Anesth Analg 2000;90:1167-1172
© 2000 International Anesthesia Research Society
OBSTETRIC ANESTHESIA
Alfentanil Given Immediately Before the Induction of Anesthesia for Elective Cesarean Delivery
Tony Gin, MD, FRCA, FANZCA*,
Warwick D. Ngan-Kee, MD, FANZCA*,
Yuk K. Siu, MRCP
,
Joyce C. Stuart, FRCA*,
Perpetua E. Tan, MPhil*, and
Kwok K. Lam, FANZCA*
Departments of
*Anaesthesia and Intensive Care and
Paediatrics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong
Address correspondence to Dr. Tony Gin, Department of Anaesthesia and Intensive Care, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong. Address e-mail to tgin{at}cuhk.edu.hk
 |
Abstract
|
|---|
Opioids are routinely omitted at the induction of general anesthesia for cesarean delivery because of concerns about neonatal respiratory depression. The subsequent unmodified maternal stress response to tracheal intubation reduces placental perfusion. The short-acting opioid alfentanil may afford advantages at the induction, without subsequent neonatal depression. In this double-blinded study of elective cesarean deliveries, 40 patients were allocated randomly to receive either alfentanil 10 µg/kg (n = 18) or placebo (n = 22), 1 min before the induction of anesthesia with thiopental 4 mg/kg and succinylcholine 1.5 mg/kg. Anesthesia was maintained with 50% nitrous oxide, 0.5% isoflurane in oxygen, and atracurium. Neonates were assessed by using Apgar scores, Neurologic and Adaptive Capacity Scores, and umbilical cord blood gas and catecholamine analysis. After intubation, mothers receiving alfentanil had a smaller increase in mean arterial blood pressure, (11 ± 15 vs 31 ± 13 mm Hg, P < 0.001) and lower plasma norepinephrine concentrations, (336 ± 152 vs 486 ± 241 pg/mL, P < 0.05). Neonates in the alfentanil group had greater umbilical arterial oxygen tensions (27.8 ± 7.0 vs 22.6 ± 7.4 mm Hg), slightly reduced Apgar scores (both P < 0.05), but similar Neurologic and Adaptive Capacity Scores. One neonate in the alfentanil group required naloxone. The maternal stress response was attenuated in the alfentanil group but at the cost of early neonatal depression. However, all neonates should be monitored for possible immediate, but transient, respiratory depression.
Implications: Alfentanil 10 µg/kg given at the induction of general anesthesia for cesarean delivery attenuates the subsequent maternal stress response. However, all neonates should be monitored for possible immediate but transient respiratory depression.
|
Introduction
|
|---|
Opioids are an integral component of general anesthetic techniques for major surgery. They are usually given during the induction of anesthesia to provide analgesia for the impending noxious stimuli of surgery. The early administration of opioids also allows a reduction in the dose of other anesthetics because of synergistic drug interactions (1), attenuates the hemodynamic and catecholamine ("stress") response to tracheal intubation (2), and may provide preemptive analgesia to reduce postoperative pain (3).
In obstetric general anesthesia, opioid drugs traditionally have not been given until after delivery because of concerns about the placental transfer of drug resulting in neonatal respiratory depression. However, opioids given at the induction of anesthesia have both fetal and maternal benefits. The uterine vascular bed during late pregnancy is considered to be maximally vasodilated, but responsive to stimuli causing vasoconstriction (4). An increase in maternal concentrations of catecholamines can decrease uterine blood flow (5,6) and this may adversely affect the neonate (7). Plasma concentrations of catecholamines increase after tracheal intubation in pregnant women having cesarean delivery (8,9), and uterine blood flow is decreased by 20%–35% (10). Preventing this increase in catecholamines may thus be beneficial for placental perfusion.
