fentanyl concentration ratio was 0.34 (0.26-0.48) when the fentanyl groups were taken together. Neurologic and adaptive capacity scores were evaluated at 2 and 24 h. Neonates whose mothers received fentanyl had lower scores with regard to supporting reaction at 2 h and active tone at 24 h, when compared to controls (PC 0.05), but there were no differences among the groups with regard to the other test criteria in the neurohehavioural test. In conclusion, epidural injection of fentanyl SO-100 ug did not produce depression of the term neonate.
When opioids are administered to the mother during labour or caesarean section before the birth of the infant there is a risk of neonatal depression.’ The addition of epidural fentanyl to 0.5% bupivacaine has been introduced to improve analgesia during caesarean section,‘-‘0 but in the majority of the studies, the neonatal condition at delivery has only been evaluated by Apgar scores and umbilical cord acid-base measurements.2.3*5-10 These tests evaluate depression of vital functions, but they are insensitive to minor or delayed effects of drugs.” The present dose-response study was designed to evaluate the potential risk for neonatal respiratory depression by quantifying the placental transfer of fentanyl and to evaluate neonatal effects by using, in addition to the traditional tests, the Neurologic and Adaptive Capacity Scoring System (NACS), l2 which was specifically designed to detect central nervous system depression from drugs. MATERIAL AND METHODS Eighty neonates delivered by elective caesarean section under epidural anaesthesia were recruited to the H. S. Helbo-Hansen MD, U. Bang MD, P. Lindholm MD, Department of Anaesthesia, N.A. Klitgaard Lie Pharm, Department of Clinical Chemistry. Odense University Hospital, DK-5000 Odense C. Denmark. Correspondence to: H. S. Helbo-Hansen.
study. Exclusion criteria were: preeclampsia, diabetes mellitus, evidence of fetal distress, gestational age less than 36 weeks, birthweight less than 2.5 kg, multiple pregnancy, ruptured membranes and established labour. The study was approved by the local Ethics Committee and informed consent was obtained from the mothers. Eighty healthy women were assigned in a random double-blind fashion to four groups of 20, with each group receiving a different 2 ml study solution: saline (control) or 50, 75 or 100 ug of fentanyl added to 20 ml of 0.5% bupivacaine. The mixture was injected epidurally in 4 increments over 9 min. Further increments of bupivacaine without fentanyl were given as required to achieve a block extending to T4. Ephedrine 5-10 mg i.v. and/or atropine 0.5 mg i.v. were given as needed to maintain stable maternal circulation. Details concerning the anaesthetic technique and the mothers are reported elsewhere.13 At delivery, heparinized maternal venous blood samples were drawn from the arm contralateral to the iv. infusion. Umbilical arterial and venous blood samples were obtained from a segment of cord, doubly clamped before the baby’s first breath and heparinized. Umbilical cord vessel blood gas tensions and acid-base status were measured using an ABL-3 blood gas analyser (Radiometer, Denmark). Maternal and umbilical blood samples were centrifuged and
28
International
Journal
of Obstetric
Anesthesia
the plasma fractions stored at - 20°C until analysed by radioimmunoassay for fentanyl using a commercial kit (Diagnostic Product Corporation). All determinations were made in duplicate with a coefficient of variation (intra-assay and inter-assay) of 12%, 6.9% and 7.2% at the levels 0.050, 0.100 and 0.750 ng/ml, respectively. The detection limit defined as the lowest concentration of fentanyl discernible from zero was 0.030 ng/ml. The time from injection of the maternal epidural test dose to delivery, induction-delivery time (I-D time), the time from uterine incision to delivery (UD time) and the time from delivery to sustained respiration in the neonate (TSR) were recorded. The condition of the neonate was further evaluated using Apgar scores at 1 and 5 min and the NACS” at 15 min, 2 h and 24 h of age. Using 20 criteria, the NACS evaluates five categories: adaptive capacity, passive tone, active tone, primary reflexes, and general neurologic status. Each criterion is given a score of 0, 1 or 2, based on whether the response to testing that criterion is absent or grossly abnormal (0), mediocre or slightly abnormal (1) or normal (2). Therefore the maximum possible score is 40. Evaluation of the NACS at 24 h was postponed, if needed, to allow at least 2 h to elapse from the last meal. Statistical analysis Data are reported as median (range). Patient characteristics were analysed using the Kruskal-Wallis test and x2 test. Dependent variables (clinical data that might be influenced by the dose of fentanyl), were analysed using the x2 test for trend14 (nominal data)r5 or the Jonckheere test for ordered alternatives16 (ordinal and ratio/interval data)r5. Where differences existed, the fentanyl groups were compared pairwise with the control group using the Fisher exact test for 2 x 2 tables (nominal data) or the Mann-Whitney rank sum test (ordinal and ratio/interval data). Where no significant differences concerning the main outcome variables were found, the 95% confidence limits of the median difference between the control group and each of the fentanyl groups were calculated.” The Spearman non-parametric test as used to analyse for correlation between dependent variables and dose of fentanyl. Confidence intervals for the correlation coefficients were calculated.” A P value < 0.05 was considered statistically significant.
