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Print version ISSN 0034-7094
Rev. Bras. Anestesiol. vol.51 no.4 Campinas 2001
Effects of analgesic intrathecal sufentanil and 0.25% epidural bupivacaine on oxytocin and cortisol plasma concentration in labor patients*
Efeitos da analgesia do sufentanil por via subaracnóidea e bupivacaína a 0,25% por via peridural sobre as concentrações plasmáticas de ocitocina e cortisol em gestantes em trabalho de parto
Efectos de la analgesia del sufentanil por vía subaracnóidea y bupivacaína a 0,25% por vía peridural sobre las concentraciones plasmáticas de ocitocina y cortisol en embarazadas en trabajo de parto
Renato Mestriner Stocche, TSA, M.D.I; Luiz Vicente Garcia, TSA, M.D.II; Jyrson Guilherme Klamt, TSA, M.D.II
IMédico Assistente do Hospital
de Clínicas da USP
IIProfessor da Faculdade de Medicina da USP, Ribeirão Preto, SP
BACKGROUND AND OBJECTIVES: Intrathecal
sufentanil provides analgesia comparable to epidural local anesthetics for labor
pain. Both techniques decrease some parameters of neuroendocrine response to
labor pain and both may mitigate reflex oxytocin release in animals. This study
aimed to compare the effect of both techniques on cortisol (CPC) and oxytocin
(OPC) plasma concentrations in labor patients.
METHODS: Participated in this randomized covered study 30 healthy parturients in spontaneous labor with 4-7 cm cervical dilatation. Group S patients received intrathecal sufentanil (10 mg) and group B received epidural 0.25% bupivacaine. Analgesia was assessed by a visual analogue scale and blood oxytocin and cortisol samples were collected before, 30 and 60 minutes after drug administration. Plasma cortisol and oxytocin concentrations were determined by radioimmunoassay.
RESULTS: Group S analgesia was more intense at 30 minutes. OPC and CPC before analgesia were similar for both groups. Group S showed a significant decrease in OPC at 60 minutes and in CPC at 30 and 60 minutes (p<0.05), while for Group B such values remained stable throughout the study.
CONCLUSIONS: In the conditions of this study, epidural bupivacaine analgesia was associated to stable plasma cortisol and oxytocin concentrations. Conversely, intrathecal sufentanil promoted a more intense analgesia and decreased OPC and CPC.
Key words: ANALGESIA, labor; ANALGESICS, Opioids: sufentanil; ANESTHETIC TECHNIQUES, Regional: epidural; HORMONES: cortisol, oxytocin
JUSTIFICATIVA E OBJETIVOS: O sufentanil
por via subaracnóidea promove analgesia do trabalho de parto comparável
à peridural com anestésicos locais. As duas técnicas diminuem
alguns parâmetros da resposta neuroendócrina à dor do parto,
e ambas podem atenuar a liberação reflexa de ocitocina em animais.
O objetivo deste estudo foi comparar os efeitos das duas técnicas nas concentrações
plasmáticas de ocitocina (CPO) e cortisol (CPC) durante o trabalho de parto.
MÉTODO: Trinta parturientes com 4 - 7 cm de dilatação foram arroladas neste estudo de forma aleatória e encoberta. No grupo S receberam sufentanil (10 mg) por via subaracnóidea e no grupo B receberam bupivacaína a 0,25% por via peridural. A analgesia foi medida usando Escala Analógica Visual e amostras sangüíneas de ocitocina e cortisol foram obtidas antes, 30 e 60 minutos após a administração das drogas. As CPO e CPC foram determinadas através da técnica de radioimunoensaio.
RESULTADOS: A analgesia no grupo S foi mais intensa aos 30 minutos. As CPO e CPC nos dois grupos foram semelhantes antes da analgesia. No grupo S, houve diminuição significativa da CPO aos 60 minutos e CPC aos 30 e 60 minutos, enquanto no grupo B, CPO e CPC permaneceram estáveis durante todo o estudo.