With the availability of short-acting opioids such as alfentanil, opioid antagonists such as naloxone, and neonatologists in attendance at delivery, the dangers of opioid-induced neonatal depression would be minimized. Alfentanil 15–30 µg/kg is one of several recommended regimens for attenuation of the "stress" response in nonpregnant patients (2). Alfentanil 10–125 µg/kg has been used successfully during general anesthesia for parturients with cardiac disease (11–14). In preeclampsia, the benefits of using opioids outweigh the risks of uncontrolled hypertension at tracheal intubation, and the use of alfentanil 7.5–10 µg/kg has been well described as part of a general anesthetic technique (15–17). In normal parturients, alfentanil 10 µg/kg did not decrease Apgar scores (18) but more sophisticated neurobehavioral testing was not performed. This study also avoided inhaled anesthetics allowing 4 of 37 patients to experience awareness. Thus these results may be less applicable to current anesthetic practice.
We postulated that the use of alfentanil at the induction of anesthesia for uncomplicated cesarean delivery would reduce the maternal stress response after tracheal intubation, with subsequent benefit to the neonate.
|
Methods
|
|---|
This randomized, double-blinded controlled study was approved by the local research ethics committee, and written informed consent was given by all patients. Power analysis from a previous study with a similar control group (8) indicated that a sample size of 20 would be sufficient to detect a mean difference of 15 mm Hg in mean arterial pressure (MAP) after tracheal intubation and a mean difference of 2 in the neonatal Neurologic and Adaptive Capacity Scores (NACS) with 80% power and an 
value of 0.05. Forty ASA physical status I patients with uncomplicated, singleton pregnancies of at least 36 wk gestation scheduled for elective cesarean delivery were allocated by simple randomization to receive either alfentanil or placebo at the induction of anesthesia. The indications for cesarean delivery were breech presentation, cephalopelvic disproportion, or previous cesarean delivery. Patients were excluded if there was any evidence of intrauterine growth retardation or other fetal abnormality.
In both groups, ranitidine 150 mg was given the night before and on the morning of surgery, with 0.3 mol/L sodium citrate (30 mL) given 15 min before operation. Routine monitoring included end-tidal carbon dioxide concentration, isoflurane concentration, and noninvasive arterial pressure measured at 1-min intervals by the integrated module in the Narkomed 4 anesthetic machine (North American Drager, Telford, PA).
Patients underwent preoxygenation for 3 min before IV injection of alfentanil 10 µg/kg or saline placebo (2 mL) over 5 s (time = -1 min). One minute later, rapid-sequence induction of anesthesia was performed with thiopentone 4 mg/kg given over 10 s followed by succinylcholine 1.5 mg/kg (time = 0 min). Laryngoscopy was performed after the 1-min arterial pressure recording, and tracheal intubation was completed before the 2-min reading. Anesthesia was maintained with end-tidal concentrations of 50% nitrous oxide and 0.5% isoflurane in oxygen. Neuromuscular block was continued with atracurium 0.5 mg/kg, and the lungs were ventilated to maintain an end-tidal carbon dioxide tension of 30 mm Hg. Hartmann’s solution 500 mL was infused over the first 10 min. Induction to delivery times and uterine incision to delivery (U-D) times were recorded by using a stopwatch. After delivery, oxytocin 10 IU and morphine 0.2 mg/kg were given IV.
Maternal venous blood samples (10 mL) were taken for assay of catecholamines immediately before the alfentanil or placebo (time = -1 min), at 0, 1, 2, 3, and 4 min after the induction, at 1 min after skin incision, and at the time of delivery. Umbilical venous and umbilical arterial (UA) blood samples were taken from a double-clamped segment of cord. Blood was put into lithium-heparin tubes containing metabisulphite as an antioxidant and the tubes immediately placed in ice. These were centrifuged at 4°C immediately after the last sample was drawn, and the plasma was separated and stored at -70°C. Norepinephrine and epinephrine were measured by using high performance liquid chromatography within 2 wk of collection. Catecholamines were extracted with alumina, analyzed on a reversed phased Ultrasphere IP C18 column (Beckman Instruments Incorporated, Altex Division, San Ramon, CA), and detected by using an electrochemical method on an ESA 5100A coulometric detector (Environmental Science Associates, Bedford, MA). The within-day coefficients of variation for norepinephrine and epinephrine were 5.68% and 7.98%, respectively, and the between-day coefficients of variation were 6.29% and 15.73%, respectively. The assay was linear to the lower limit of detection (25 pg/ mL for both norepinephrine and epinephrine).