each. The groups were comparable with regard to maternal demographic data, gestational age, infant weight, parity and fetal presentation (Table 1). Median dose of bupivacaine per kg maternal body weight at term, incidence of mothers with systolic pressure less than 90 mmHg, I-D interval and U-D interval did not differ significantly among the groups, although the U-D interval was greater than 90 s in 3 babies in the control group and 1 in the fentanyl 50 ug group (Table 2). Apgar scores were in all cases 2 7 at 1 min and 28 at 5 min and similar in the four groups. The median TSR was lo-15 s with maximum values of 68, 120, 34 and 45 s in the control. fentanyl 50, 75, and 100 pg groups, respectively (Table 3). The median differences (with 95% confidence intervals) between the control group and the fentanyl 50, 75, and 100 ug groups were -4 (- 15 to 5 s), 2 (-4 to 10 s) and - 3 (- 10 to 5 s). respectively. Umbilical blood gas and acid-base values did not differ among the groups (Table 4). Sampling of umbilical cord blood failed in 1 neonate in the fentanyl 75 ng group. Fentanyl was detected in all maternal vein samples. However the umbilical vein fentanyl concentration was below the detection limit in 2 neonates, while the umbilical artery fentanyl concentration was below the detection limit in 4, 3 and 2 neonates in the fentanyl 50, 75 and 100 ug groups, respectively. Values below the detection limit were all given the same rank and were all included in the statistical calculations. The median maternal plasma concentration of fentanyl at delivery increased significantly (P< 0.0000 1) and nearly doubled when the epidural dose of fentanyl was doubled (Table 5). Also the median umbilical artery and vein concentrations of fentanyl increased significantly (P< 0.01 and P < 0.00001, respectively), but only by about 50% when the epidural dose of fentanyl was doubled. The fetal/maternal concentration ratios (Uv/Mv, Ua/Mv) and the umbilical arterial/venous ratio (UajUv) varied considerably among individuals. The Uv/Mv and Ua/Mv ratios decreased slightly (P= 0.025 and P= 0.0094, respectively) when the epidural Table 1. Patient characteristics. Values are median (range) or numbers (n). There were no significant differences among the groups
Gestational (weeks)
RESULTS Four neonates were withdrawn from because of birthweight less than 2.5 kg their mothers needed supplementation spinal or general anaesthesia before remaining neonates constituted four
Infant
the study, 2 and 2 because with either delivery. The groups of 19
Fentanyl
Fentanyl
Fentanyl
50 pg (n= 19)
75 pg (n= 19)
IOOpg (I?= 19)
39 (37-40)
;z-40)
39 (38-41)
$40)
3.3 (2.8-4.1)
3.3 (2.7-4.3)
3.5 (2.8-3.9)
3.2 (2.7-5.0)
15 4
11 8
14 5
13 6
8
II
9
7
Control (n= 19)
Groups
age
weight (kg)
Parity Primiparous Multiparous
(n) (n)
Breech presentation (n)
Neonatal
effects of adding
epidural
fentanyl
IO 0.5% bupivacaine
for caesarean
section
29
Table 2. Maternal dose of bupivacaine, time from test dose to delivery (I-D interval), time from uterine incision to delivery (U-D interval) and numbers of mothers with systolic pressure (SP) below 90 mmHg. Values are median (range) or numbers. There were no significant differences among the groups
Control (n= 19)
Groups
Matrrnal
dose of bupivacaine
1.83
mgikg)
(I .2-2.6) Maternal
SP < 90 mmHg
I-D Interval
(min)
U-D interval
(s)
Control (n= 19)
Apgar scores I min 01) 5 min (n)
Fentanyl
Fentanyl
50 pg (n= 19)
75 c1g 07 =
-I
TSR is)
IO (T-68)
15 (I-120)
Control
43 (15-77)
( I j--79)
Fentanyl 100 pg 19)
19)
(n=
I 0 15 (l-45)
IO (l-34)
Fentanyl
Fentanyl
75 pg
100 pg
17
I9
I7
19
uv pH
7.36 (7.30-7.40)
7.34 (7.31-7.40)
7.35 (7.30-7.38)
7.36 (7.32-7.39)
Uv PO, (kPa)
4.00 (2.80-5.33)
4.13 (2.40-5.33)
4.27 (X7-5.87)
3.73 (X53-5.33)
Uv PCO,
5.47 (4.80&5.40)
5.60 (4.67-6.53)
5.41 (4.80-6.00)
5.47 (4.93-6.27)
Uv base deficit (mEq.1)
2.1 (0.6-3.9)
3.1 (1.1-4.9)
3.2 (1.0-6.3)
2.4 (1.4-4.5)
Ua 01)
IX
I9
18
I9
Ua pH
7.30 (7.22-7.35)
7.30 (7.20-7.35)
7.30 (7.26-7.35)
7.31 (7.26-7.35)
Ua PO2 (kPa)
2.00 (0.93-3.47)
3.27 (1.07-3.73)
2.17 (0.93-3.87)
1.27 (0.67-4.00)
Ua PCO,
6.93 (6.00&8.40)
6.80 (5.47-8.13)
6.93 (5.47-7.73)
6.93 (5.20-7.60)
1.1 (0.5-4.4)
3.3 (0.3-9.8)
1.4 (0.0-6.1)
?.I (0.5-4.3)
(kPa)
(kPa)
Ua base d&it (mEq:l)
4
42 (12-120)
50 pg (111
J
54 (20-I 15)
Fentanyl
uv
I.65 (1.3~2.6)
55 (45-70)
Table 4. Umbilical vein (Uv) and umbilical artery (Ua) blood gas and acid-base data. Values are median (range). There were no significant differences among the groups
Groups
1.79 (I.’ 2.6)
5x (4X-75)
0 0
;
1.68
( I. I -2.4) 56 (47-71)
i 8 I 0
Fentanyl IO0 pg III- 19)
58 (50-76)
Table 3. Apgar scores and time to sustained respiration (TSR). Values are numbers of neonates (n) or median (range). There were no significant differences among the groups
Groups
Fentanyl 75 FL! (n= 19)
4
6
01)
Fentanyl 50 Llg (?I= I’))
dose of fentanyl was doubled, while the Ua/Uv ratio was similar in the three groups. The median (interquartile range) Uv/Mv, Ua/Mv and Ua/Uv ratios were 0.54 (0.43-0.72), 0.34 (0.26-0.48) and 0.71 (0.56-0.81), respectively, when the fentanyl groups were taken together. The percentage of infants who obtained a score of 2 in each of the individual criteria of the neurobehav-
35
ioural examination are presented in Table 6. Neonates whose mothers received fentanyl had lower scores for supporting reaction at 2 h compared to controls (P