CONCLUSÕES: Nas condições deste estudo, a analgesia peridural com bupivacaína esteve associada à manutenção das concentrações plasmáticas de cortisol e ocitocina. Contrariamente, a analgesia promovida pelo sufentanil, por via subaracnóidea, foi mais intensa e produziu diminuição nas concentrações destes hormônios.
Unitermos: ANALGESIA: parto; ANALGÉSICOS, Opióides: sufentanil; HORMÔNIOS: cortisol, ocitocina; TÉCNICAS ANESTÉSICAS, Regional: peridural
JUSTIFICATIVA Y OBJETIVOS: El sufentanil
por vía subaracnóidea promueve analgesia del trabajo de parto comparable
a la peridural con anestésicos locales. Las dos técnicas diminuyen
algunos parámetros de la respuesta neuroendócrina al dolor del parto,
y ambas pueden atenuar la liberación refleja de ocitocina en animales.
El objetivo de este estudio fue comparar los efectos de las dos técnicas
en las concentraciones plasmáticas de ocitocina (CPO) y cortisol (CPC)
durante el trabajo de parto.
MÉTODO: Treinta parturientas con 4-7 cm de dilatación, fueron escogidas en este estudio de forma aleatoria y encubierta. En el grupo S recibieron sufentanil (10 mg), por via subaracnoidea y en el grupo B recibieron bupivacaína a 0,25% por vía peridural. La analgesia fue medida usando Escala Analógica Visual y muestras sanguíneas de ocitocina y cortisol fueron obtenidas antes, 30 y 60 minutos después la administración de las drogas. As CPO y CPC fueron determinadas por medio de la técnica de radioinmunoensayo.
RESULTADOS: La analgesia en el grupo S fue más intensa con 30 minutos. Las CPO y CPC en los dos grupos fueron semejantes antes de la analgesia. En el grupo S, hubo diminución significativa de la CPO a los 60 minutos y CPC a los 30 y 60 minutos, en cuanto en el grupo B, CPO y CPC permanecieron estables durante todo el estudio.
CONCLUSIONES: En las condiciones de este estudio, la analgesia peridural con bupivacaína estuvo asociada a la manutención de las concentraciones plasmáticas de cortisol y ocitocina. Contrariamente, la analgesia promovida por el sufentanil, por vía subaracnóidea, fue más intensa y produjo diminución en las concentraciones de estas hormonas.
Labor induces a neuroendocrine and metabolic response very similar to surgical trauma. It increases the levels of catecholamine 1, cortisol and ACTH 2, corticotrophin (CFG) releasing hormones and b-endorphins 3. Induced acute stress in pregnant monkeys decreased uterus-placental flow leading, as a consequence, to fetal hypoxia, hypotension and bradycardia 4. Exacerbated acute stress may also cause lactogenesis delay and transient fetal acidosis, which has a correlation with maternal cortisol plasma concentrations 5,6.
So, cortisol plasma concentrations may be used as a measure of such response. Oxytocin effect and importance during labor are well established. Oxytocin is also involved in lactation 7 and stress response8.
Labor analgesia with epidural local anesthetics allows for pain control with a consequent decrease in cortisol plasma levels, however without changing uterine contractility 9. Nevertheless, the influence of such technique in oxytocin plasma concentrations remains controversial 10,11. The combined spinal-epidural technique has made easier the use of epidural opioids. Intrathecal opioids produce intense analgesia with fast onset and without motor block. Animal studies have shown that opioids inhibit oxytocin release in the hypothalamohypophyseal axle and, in humans, intravenous morphine may inhibit labor 12,13.The effects of labor analgesia with intrathecal opioids on cortisol and oxytocin plasma concentrations has not been reported to date.