Umbilical blood-gas tension and oxygen content analysis were performed on a Ciba-Corning 288 Blood Gas System (Ciba-Corning, Medfield, MA) and an IL 482 CO-Oximeter (Instrumentation Laboratory, Lexington, MA) with correction for 70% fetal hemoglobin.
Neonatal Apgar scores at 1 and 5 min and NACS at 15 min and 2 h were assessed by a pediatrician who was unaware of the anesthetic technique.
Statistical analysis was performed with the program Statview 4 (Abacus Concepts Inc, Berkeley, CA). Demographic and blood gas analysis data were compared by using the unpaired t-test. Apgar scores, NACS, and maternal and umbilical catecholamine data were compared by using the Mann-Whitney U-test. Serial changes in hemodynamic and catecholamine data at induction were analyzed with repeated measures analysis of variance. Baseline values were taken as those values measured at time = -1 min. Significant differences were confirmed by using nonparametric tests. P values < 0.05 were considered significant.
|
Results
|
|---|
There were no differences in age, weight, or height between the two groups (Table 1). After the induction, the groups differed in the pattern of changes in maternal arterial pressure, heart rate, and catecholamines. Results are presented were mean ± SD unless otherwise indicated.
Arterial Pressure
Baseline arterial pressures were similar between the groups (Figures 1 and 2). In the control group, systolic arterial pressure (SAP) was greater than baseline values from 2 to 4 min (P < 0.001). In the alfentanil group, SAP was decreased slightly at 1 min (P < 0.05) but was subsequently not different from the baseline value. The increases in MAP were similarly more pronounced in the control group. The change in SAP and MAP from baseline values after tracheal intubation (at 2 min) was greater in the control group (34 ± 17 mm Hg and 31 ± 13 mm Hg, respectively) than in the alfentanil group (9 ± 18 mm Hg and 11 ± 15 mm Hg, respectively; both P < 0.001).
View larger version (21K):
[in this window]
[in a new window]
|
Figure 1. Systolic arterial pressure at the induction of anesthesia. *P < 0.05, **P < 0.001 compared with baseline value at -1 min.
|
|
View larger version (21K):
[in this window]
[in a new window]
|
Figure 2. Mean arterial pressure at the induction anesthesia. *P < 0.05, **P < 0.001 compared with baseline value at -1 min.
|
|
Heart Rate
Baseline heart rates were similar between the groups (Figure 3). In the control group, the heart rate increased immediately after thiopental was given. In the alfentanil group, the heart rate decreased slightly at 0 min, before increasing. The change in heart rate from baseline values after tracheal intubation (at 2 min) was greater in the control group (26 ± 18 bpm) than in the alfentanil group (13 ± 14 bpm) (P = 0.02).
View larger version (23K):
[in this window]
[in a new window]
|
Figure 3. Heart rate at the induction of anesthesia. *P <0.005, **P < 0.001 compared with the baseline value at 1 min.
|
|
Catecholamines
Baseline maternal norepinephrine concentrations in the control group, 311 ± 128 pg/mL, were similar to those in the alfentanil group, 310 ± 159 pg/mL (Figures 4 and 5; Table 2). After tracheal intubation, norepinephrine concentrations at 2 and 3 min were increased above baseline levels in the control group (P < 0.05), while they were unchanged in the alfentanil group. At 3 min, norepinephrine concentrations were greater in the control group, 486 ± 241 pg/mL compared with the alfentanil group, 336 ± 152 pg/mL (P < 0.05).
View larger version (19K):
[in this window]
[in a new window]
|
Figure 4. Plasma norepinephrine concentrations at the induction of anesthesia. *P < 0.05 compared with baseline value at -1 min.
|
|
In the control group, some patients had very high epinephrine concentrations after tracheal intubation, whereas there appeared to be little change in the alfentanil group. Although there were no initial differences between groups, the epinephrine concentrations in the control group 140 ± 109 pg/mL (n = 21) were greater than those in the alfentanil group 54 ± 44 pg/mL (n = 16) (P < 0.01) at 1 min after skin incision.