DISCUSSION The risk of neonatal depression from maternal epidural administration of the highly lipophilic opioids alfentanil, fentanyl and sufentanil has been investigated by using neurobehavioural tests”.‘” -26 and by monitoring breathing patterns.2’.28 Neonatal depression did occur with the higher dose of alfentanil 30 ug/kg+ 30 t.tg/kg/h” and sufentanil 80 ug,” but not with alfentanil 5 ug/kg+ 1 ug/kg/h,2’ sufentanil 20-30 ug25.26 or with fentanyl 5Op IO0 pg. 4.19.23.24.27.28 None of the neonates in the present study showed any clinical signs of respiratory depression. and the time to sustained respiration was not affected by maternal fentanyl administration. This accords with a recent study in which the respiratory function of the neonates was closely monitored for the first 7 h following caesarean section. for which epidural fentanyl 100 ug had been administered to the mother,28 and with other studies during labour or caesarean
30 International Journal of Obstetric Anesthesia Table 5. Maternal dose of fentanyl, fentanyl concentration in maternal vein (Mv), umbilical vein (Uv), umbilical artery (Ua) and the Uv/ Mv, Ua/Mv and Ua/Uv ratios. Values are median (range)
Groups
Fentanyl 50 ug (II=19)
Fentanyl 75 ug (it= 18)
Fentanyl 100 ug 19)
P
(n=
Dose of fentanyl (ugkg)
0.65 (0.5-0.82)
0.99 (0.71-1.25)
1.33 (1.02-1.67)
< 0.00001
Mv (ngiml)
0.100 (0.040-O. 145)
0.114 (0.065-0.232)
0.198 (0.133-0.280)
~0.00001
Uv (ngiml)
0.061 (<0.030-0.117)
0.068 (0.049-0.095)
0.099 (0.053-0.131)
< 0.00001
Ua (ngiml)
0.042 (< 0.030-0.092)
0.050 (< 0.030-0.075)
0.066 (<0.030-O. 108)
0.007
Uv/Mv ratio
0.63 (<0.42-1.45)
0.51 (0.31-1.12)
0.53 (0.25-0.77)
0.025
Ua/Mv ratio
0.38 (<0.23-1.20)
0.34 (< 0.22-0.85)
0.29 (<0.21-0.67)
0.0094
Ua/Uv ratio
0.73 (n= 17) (<0.33-1.17)
(0.72 (0.31-1.12)
0.67 (~0.2990.86)
Table 6. Percentage of infants who scored 2 (best score) for each test item of the Neurologic cesarean section
Groups n
15 mm 0 19
NS
and Adaptive Capacity Score (NACS) after
50 I9
75 19
100 19
2h 0 I9
50 19
75 I9
100 I9
24 h 0 19
50 19
75 19
100 I9
Adaptive capacity Sound Habituation to sound Light Habituation to light Consolability
74 79 95 68 89
47 53 95 74 79
74 74 100 68 95
68 95 100 89 100
84 89 100 89 74
53 63 100 74 63
63 79 100 84 84
84 95 100 89 79
84 79 100 89 84
74 89 100 89 84
89 100 100 100 68
84 95 100 89 79
Passive tone Scarf sign Elbow recoil Popliteal angle Lower limb recoil
89 89 79 79
84 68 47 53
89 79 63 68
84 68 74 74
95 95 79 89
84 58 53 63
100 89 74 89
100 74 84 84
100 100 89 95
100 89 89 100
100 89 89 100
100 89 100 100
Active tone Neck flexors Neck extensors Palmar grasp Response to traction Supporting reaction
84 74 100 53 37
53 53 68 32 16
95 84 79 42 32
74 58 74 47 37
89 84 95 32 37
84 84 47 II 5*
95 95 58 32 5*
100 100 84 37 53
95 89 68 I6 42
100 100 74 32 26
89 89 58 21 32
Primary reflexes Automatic walking Moro Sucking
37 100 68
26 89 47
16 100 79
42 100 52
II 89 95
0 89 84
0 84 95
II 95 100
37 100 100
37 95 95
21 95 100
26 89 100
General assessment Alertness Crying Motor activity
100 89 89
79 79 74
100 95 100
100 100 100
100 74 100
74 58 68
95 84 95
100 74 100
100 84 100
89 84 100
100 74 100
100 79 100
95 89 79 II 5*
*P< 0.05 when compared with the control group (group 0).
delivery in which fentanyl had been administered epidurally to the mother without clinical signs of respiratory depression in the neonate.2-9.19~23*24*27-29 In adult patients and healthy adult volunteers, plasma fentanyl levels of l-2 ng/ml have been associated with a slight depression of the ventilatory response to C02, whereas levels of 2-4.6 ng/ml were found to produce a 50% depression of the CO, response curve. 30-34 Similar studies have not been
performed in the newborn, but it is likely that they are more sensitive to the respiratory depressant effect of fentanyl.35-38 In a study on neonates undergoing major surgical procedures, during which 25-50 ug of fentanyl were given intravenously as part of the anaesthetic technique, the decision to extubate was taken at plasma fentanyl levels of 0.050-0.770 ng/ ml 39 This is close to the highest plasma fentanyl concentrations measured in the present study (0.066
Neonatal
effects of adding
epidural
fentanyl
to 0.5% bupivacaine
for caesarean
Table 7. Percentage of infants with maximum score at each category of the Neurologic and Adaptive Capacity Score (NAB) caesarean section, and percentage of infants with total score of 35-40
section
3I
after
15min 0 19
50 19
75 19
100 19
2h 0 19
50 19
75 19
too 19
24 h 0 19
50 I9
75 I9
100
53
32
47
53
42
27
53
5X
5X
63
5X
63
Passive tone
6X
42
47
53
74
42
6X
6X
95
X4
79
X9
Active tone
21
0
5
I6
I6
0
0
0
37
I6
5’
Groups
n Adaptive
capacity
5*
I9
27
21
I6
21
II
0
0
5
37
32
‘I
21
General assessment Total score 35-40
X4 53
68 5
95 32
100 42
74 47
5X 27
84 41
74 47
X4 6X
79 5x
74 53
63
*PC 0.05 when compared
with the control
1.0
1.2
Primary
reflexes
group
(group
Total NACS’score
79
0).
at 15 minutes
15 --
5 -o-
1 0.0
0.2
0.4
0.6
0.6
1.4
1.6
I 1.6
Maternal dose of fentanyl @g/kg) Figure-Total NACS score and epidurai dose of fentanyl per kg maternal correlation (correlation coefficient with 95% confidence limits 0.12 (-0.1 NACS score.
and 0.099 ng/ml in umbilical artery and umbilical vein. respectively) and the safety margin may therefore be small. A few cases of neonatal respiratory depression following epidural administration of fentanyl to the mother have already been reported.‘0.40 In one of these cases an umbilical arterial fentanyl concentration of 0.250 ng/ml was measured, but in neither of the cases, however, was it possible to incriminate or definitely to exclude fentanyl as the cause of the infants condition. Neurobehavioural testing in the present study revealed subtle differences as the neonates whose mothers received fentanyl had lower scores at 2 h compared to controls in the criterion supporting reaction. and at 24 h in the category active tone (which includes supporting reaction). The significance of these findings should be considered with care, however, as none of the other signs normally associated with opioid depression, such as mild hypotonia, mediocre primary reflex responses and absent or poor habituation to repeated stimuliZ0.21.41.42were present and no correlations between the dose of fentanyl and
body weight at 15 min after delivery.