This study aimed to evaluate and compare the effects of epidural analgesia with 0.25% bupivacaine and with intrathecal sufentanil as to cortisol and oxytocin concentrations in pregnant women with intense labor pain during the active phase of the first labor stage.
This prospective, randomized and blind study was performed in Hospital das Clinicas, Ribeirão Preto and Maternidade MATER after the Institutions Research Ethics Committee approval and the informed consent of patients.
Participated in this study 30 patients aged 18 to 35 years, weighing 50 to 90 kg, physical status ASA I, primiparous or on second gestation with Cesarean section in the first gestation (functional primiparous), in the active phase of the first labor stage (cervical dilatation = 4 - 7 cm) and with the fetus fit in the pelvis. Patients with pre or post term gestation, presenting signs of acute or chronic fetal suffering and those having received exogenous oxytocin less than one hour before were excluded from the study. Data of one patient who quickly evolved to delivery before the end of the study (60 minutes) were excluded and replaced in the sample.
Groups Distribution and Analgesic Technique
When patients asked for analgesia (VAS pain above 7), they were randomly distributed into one of two groups according to the analgesic technique used. Ten minutes before blockade, all patients received venous hydration with 300 ml lactated Ringers. Puncture was performed in Group S (n = 15) with a combined spinal-epidural set with 17G Tuhoy and 27G pencil tip needles and 2 ml solution with 10 mg sufentanil was intrathecally injected. Epidural puncture was performed in Group B (n = 15) with 17G Tuhoy needles and 12 ml of 0.25% bupivacaine were injected. All punctures were performed at L3-L4 interspace with patients in the sitting position. Immediately after drug administration and epidural catheter fixation, patients were placed in the left lateral position with heads up 15º to 20º. After data collection, 60 minutes after, all patients received epidural bupivacaine as needed until delivery.
Monitoring and Data Collection
All patients were continuously monitored with cardioscope, pulse oximetry and respiratory frequency and blood pressure (oscilloscope) were measured before blockade, at every two minutes for 20 minutes after blockade and after this, at every 15 minutes. During this sixty-minute study, only brief and painless gynecologic exams were allowed to determine uterine dilatation. There has been no spontaneous or provoked membrane rupture during the study.
Pain intensity was evaluated with the help of a 10 cm linear visual analog pain scale (VAS) where zero was lack of pain and 10 the worst possible or imaginable pain. Evaluations were performed immediately before the blockade and 30 and 60 minutes after it. The incidence of side-effects, such as nausea, vomiting, somnolence and hypotension (SBP below 90 mmHg) were also recorded, as well as the need for specific treatments.
Blood Sample Collection and Hormone Dosage
Venous blood samples (8 ml) were collected with plastic heparin-containing syringes through a teflon catheter placed in a vein of the arm opposite to that receiving fluids and drugs at all study moments (0, 30 and 60 minutes), in a total of 24 ml collected along the experiment. After collection blood was distributed in two test tubes, one for cortisol dosage and the other containing EDTA (10 µl/ml blood) for oxytocin dosage.
Test tubes were then temporarily stored in a styrofoam box at a temperature below 4 ºC, until delivery. After collection, samples were centrifuged and plasma was stored for three months at 60 ºC until hormonal dosage.
Oxytocin dosages were obtained by radioimmunoassay with previous plasma extraction. Intra and inter-assay errors were 2.5% and 14.1% respectively at the level of P0 and ED 50 of the standard curve.
Cortisol dosages were also performed by radioimmunoassay in duplication without previous extraction 14. Intra and inter-assay errors were 3.5% and 14% respectively at the level of P0 and ED 50 of the standard curve.
Hormonal measurements of patients were used as control and obtained before blockade (paired analysis). To compare groups, initial hormonal measurement variations were calculated. Data are shown in mean ± EPM. Hormonal concentrations were analyzed intra and inter groups by Friedman (paired and non-parametric analysis of variance) and Kruskal-Wallis tests, respectively. Qualitative variables or proportions were analyzed by Fishers Exact or Chi-square test. P < 0.05 was considered statistically significant.