Maternal catecholamine concentrations at delivery were similar between groups.
Neonatal Data
Data from two neonates were excluded from analysis (Tables 2, 3, and 4). One neonate in the alfentanil group had a difficult delivery with a U-D time of 385 s (all other U-D times were <240 s). Another neonate in the alfentanil group unexpectedly had a low birth weight of 1.9 kg. Apgar scores were 9 and 10; although there were no complications, all data from this neonate have also been excluded because of possible intrauterine growth retardation.
One neonate in the alfentanil group was given naloxone at delivery because the initial Apgar score was 2. However, the 5 min Apgar score was 10, and there were no further complications. The NACS were 32 and 36, but these values have been excluded from analysis.
The Apgar scores at 1 min (P = 0.04) were lower in the alfentanil group, but similar at 5 min. NACS was not measured in one neonate from the alfentanil group because of logistic difficulties, but the remaining NACS at 15 min and 120 min were similar between the groups.
There was insufficient UA blood for catecholamine assay in two neonates from the control group and three from the alfentanil group. The umbilical artery catecholamine concentrations in the control group were approximately double that found in the alfentanil group (P < 0.05). (Table 2).
Technical problems with the cooximeter meant that complete oxygen content analysis was unavailable for two neonates in the control group and four in the alfentanil group. Umbilical cord blood gas analysis showed that the neonates in the alfentanil group had a greater umbilical arterial oxygen tension compared with those in the control group (Table 4).
|
Discussion
|
|---|
The changes in maternal arterial pressure and catecholamines in our control group were similar to those reported in previous studies (8,9). From a maternal perspective, transient increases in arterial pressure are unlikely to have any significant effect in healthy women, although some isolated SAP recordings can be alarmingly high. Thus, the use of opioids to attenuate the "stress" response is probably not of great clinical benefit to the mother except for those with significant hypertensive or other cardiovascular disease. Attenuation of the stress response in our alfentanil group was similar to that reported previously in nonpregnant patients (19). Opioids administered at the induction of anesthesia may still be useful for the mother because of preemptive analgesia, synergistic effects with other anesthetics, and decreased risk of early awareness. We did not investigate these theoretical benefits but believe that further study would be warranted.
We postulated that preventing the increase in the concentration of maternal catecholamines might improve placental blood flow and neonatal outcome. We did not directly measure placental blood flow at the induction of anesthesia, and the reduction in catecholamines is only indirectly suggestive that alfentanil may have improved placental blood flow. However, we would not have been able to measure placental blood flow during the operation or standardize all of the surgical factors that could influence placental blood flow. We did not measure maternal catecholamines frequently between four minutes and delivery, so we cannot be sure of the difference between groups during this time. However, the normal "stress" response only lasts for several minutes, and by the time of delivery, concentrations of catecholamines were similar in the groups. Thus, any beneficial effect of reduced catecholamines may be negated if induction to delivery times are long, and if other factors affecting placental blood flow and neonatal outcome intervene.
Umbilical artery catecholamine concentrations in the control group were approximately double that found in the alfentanil group. There is some controversy over the significance of catecholamine concentrations at delivery. Increased concentrations of umbilical catecholamines are thought to be a response to the fetal stress associated with delivery. An increased concentration of catecholamines in the neonate may be beneficial because it provides better adaptability for extrauterine life (20). Umbilical concentrations of catecholamines after general anesthesia are much smaller than after vaginal delivery or cesarean delivery under regional anesthesia, and this may be a factor in the poorer neonatal outcome after general anesthesia (20). However, the greatest concentrations of catecholamines are found with fetal acidosis and hypoxia after forceps and breech deliveries (21), and in these situations elevated catecholamines are obviously a sign of fetal stress. Thus, a lower concentration of catecholamines could imply that the fetus has not been exposed to excessive stress.
We relied on assessment of neonatal outcome to evaluate the use of alfentanil. Although there was no significant difference in umbilical venous oxygenation, there was increased UA oxygenation. This may indicate decreased oxygen consumption by the fetus, perhaps because of the rapid placental transfer of alfentanil (22,23). In our elective operations, there was no obvious benefit gained from increased UA oxygenation. However, this could be useful when there is limited fetal oxygen delivery.