There was no
I to 0.34, P value 0.30) between the dose of fentanyl and total
the total NACS at 15 min, 2 h or 24 h were found. Furthermore, no allowances were made for the multiple comparisons and moreover the differences were found in the criterion supporting reaction, which may be difficult to evaluate in neonates who had presented by the breech. The median Ua/Uv ratio of fentanyl did not vary among the fentanyl groups and the median ratio of 0.71 in the groups taken together indicates that the drug redistribution process throughout the fetus was not yet complete at delivery. Though free fentanyl equilibrates rapidly across the placental membrane and even unbinds from plasma proteins in a single transit of the placenta,43 equilibration throughout the fetal compartment clearly takes longer. Fentanyl does not, however, affect uterine blood flo~.~ In the fentanyl groups taken together the median Ua/Mv ratio was 0.34. In comparison Milon et al reported a mean Ua/Mv ratio of 0.52 following an epidural dose of 1 ug/kg,* while Craft et aP found a Ua/Mv ratio of 0.40 following an i.v. dose of 50-100 ug of fentanyl in pregnant ewes. The fetal/maternal gradient
32
International Journal of Obstetric Anesthesia
is, for some drugs, most likely related to differences in plasma protein binding between mother and baby, as well as to the ongoing redistribution process in the fetus. Fentanyl is a weak base (pKa 8.43) which is highly protein bound to a,-acid glycoprotein, albumin and to a lesser extent to o?- and p-globulins.38 The protein binding is pH-dependent (protein binding 84.4% at pH 7.4 and 80.4% at pH 7.2) but independent of plasma fentanyl concentration.38 As at term q-acid glycoprotein concentrations are less37 and albumin concentrations are greater45 in the fetus than in the mother, the results of the present study are in accordance with the view that fentanyl is not bound predominantly to albumin,38 as otherwise stated by Bower.46 Despite similar doses of fentanyl, the concentrations in the present study were lower than those Since plasma fentanyl reported by others. 2*4*8*24*40 concentrations peak within 5- 10 min following epidural administration47-49 and have been shown to decline at roughly parallel rates in ewe and lamb,44 the lower concentrations may be explained by the longer I-D intervals in the present study. In conclusion, epidural administration of fentanyl 50-100 ug added to 0.5% bupivacaine at elective caesarean section did not depress the term neonate. The umbilical plasma fentanyl concentrations, however, indicate that the safety margin is small implying that it is important to choose the lowest effective dose of fentanyl for improvement of epidural anaesthesia before delivery.
9
10
11
12.
13.
14. 15.
16.
17.
18.
19.
20.
Acknowledgements The study was supported by a grant from Oberstinde Jensa la Cours forskningslegat.
21. Kirsten 22.
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28
29.
blind comparison of epidural bupivacaine and bupivacaine-fentanyl for caesarean section. Anaesth Intensive Care 1990; 18: 22-30. Breen T W. Janzen J A. Fentanyl supplementation of epidural anaesthesia for caesarean section: comparison of two methods. Can Sot J Anaesth 1991; 38: Al 19. Noble D W, Morrison L M, Brockway M S. McClure J H. Adrenaline, fentanyl or adrenaline and fentanyl as adjuncts to bupivacaine for extradural anaesthesia in elective caesarean section. Br J Anaesth 1991: 66: 645-650. Cohen S E. Evaluation of the neonate. In: Shnider S M, Levinson G, eds. Anesthesia for obstetrics. Baltimore: Williams & Wilkins. 1987: 489-507. Amiel-Tison C, Barrier G, Shnider S’M, Levinson G. Hughes S C, Stefani S J. A new neurologic and adaptive capacity scoring system for evaluating obstetric medications in full-term newborns. Anesthesiology 1982; 56: 340-350. Helbo-Hansen H S, Bang U, Lindholm P, Klitgaard N A. Maternal effects of adding epidural fentanyl to 0.5% bupivacaine for caesarean section. Int J Obstet Anesth 1993; 2: 27-33. Kirkwood B R. Essentials of medical statistics. Oxford: Blackwell. 1988: 102-104. Siegel S, Castellan N J. Nonparametric statistics for the behavioral sciences. Singapore: McGraw-Hill, 1988: 23-36. Siegel S, Castellan N J. Nonparametric statistics for the behavioral sciences. Singapore: McGraw-Hill. 1988: 216-223. Campbell M J, Gardner M J. Calculating confidence intervals for some non-parametric analyses. Br Med J 1988: 296: 145441456. Altman D G. Gardner M J. Calculating confidence intervals for regression and correlation. Br Med J 1988; 296: 1238-1242. Cohen S E, Shirley T, Albright G A, Halpern J. Epidural fentanyl/bupivacaine mixtures for obstetric analgesia. Anesthesiology 1987; 67: 403-407. Heytens L, Cammu H, Camu F. Extradural analgesia during labour using alfentanil. Br J Anaesth 1987; 59: 331-337. Capogna G, Celleno D, Tomassetti M. Maternal analgesia and neonatal effects of epidural sufentanil for cesarean section. Reg Anesth 1989; 14: 282-287. Kavuri S. Janardhan Y. Fernando E, Shevde K, Eddi D. A comparative study of epidural alfentanil and fentanyl for labor pain relief. Anesthesiology 1989; 71: A846. Hoyt M, Youngstrom P. Neonatal neurobehavioral effects of continuous epidural infusion of fentanyl/ bupivacaine/epinephrine in labor. Anesthesiology 1990; 13: A984. Palot M. Visseaux H. Levron J C. Le Moing J P, Rendoing J. Pharmacokinetics in mothers and neonates of fentanyl, alfentanil and sufentanil administered by epidural continuous infusion during labor. Anesthesiology 1990; 73: Al002. Vertommen J D, van Aken H, Vandermeulen E et al. Maternal and neonatal effects of adding epidural sufentanil to 0.5% bupivacaine for cesarean delivery. J Clin Anesth 1991: 3: 371-376. Vertommen J D. Vandermeulen E, van Aken H et al. The effects of the addition of sufentanil to 0.125% bupivacaine on the quality of analgesia during labor and on the incidence of instrumental deliveries. Anesthesiology 1991; 74: 809-8 14. Francke V A. Frahm R, Nagel H. Adaptationsverhalten reifer neugeborener nach geburtshilflicher schmertzbekampfung mit periduralem fentanyl. Zentralbl Gynakol 1989; I I 1: l572- 1579. Benlabed M, Dreizzen E, Ecoffey C, Escourrou P. Migdal M. Gaultier C. Neonatal patterns of breathing after cesarean section with or without epidural fentanyl. Anesthesiology 1990; 73: I I IO-1 I 13. Chestnut D H. Laszewski L J, Pollack K L, Bates
Neonatal
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
effects of adding
J N. Manago N K, Choi W W. Continous epidural infusion of 0.0625% bupivacaine - 0.0002% fentanyl during the second stage of labor. Anesthesiology 1990; 72: 613-618. Fung D L. Eisele J H. Narcotic concentrationrespiratory effect curves in man. Anesthesiology 1980: 53: s397. Andrews C J H. Sinclair M. Dye A. Dye J, Harvey J, Prys-Roberts C. The additive effect of nitrous oxide on respiratory depression in patients having fentanyl or alfentanil infusions. Br J Anaesth 1982: 54: 1129 (abstract). Stoeckel H. Schiittler J. Magnussen H. Hengstmann J H. Plasma fentanyl concentrations and the occurrence of respiratory depression in volunteers. Br J Anaesth 1982; 54: 1087-1095. Cartwright P. Prys-Roberts C, Gill K. Dye A. Stafford M. Gray A. Vcntilatory depression related to plasma fentanyl concentrations during and after anesthesia in humans. Anesth Analg 1983; 62: 966674. Negre I. Gueneron J P. Ecoffey C et al. Ventilatory response to carbon dioxide after intramuscular and epidura) fentanyl. Anesth Analg 1987; 66: 707-710. Kupferberg H J, Way E L. Pharmacologic basis for the increased sensitivity of the newborn rat to morphine. J Pharmacol Exp Ther 1963; 141: 1055112. Way W L, Costley E C. Way E L. Respiratory scnsitivrty of the newborn infant to meperidine and morphine. Clin Pharmacol Ther 1965: 6: 4544461. Wood M. Wood A J J. Changes in plasma drug binding and a,-acid glycoprotein in mother and infant. Clin Pharmacol Ther 1981: 29: 522-526. Meuldermans W E G, Hurkmans R M A. Heykants J J P. Plasma protein binding and distribution of fentanyl. sufentanil. alfentanil and lofentanil in blood. Arch Int Pharmacodyn Ther 1982: 257: 4-19. Koehntop D E, Rodman J H. Brundage D M,
epidural
40. 41.