There were no statistical differences between groups as to demographics data (Table I). All patients were normotensive before blockade (time 0). Baseline heart and respiratory rates were also similar for both groups, as well as the degree of parity and cervical dilatation (Table II). After blockade there has been a transient decrease in systolic blood pressure in Group B (30 minutes) with pressure levels recovery at 60 minutes. One group B patient presented with systolic blood pressure of 90 mmHg, which responded to a fast infusion of 300 ml lactated Ringers. Diastolic blood pressure and heart rate remained stable for both groups during the observation period.
All patients had satisfactory analgesia with AVS below 3 cm, at 30 and 60 minutes. There has been difference between groups in AVS values at 30 minutes (Figure 1).
Oxytocin plasma concentrations before labor analgesia were increased and similar for both groups, with means ± EPM of 9.1 ± 1.1 pg.ml-1 for group S and 9.8 ± 1.5 pg.ml-1 for group B. After blockade, there has been a decrease in oxytocin plasma levels in group S at 30 and 60 minutes, which was statistically significant in paired analysis with pre-blockade concentrations (p < 0.05). Group B behaved differently and maintained baseline values throughout the study (Figure 2).
Percentage variation of pre-blockade oxytocin values was used for intergroup comparisons. There were negative percentage variations in group S while there were positive percentage variations in group B, with statistical difference at 60 minutes (p < 0.05). In spite of percentage oxytocin decreases at moment 30 in group S, there has been no statistical difference between groups due to major group B variations (Figure 3).
Initial plasma cortisol concentrations were similar for groups S and B, with mean ± SD of 47.8 ± 3.6 and 50.5 ± 2.8 pg.ml-1, respectively. After blockade, cortisol plasma levels decreased in group S at moment 60, with statistical difference in paired analysis with pre-blockade concentrations (p < 0.05). Plasma concentrations remained stable in group B (Figure 4).
Percentage variations of initial individual concentrations were used for intergroup comparisons. There were differences in percentage variations of initial cortisol concentrations between groups S and B at 30 and 60 minutes (p < 0.05) (Figure 5).
All group S patients presented with mild and moderate pruritus with no need for naloxone administration. Ten group S patients (66.6%) presented with mild or moderate somnolence. There has been no pruritus in group B and two patients (16.6%) presented with somnolence. There has been no oxygen saturation decrease below 92%. However, two group B patients presented with transient bradypnea with respiratory rate of 9 ir/min, but with no need for intervention because both patients were asleep at that time and as soon as awakened their respiratory rate increased.
Although not being blind, this study was homogeneous as to groups distribution. Hormone values before analgesia were especially important for this study because they worked as controls in paired analysis with post-blockade values, thus allowing for an accurate analysis of analgesia-induced changes in all variables studied.
Obstetric hypotension may be noxious both for the mother and the fetus (decreases uterine perfusion), and may decrease uterine activity leading to fetal hypoxia 15. Clinical studies have shown that both spinal sufentanil and epidural analgesia reduce blood pressure in a similar manner 16,17.
Our results are different from those studies because systolic blood pressure (SBP) variations were higher for group B at 30 minutes, as compared to controls (time zero). However, there are no descriptions in those studies of patients receiving pre-blockade volume expansion, leading to a higher chance of hypotension, what is different from our method. In our study, one group B patient had an SBP decrease below 90 mmHg, which responded to lactated Ringers infusion, thus suggesting that there were more intense hemodynamic changes in this group.
Two group S patients had a respiratory rate of 9 irpm, but none had SpO2 below 92%. Somnolence after analgesia induction may be explained by maternal stress and fatigue attenuation. However, a higher incidence of somnolence in group S (66.6%), as compared to 16.6% in group B, as well as all group S patients presenting with pruritus, suggest a rostral spread of the drug. Pharmacokinetic studies of sufentanil in ewes have shown that intrathecal administration is followed by high drug concentrations in the cisterna magna after 10 minutes and that CSF concentrations are always higher than plasma concentrations, confirming CSF rostral spread 18.