Apgar scores were lower in the alfentanil group, and this is probably a result of the placental transfer of alfentanil. It was difficult to standardize other contributory factors, such as the induction to delivery times and uterine incision to delivery times, but there were no obvious differences to otherwise account for the neonatal depression. The only previous study in healthy parturients showed that alfentanil 10 µg/kg did not decrease Apgar scores, although the anesthetic technique also avoided inhaled anesthetics with the result that 4 of 37 patients experienced awareness (18). Other studies are not directly comparable because of differences in the alfentanil dose and the use of patients with preeclampsia and fetal compromise. In our study, neonatal depression was only transient with all the Apgar scores at five minutes being 9 or 10, and the NACS being similar between groups. The availability of a neonatologist at delivery would also minimize the risk of complications from neonatal respiratory depression.
A shorter acting, rapidly metabolized opioid, such as remifentanil, should be less likely to cause neonatal depression. There is limited experience with this drug in obstetrics, but initial reports are encouraging (24,25).
General anesthesia for elective cesarean delivery is uncommon in most hospitals. A regional technique, when possible, is associated with a reduced maternal catecholamine response and better placental blood flow. When general anesthesia is indicated, our maternal findings can probably be extrapolated to emergency cesarean delivery (assuming no previous opioid or extradural analgesia use), but not to severe preeclampsia in which the maternal hemodynamic response may be altered.
There are several theoretical benefits from the use of opioids at the induction of anesthesia for cesarean delivery. Although alfentanil 10 µg/kg provided maternal hemodynamic stability, there was not improved neonatal outcome after elective cesarean delivery. However, we believe that further research is warranted and would best be conducted by using opioids that are shorter-acting and more rapidly cleared than alfentanil.
|
References
|
|---|
-
Glass PSA. Anesthetic drug interactions: an insight into general anesthesia—its mechanism and dosing strategies. Anesthesiology 1998;88:5–6.[Web of Science][Medline]
-
Kovac AL. Controlling the hemodynamic response to laryngoscopy and endotracheal intubation. J Clin Anesth 1996;8:63–79.[Web of Science][Medline]
-
Kissin I. Preemptive analgesia: why its effect is not always obvious. Anesthesiology 1996;84:1015–9.[Web of Science][Medline]
-
Greiss FC Jr. A clinical concept of uterine blood flow during pregnancy. Obstet Gynecol 1967;30:595–604.[Web of Science][Medline]
-
Rosenfeld CR, Barton MD, Meschia G. Effects of epinephrine on distribution of blood flow in the pregnant ewe. Am J Obstet Gynecol 1976;124:156–63.[Web of Science][Medline]
-
Shnider SM, Wright RG, Levinson G, et al. Uterine blood flow and plasma norepinephrine changes during maternal stress in the pregnant ewe. Anesthesiology 1979;50:524–7.[Web of Science][Medline]
-
Nandi PR, Morrison PJ, Morgan BM. Effects of general anaesthesia on the fetus during Caesarean section. In: Kaufman L, ed. Anaesthesia review 8. Edinburgh:Churchill Livingston 1991:103–22.