42.
43.
44.
45.
46. 47.
48.
49.
fentanyl
to 0.5% bupivacaine
for caesarean
section
Hegland M G, Buckley J J. Pharmacokinetics of fentanyl in neonates. Anesth Analg 1986; 65: 227- 232. Carrie L E S. O’Sullivan G M, Seegobin R. Epidural fentanyl in labour. Anaesthesia 1981; 36: 9655969. Scanlon J W, Brown W U Jr. Weiss J B. Alper M H. Neurobehavioral responses of newborn infants after maternal epidural anesthesia. Anesthesiology 1974: 40: l?l-128. Brackbill Y, Kane J, Manniello R L. Abramson D. Obstetric meperidine usage and assessment 01 neonatal status, Anesthesiology 1974: 30: I I h- 120. Vella L M. Knott C, Reynolds F. Transfer of fentanyl across the rabbit placenta. Effect of umbilical flow and concurrent drug administration. Br J Anaesth 1986; 58: 49954. Craft J B Jr. Coaldrake L A. Bolan J c‘ et al. Placental passage and uterine effects of fentanyl. Anesth Analg 1983: 62: 894-898. Ganrot P 0. Variation of the concentrations of some plasma proteins in normal adults, in pregnant women and in newborns. Stand J Clin Lab Invest 1972; 39 (suppl 124): X3--88. Bower S. Plasma protein binding of fentanyl. J Pharm Pharmacol 1981; 33: 507-514. Justins D M, Knott C. Luthman J. Reynolds F. Epidura) versus intramuscular fentanyl. Analgesia and pharmacokinetics in labour. Anaesthesia 1983: 3X: 937-942. Lomessy A. Magnin C. Viale J P, Motin J, Cohen R. Clinical advantages of fentanyl given epidurally for postoperative analgesia. Anesthesiology IYX4: 61: 466469. Ahuja B R. Strunin L. Respiratory effects of epidural fentanyl. Changes in endtidal COz and respiratory rate following single doses and continuous infusions of epidural fentanyl. Anaesthesia 1985: 3U 949 955.
33
1991
I.ongman
Group
llK
Ltd
International Journal of Obst tric Anest Resia
-
7
Neonatal effects of adding epidural fentanyl to 0.5% bupivacaine for caesarean section H. S. Helbo-Hansen, Department
U. Bang, P. Lindholm, N. A. Klitgaard
ofAnaesthesia and Department of Clinical Chemistry, Odense University Hospital. Denmark
S U M MA R Y. Epidural injection of opioids has been introduced to improve analgesia during labour and caesarean section. This study was designed to quantify placental transfer of fentanyl and to evaluate neonatal effects of adding fentanyl to 0.5% bupivacaine for epidural anaesthesia in women undergoing elective caesarean section at term. The parturients were randomly allocated to one of four groups of 20, who received either saline (control) or SO,75 or 100 pg of fentanyl added to 20 ml of 0.5% bupivacaine. Apgar scores, time to sustained respiration and umbilical acid-base values did not differ among the groups. The median (interquartile range) umbilical artery to maternal vein fentanyl concentration ratio was 0.34 (0.26-0.48) when the fentanyl groups were taken together. Neurologic and adaptive capacity scores were evaluated at 2 and 24 h. Neonates whose mothers received fentanyl had lower scores with regard to supporting reaction at 2 h and active tone at 24 h, when compared to controls (PC 0.05), but there were no differences among the groups with regard to the other test criteria in the neurohehavioural test. In conclusion, epidural injection of fentanyl SO-100 ug did not produce depression of the term neonate.
When opioids are administered to the mother during labour or caesarean section before the birth of the infant there is a risk of neonatal depression.’ The addition of epidural fentanyl to 0.5% bupivacaine has been introduced to improve analgesia during caesarean section,‘-‘0 but in the majority of the studies, the neonatal condition at delivery has only been evaluated by Apgar scores and umbilical cord acid-base measurements.2.3*5-10 These tests evaluate depression of vital functions, but they are insensitive to minor or delayed effects of drugs.” The present dose-response study was designed to evaluate the potential risk for neonatal respiratory depression by quantifying the placental transfer of fentanyl and to evaluate neonatal effects by using, in addition to the traditional tests, the Neurologic and Adaptive Capacity Scoring System (NACS), l2 which was specifically designed to detect central nervous system depression from drugs. MATERIAL AND METHODS Eighty neonates delivered by elective caesarean section under epidural anaesthesia were recruited to the H. S. Helbo-Hansen MD, U. Bang MD, P. Lindholm MD, Department of Anaesthesia, N.A. Klitgaard Lie Pharm, Department of Clinical Chemistry. Odense University Hospital, DK-5000 Odense C. Denmark. Correspondence to: H. S. Helbo-Hansen.
study. Exclusion criteria were: preeclampsia, diabetes mellitus, evidence of fetal distress, gestational age less than 36 weeks, birthweight less than 2.5 kg, multiple pregnancy, ruptured membranes and established labour. The study was approved by the local Ethics Committee and informed consent was obtained from the mothers. Eighty healthy women were assigned in a random double-blind fashion to four groups of 20, with each group receiving a different 2 ml study solution: saline (control) or 50, 75 or 100 ug of fentanyl added to 20 ml of 0.5% bupivacaine. The mixture was injected epidurally in 4 increments over 9 min. Further increments of bupivacaine without fentanyl were given as required to achieve a block extending to T4. Ephedrine 5-10 mg i.v. and/or atropine 0.5 mg i.v. were given as needed to maintain stable maternal circulation. Details concerning the anaesthetic technique and the mothers are reported elsewhere.13 At delivery, heparinized maternal venous blood samples were drawn from the arm contralateral to the iv. infusion. Umbilical arterial and venous blood samples were obtained from a segment of cord, doubly clamped before the baby’s first breath and heparinized. Umbilical cord vessel blood gas tensions and acid-base status were measured using an ABL-3 blood gas analyser (Radiometer, Denmark). Maternal and umbilical blood samples were centrifuged and
28
International
Journal
of Obstetric
Anesthesia
the plasma fractions stored at - 20°C until analysed by radioimmunoassay for fentanyl using a commercial kit (Diagnostic Product Corporation). All determinations were made in duplicate with a coefficient of variation (intra-assay and inter-assay) of 12%, 6.9% and 7.2% at the levels 0.050, 0.100 and 0.750 ng/ml, respectively. The detection limit defined as the lowest concentration of fentanyl discernible from zero was 0.030 ng/ml. The time from injection of the maternal epidural test dose to delivery, induction-delivery time (I-D time), the time from uterine incision to delivery (UD time) and the time from delivery to sustained respiration in the neonate (TSR) were recorded. The condition of the neonate was further evaluated using Apgar scores at 1 and 5 min and the NACS” at 15 min, 2 h and 24 h of age. Using 20 criteria, the NACS evaluates five categories: adaptive capacity, passive tone, active tone, primary reflexes, and general neurologic status. Each criterion is given a score of 0, 1 or 2, based on whether the response to testing that criterion is absent or grossly abnormal (0), mediocre or slightly abnormal (1) or normal (2). Therefore the maximum possible score is 40. Evaluation of the NACS at 24 h was postponed, if needed, to allow at least 2 h to elapse from the last meal. Statistical analysis Data are reported as median (range). Patient characteristics were analysed using the Kruskal-Wallis test and x2 test. Dependent variables (clinical data that might be influenced by the dose of fentanyl), were analysed using the x2 test for trend14 (nominal data)r5 or the Jonckheere test for ordered alternatives16 (ordinal and ratio/interval data)r5. Where differences existed, the fentanyl groups were compared pairwise with the control group using the Fisher exact test for 2 x 2 tables (nominal data) or the Mann-Whitney rank sum test (ordinal and ratio/interval data). Where no significant differences concerning the main outcome variables were found, the 95% confidence limits of the median difference between the control group and each of the fentanyl groups were calculated.” The Spearman non-parametric test as used to analyse for correlation between dependent variables and dose of fentanyl. Confidence intervals for the correlation coefficients were calculated.” A P value < 0.05 was considered statistically significant.
each. The groups were comparable with regard to maternal demographic data, gestational age, infant weight, parity and fetal presentation (Table 1). Median dose of bupivacaine per kg maternal body weight at term, incidence of mothers with systolic pressure less than 90 mmHg, I-D interval and U-D interval did not differ significantly among the groups, although the U-D interval was greater than 90 s in 3 babies in the control group and 1 in the fentanyl 50 ug group (Table 2). Apgar scores were in all cases 2 7 at 1 min and 28 at 5 min and similar in the four groups. The median TSR was lo-15 s with maximum values of 68, 120, 34 and 45 s in the control. fentanyl 50, 75, and 100 pg groups, respectively (Table 3). The median differences (with 95% confidence intervals) between the control group and the fentanyl 50, 75, and 100 ug groups were -4 (- 15 to 5 s), 2 (-4 to 10 s) and - 3 (- 10 to 5 s). respectively. Umbilical blood gas and acid-base values did not differ among the groups (Table 4). Sampling of umbilical cord blood failed in 1 neonate in the fentanyl 75 ng group. Fentanyl was detected in all maternal vein samples. However the umbilical vein fentanyl concentration was below the detection limit in 2 neonates, while the umbilical artery fentanyl concentration was below the detection limit in 4, 3 and 2 neonates in the fentanyl 50, 75 and 100 ug groups, respectively. Values below the detection limit were all given the same rank and were all included in the statistical calculations. The median maternal plasma concentration of fentanyl at delivery increased significantly (P< 0.0000 1) and nearly doubled when the epidural dose of fentanyl was doubled (Table 5). Also the median umbilical artery and vein concentrations of fentanyl increased significantly (P< 0.01 and P < 0.00001, respectively), but only by about 50% when the epidural dose of fentanyl was doubled. The fetal/maternal concentration ratios (Uv/Mv, Ua/Mv) and the umbilical arterial/venous ratio (UajUv) varied considerably among individuals. The Uv/Mv and Ua/Mv ratios decreased slightly (P= 0.025 and P= 0.0094, respectively) when the epidural Table 1. Patient characteristics. Values are median (range) or numbers (n). There were no significant differences among the groups
Gestational (weeks)
RESULTS Four neonates were withdrawn from because of birthweight less than 2.5 kg their mothers needed supplementation spinal or general anaesthesia before remaining neonates constituted four