-
Gin T, O’Meara ME, Kan AF, et al. Plasma catecholamines and neonatal condition after induction of anaesthesia with propofol or thiopentone at Caesarean section. Br J Anaesth 1993;70:311–6.[Abstract/Free Full Text]
-
Loughran PG, Moore J, Dundee JW. Maternal stress response associated with caesarean delivery under general and epidural anaesthesia. Br J Obstet Gynecol 1986;93:943–9.[Web of Science][Medline]
-
Jouppila P, Kuikka J, Jouppila R, Hollmén A. Effect of induction of general anesthesia for cesarean section on intervillous blood flow. Acta Obstet Gynecol Scand 1979;58:249–53.[Web of Science][Medline]
-
Redfern N, Bower S, Bullock RE, Hull CJ. Alfentanil for caesarean section complicated by severe aortic stenosis. Br J Anaesth 1987;59:1309–12.[Abstract/Free Full Text]
-
Field LM, Barton FL. The management of anaesthesia for Caesarean section in a patient with paroxysmal ventricular tachycardia. Anaesthesia 1993;48:593–5.[Web of Science][Medline]
-
Rowbottom SJ, Gin T, Cheung LP. General anaesthesia for caesarean section in a patient with uncorrected complex cyanotic heart disease. Anaesth Intensive Care 1994;22:74–8.[Web of Science][Medline]
-
Batson MA, Longmire S, Csontos E. Alfentanil for urgent Caesarean section in a patient with severe mitral stenosis and pulmonary hypertension. Can J Anaesth 1990;37:685–8.[Web of Science][Medline]
-
Rout CC, Rocke DA. Effects of alfentanil and fentanyl on induction of anaesthesia in patients with severe pregnancy-induced hypertension. Br J Anaesth 1990;65:468–74.[Abstract/Free Full Text]
-
Allen RW, James MFM, Uys PC. Attenuation of the pressor response to tracheal intubation in hypertensive proteinuric pregnant patients by lignocaine, alfentanil and magnesium sulphate. Br J Anaesth 1991;66:216–23.[Abstract/Free Full Text]
-
Ashton WB, James MFM, Janicki P, Uys PC. Attenuation of the pressor response to tracheal intubation by magnesium sulphate with and without alfentanil in hypertensive proteinuric pregnant patients undergoing Caesarean section. Br J Anaesth 1991;67:741–7.[Abstract/Free Full Text]
-
Dann WL, Hutchinson A, Cartwright DP. Maternal and neonatal responses to alfentanil administered before induction of general anaesthesia for Caesarean section. Br J Anaesth 1987;59:1392–6.[Abstract/Free Full Text]
-
Miller DR, Martineau RJ, O’Brien H, et al. Effects of alfentanil on the hemodynamic and catecholamine response to tracheal intubation. Anesth Analg 1993;76:1040–6.[Abstract/Free Full Text]
-
Jouppila R, Puolakka J, Kauppila A, Vuori J. Maternal and umbilical cord plasma noradrenaline concentrations during labour with and without segmental extradural analgesia, and during Caesarean section. Br J Anaesth 1984;56:251–5.[Abstract/Free Full Text]
-
Falconer AD, Lake DM. Circumstances influencing umbilical-cord plasma catecholamines at delivery. Br J Obstet Gynecol 1982;89:44–9.[Web of Science][Medline]
-
Cartwright DP, Dann WL, Hutchinson A. Placental transfer of alfentanil at Caesarean section. Anaesthesiol 1989;6:103–10.
-
Zakowski MI, Ham AA, Grant GJ. Transfer and uptake of alfentanil in the human placenta during in vitro perfusion. Anesth Analg 1994;79:1089–93.[Abstract/Free Full Text]
-
Kan RE, Hughes SC, Rosen MA, et al. Intravenous remifentanil: placental transfer, maternal and neonatal effects. Anesthesiology 1998;88:1467–74.[Web of Science][Medline]
-
Scott H, Bateman C, Price M. The use of remifentanil in general anaesthesia for Caesarean section in a patient with mitral valve disease. Anaesthesia 1998;53:695–7.[Web of Science][Medline]
Accepted for publication January 20, 2000.
This article has been cited by other articles:
|
|
|
|
 
K. Y. Yoo, C. W. Jeong, B. Y. Park, S. J. Kim, S. T. Jeong, M. H. Shin, and J. Lee
Effects of remifentanil on cardiovascular and bispectral index responses to endotracheal intubation in severe pre-eclamptic patients undergoing Caesarean delivery under general anaesthesia
Br. J. Anaesth.,
June 1, 2009;
102(6):
812 - 819.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. D. Ngan Kee, K. S. Khaw, K. C. Ma, A. S. Y. Wong, and B. B. Lee
Randomized, double-blind comparison of different inspired oxygen fractions during general anaesthesia for Caesarean section{dagger}
Br. J. Anaesth.,
October 1, 2002;
89(4):
556 - 561.
[Abstract]
[Full Text]
[PDF]
|
|
|
Top
Abstract
Introduction