Infant
the study, 2 and 2 because with either delivery. The groups of 19
Fentanyl
Fentanyl
Fentanyl
50 pg (n= 19)
75 pg (n= 19)
IOOpg (I?= 19)
39 (37-40)
;z-40)
39 (38-41)
$40)
3.3 (2.8-4.1)
3.3 (2.7-4.3)
3.5 (2.8-3.9)
3.2 (2.7-5.0)
15 4
11 8
14 5
13 6
8
II
9
7
Control (n= 19)
Groups
age
weight (kg)
Parity Primiparous Multiparous
(n) (n)
Breech presentation (n)
Neonatal
effects of adding
epidural
fentanyl
IO 0.5% bupivacaine
for caesarean
section
29
Table 2. Maternal dose of bupivacaine, time from test dose to delivery (I-D interval), time from uterine incision to delivery (U-D interval) and numbers of mothers with systolic pressure (SP) below 90 mmHg. Values are median (range) or numbers. There were no significant differences among the groups
Control (n= 19)
Groups
Matrrnal
dose of bupivacaine
1.83
mgikg)
(I .2-2.6) Maternal
SP < 90 mmHg
I-D Interval
(min)
U-D interval
(s)
Control (n= 19)
Apgar scores I min 01) 5 min (n)
Fentanyl
Fentanyl
50 pg (n= 19)
75 c1g 07 =
-I
TSR is)
IO (T-68)
15 (I-120)
Control
43 (15-77)
( I j--79)
Fentanyl 100 pg 19)
19)
(n=
I 0 15 (l-45)
IO (l-34)
Fentanyl
Fentanyl
75 pg
100 pg
17
I9
I7
19
uv pH
7.36 (7.30-7.40)
7.34 (7.31-7.40)
7.35 (7.30-7.38)
7.36 (7.32-7.39)
Uv PO, (kPa)
4.00 (2.80-5.33)
4.13 (2.40-5.33)
4.27 (X7-5.87)
3.73 (X53-5.33)
Uv PCO,
5.47 (4.80&5.40)
5.60 (4.67-6.53)
5.41 (4.80-6.00)
5.47 (4.93-6.27)
Uv base deficit (mEq.1)
2.1 (0.6-3.9)
3.1 (1.1-4.9)
3.2 (1.0-6.3)
2.4 (1.4-4.5)
Ua 01)
IX
I9
18
I9
Ua pH
7.30 (7.22-7.35)
7.30 (7.20-7.35)
7.30 (7.26-7.35)
7.31 (7.26-7.35)
Ua PO2 (kPa)
2.00 (0.93-3.47)
3.27 (1.07-3.73)
2.17 (0.93-3.87)
1.27 (0.67-4.00)
Ua PCO,
6.93 (6.00&8.40)
6.80 (5.47-8.13)
6.93 (5.47-7.73)
6.93 (5.20-7.60)
1.1 (0.5-4.4)
3.3 (0.3-9.8)
1.4 (0.0-6.1)
?.I (0.5-4.3)
(kPa)
(kPa)
Ua base d&it (mEq:l)
4
42 (12-120)
50 pg (111
J
54 (20-I 15)
Fentanyl
uv
I.65 (1.3~2.6)
55 (45-70)
Table 4. Umbilical vein (Uv) and umbilical artery (Ua) blood gas and acid-base data. Values are median (range). There were no significant differences among the groups
Groups
1.79 (I.’ 2.6)
5x (4X-75)
0 0
;
1.68
( I. I -2.4) 56 (47-71)
i 8 I 0
Fentanyl IO0 pg III- 19)
58 (50-76)
Table 3. Apgar scores and time to sustained respiration (TSR). Values are numbers of neonates (n) or median (range). There were no significant differences among the groups
Groups
Fentanyl 75 FL! (n= 19)
4
6
01)
Fentanyl 50 Llg (?I= I’))
dose of fentanyl was doubled, while the Ua/Uv ratio was similar in the three groups. The median (interquartile range) Uv/Mv, Ua/Mv and Ua/Uv ratios were 0.54 (0.43-0.72), 0.34 (0.26-0.48) and 0.71 (0.56-0.81), respectively, when the fentanyl groups were taken together. The percentage of infants who obtained a score of 2 in each of the individual criteria of the neurobehav-
35
ioural examination are presented in Table 6. Neonates whose mothers received fentanyl had lower scores for supporting reaction at 2 h compared to controls (P
DISCUSSION The risk of neonatal depression from maternal epidural administration of the highly lipophilic opioids alfentanil, fentanyl and sufentanil has been investigated by using neurobehavioural tests”.‘” -26 and by monitoring breathing patterns.2’.28 Neonatal depression did occur with the higher dose of alfentanil 30 ug/kg+ 30 t.tg/kg/h” and sufentanil 80 ug,” but not with alfentanil 5 ug/kg+ 1 ug/kg/h,2’ sufentanil 20-30 ug25.26 or with fentanyl 5Op IO0 pg. 4.19.23.24.27.28 None of the neonates in the present study showed any clinical signs of respiratory depression. and the time to sustained respiration was not affected by maternal fentanyl administration. This accords with a recent study in which the respiratory function of the neonates was closely monitored for the first 7 h following caesarean section. for which epidural fentanyl 100 ug had been administered to the mother,28 and with other studies during labour or caesarean
30 International Journal of Obstetric Anesthesia Table 5. Maternal dose of fentanyl, fentanyl concentration in maternal vein (Mv), umbilical vein (Uv), umbilical artery (Ua) and the Uv/ Mv, Ua/Mv and Ua/Uv ratios. Values are median (range)
Groups
Fentanyl 50 ug (II=19)
Fentanyl 75 ug (it= 18)
Fentanyl 100 ug 19)
P
(n=
Dose of fentanyl (ugkg)
0.65 (0.5-0.82)
0.99 (0.71-1.25)
1.33 (1.02-1.67)
< 0.00001
Mv (ngiml)
0.100 (0.040-O. 145)
0.114 (0.065-0.232)
0.198 (0.133-0.280)
~0.00001
Uv (ngiml)
0.061 (<0.030-0.117)
0.068 (0.049-0.095)
0.099 (0.053-0.131)
< 0.00001
Ua (ngiml)
0.042 (< 0.030-0.092)
0.050 (< 0.030-0.075)
0.066 (<0.030-O. 108)
0.007
Uv/Mv ratio
0.63 (<0.42-1.45)
0.51 (0.31-1.12)
0.53 (0.25-0.77)
0.025
Ua/Mv ratio
0.38 (<0.23-1.20)
0.34 (< 0.22-0.85)
0.29 (<0.21-0.67)
0.0094
Ua/Uv ratio
0.73 (n= 17) (<0.33-1.17)
(0.72 (0.31-1.12)
0.67 (~0.2990.86)
Table 6. Percentage of infants who scored 2 (best score) for each test item of the Neurologic cesarean section
Groups n
15 mm 0 19
NS
and Adaptive Capacity Score (NACS) after
50 I9
75 19
100 19
2h 0 I9
50 19
75 I9
100 I9
24 h 0 19
50 19
75 19
100 I9
Adaptive capacity Sound Habituation to sound Light Habituation to light Consolability
74 79 95 68 89
47 53 95 74 79
74 74 100 68 95
68 95 100 89 100
84 89 100 89 74
53 63 100 74 63
63 79 100 84 84
84 95 100 89 79
84 79 100 89 84
74 89 100 89 84
89 100 100 100 68
84 95 100 89 79
Passive tone Scarf sign Elbow recoil Popliteal angle Lower limb recoil
89 89 79 79
84 68 47 53
89 79 63 68
84 68 74 74
95 95 79 89
84 58 53 63
100 89 74 89
100 74 84 84
100 100 89 95
100 89 89 100
100 89 89 100
100 89 100 100
Active tone Neck flexors Neck extensors Palmar grasp Response to traction Supporting reaction
84 74 100 53 37
53 53 68 32 16
95 84 79 42 32
74 58 74 47 37
89 84 95 32 37
84 84 47 II 5*
95 95 58 32 5*
100 100 84 37 53
95 89 68 I6 42
100 100 74 32 26
89 89 58 21 32
Primary reflexes Automatic walking Moro Sucking
37 100 68
26 89 47
16 100 79
42 100 52
II 89 95
0 89 84
0 84 95
II 95 100
37 100 100
37 95 95
21 95 100
26 89 100
General assessment Alertness Crying Motor activity
100 89 89
79 79 74
100 95 100
100 100 100
100 74 100
74 58 68
95 84 95
100 74 100
100 84 100
89 84 100
100 74 100
100 79 100
95 89 79 II 5*
*P< 0.05 when compared with the control group (group 0).
delivery in which fentanyl had been administered epidurally to the mother without clinical signs of respiratory depression in the neonate.2-9.19~23*24*27-29 In adult patients and healthy adult volunteers, plasma fentanyl levels of l-2 ng/ml have been associated with a slight depression of the ventilatory response to C02, whereas levels of 2-4.6 ng/ml were found to produce a 50% depression of the CO, response curve. 30-34 Similar studies have not been
performed in the newborn, but it is likely that they are more sensitive to the respiratory depressant effect of fentanyl.35-38 In a study on neonates undergoing major surgical procedures, during which 25-50 ug of fentanyl were given intravenously as part of the anaesthetic technique, the decision to extubate was taken at plasma fentanyl levels of 0.050-0.770 ng/ ml 39 This is close to the highest plasma fentanyl concentrations measured in the present study (0.066
Neonatal
effects of adding
epidural
fentanyl
to 0.5% bupivacaine
for caesarean
Table 7. Percentage of infants with maximum score at each category of the Neurologic and Adaptive Capacity Score (NAB) caesarean section, and percentage of infants with total score of 35-40
section
3I
after
15min 0 19
50 19
75 19
100 19
2h 0 19
50 19
75 19
too 19
24 h 0 19
50 I9
75 I9
100
53
32
47
53
42
27
53
5X
5X
63
5X
63
Passive tone
6X
42
47
53
74
42
6X
6X
95
X4
79
X9
Active tone
21
0
5
I6
I6
0
0
0
37
I6
5’
Groups
n Adaptive
capacity
5*
I9
27
21
I6
21
II
0
0
5
37
32
‘I
21
General assessment Total score 35-40
X4 53
68 5
95 32
100 42
74 47
5X 27
84 41
74 47
X4 6X
79 5x
74 53
63
*PC 0.05 when compared
with the control
1.0
1.2
Primary
reflexes
group
(group
Total NACS’score
79
0).
at 15 minutes
15 --
5 -o-
1 0.0
0.2
0.4
0.6
0.6
1.4
1.6
I 1.6
Maternal dose of fentanyl @g/kg) Figure-Total NACS score and epidurai dose of fentanyl per kg maternal correlation (correlation coefficient with 95% confidence limits 0.12 (-0.1 NACS score.
and 0.099 ng/ml in umbilical artery and umbilical vein. respectively) and the safety margin may therefore be small. A few cases of neonatal respiratory depression following epidural administration of fentanyl to the mother have already been reported.‘0.40 In one of these cases an umbilical arterial fentanyl concentration of 0.250 ng/ml was measured, but in neither of the cases, however, was it possible to incriminate or definitely to exclude fentanyl as the cause of the infants condition. Neurobehavioural testing in the present study revealed subtle differences as the neonates whose mothers received fentanyl had lower scores at 2 h compared to controls in the criterion supporting reaction. and at 24 h in the category active tone (which includes supporting reaction). The significance of these findings should be considered with care, however, as none of the other signs normally associated with opioid depression, such as mild hypotonia, mediocre primary reflex responses and absent or poor habituation to repeated stimuliZ0.21.41.42were present and no correlations between the dose of fentanyl and
body weight at 15 min after delivery.
There was no
I to 0.34, P value 0.30) between the dose of fentanyl and total
the total NACS at 15 min, 2 h or 24 h were found. Furthermore, no allowances were made for the multiple comparisons and moreover the differences were found in the criterion supporting reaction, which may be difficult to evaluate in neonates who had presented by the breech. The median Ua/Uv ratio of fentanyl did not vary among the fentanyl groups and the median ratio of 0.71 in the groups taken together indicates that the drug redistribution process throughout the fetus was not yet complete at delivery. Though free fentanyl equilibrates rapidly across the placental membrane and even unbinds from plasma proteins in a single transit of the placenta,43 equilibration throughout the fetal compartment clearly takes longer. Fentanyl does not, however, affect uterine blood flo~.~ In the fentanyl groups taken together the median Ua/Mv ratio was 0.34. In comparison Milon et al reported a mean Ua/Mv ratio of 0.52 following an epidural dose of 1 ug/kg,* while Craft et aP found a Ua/Mv ratio of 0.40 following an i.v. dose of 50-100 ug of fentanyl in pregnant ewes. The fetal/maternal gradient
32
International Journal of Obstetric Anesthesia
is, for some drugs, most likely related to differences in plasma protein binding between mother and baby, as well as to the ongoing redistribution process in the fetus. Fentanyl is a weak base (pKa 8.43) which is highly protein bound to a,-acid glycoprotein, albumin and to a lesser extent to o?- and p-globulins.38 The protein binding is pH-dependent (protein binding 84.4% at pH 7.4 and 80.4% at pH 7.2) but independent of plasma fentanyl concentration.38 As at term q-acid glycoprotein concentrations are less37 and albumin concentrations are greater45 in the fetus than in the mother, the results of the present study are in accordance with the view that fentanyl is not bound predominantly to albumin,38 as otherwise stated by Bower.46 Despite similar doses of fentanyl, the concentrations in the present study were lower than those Since plasma fentanyl reported by others. 2*4*8*24*40 concentrations peak within 5- 10 min following epidural administration47-49 and have been shown to decline at roughly parallel rates in ewe and lamb,44 the lower concentrations may be explained by the longer I-D intervals in the present study. In conclusion, epidural administration of fentanyl 50-100 ug added to 0.5% bupivacaine at elective caesarean section did not depress the term neonate. The umbilical plasma fentanyl concentrations, however, indicate that the safety margin is small implying that it is important to choose the lowest effective dose of fentanyl for improvement of epidural anaesthesia before delivery.
9
10
11
12.
13.
14. 15.
16.
17.
18.
19.
20.
Acknowledgements The study was supported by a grant from Oberstinde Jensa la Cours forskningslegat.
21. Kirsten 22.
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