Opioid-containing solutions baricity may influence rostral spread and analgesia efficacy 19 and 5 µg.kg-1 sufentanil is hypobaric at 37 ºC, which favors the cephalic spread if the patient remains too long in the sitting position during blockade 20. In our study, time needed for epidural catheters insertion after intrathecal injections was less than 5 minutes.
Labor analgesia onset with intrathecal sufentanil is faster than epidural onset with local anesthetics 17. Our study has reproduced such results with statistical differences in pain intensity up to 30 minutes after beginning of analgesia.
It is a consensus that cortisol plasma concentrations progressively increase during gestation, maintaining the circadian rhythm and reaching the end of gestation with a substantially higher titration as compared to non-pregnant women 2. When labor begins there is a progressive cortisol increase with peak plasma concentration soon after birth 21. Such increase is partially inhibited by epidural labor analgesia with local anesthetics 9.
Cortisol may influence labor because, in ewes at the end of gestation, oxytocin receptor messenger RNA expression increased to prepare myometrium for labor 22. The fact that cortisol decreases progesterone and increases estrogen production via 17 a-hydroxylase 23 activation and 15-hydroxyprostaglandin dehydrogenase inhibition 24 suggests an important cortisol role in triggering labor. However, the increase during labor is directly related to emotional stress and pain intensity and seems to be related to post-partum infection and psychic alterations 25-26.
Our results confirmed high cortisol plasma concentrations in the active phase of labor, which decreased after analgesia in group B and was different from group S where it remained constant. This was probably due to the higher incidence of residual pain in group B.
Several authors tried to correlate pain blockade with neuroendocrine response attenuation 27. However, in those studies, it was impossible to rule out the participation of neural blockades, other than pain. In our study, the marked cortisol release blockade in group S suggests that pain pathways have an important role in the neuroendocrine response.
There is also the possibility of cephalic opioid spread with inhibition of corticotropin releasing factor release 28. So, intrathecal sufentanil in labor analgesia blocks cortisol release by the hipothalamohypophysial axle probably by blocking pain, suggesting an important participation of pain pathways in neuroendocrine stress response.
Studies involving oxytocin labor dosages have some methodological difficulties. Due to its fast metabolization via oxytocinase, peripheral venous blood concentration is a fraction of that found in the internal jugular vein. Oxytocin pulses release in blood flow is another factor which may influence oxytocin peripheral plasma levels 29. So, we did not allow obstetric maneuvers and membrane rupture during the 60 minutes of study, and blood samples were collected always during uterine peak contraction intensity. Another factor impairing results interpretation is the wide variation in oxytocin plasma levels among labor patients. So, we used the dose immediately before analgesia as the control for each patient, according to methods used in other studies 30.
It was to be expected that intrathecal sufentanil would not interfere with Fergusons reflex for acting specifically on the dorsal spine of the spinal cord, preferably modulating pain pathways without affecting perineal distension sensitivity pathways. However, our data show that plasma oxytocin was significantly reduced after intrathecal sufentanil administration as compared to control, what was not seen with the use of epidural local anesthetics. This oxytocin decrease shows the interference of the intrathecal administration of a potent and fast-acting µ-specific opioid on Fergusons reflex, which could directly influence labor evolution.
Two hypotheses may explain plasma oxytocin decrease in group S and not in group B. The first is that Fergusons reflex has a strong afference in pain pathways, which would justify the maintenance of oxytocin plasma concentrations in group B, because patients had adequate analgesia but not so deep as group S. In this case, the action of opioids and local anesthetics on oxytocin would preferably be in the spinal cord. The second hypothesis is that intrathecal sufentanil would have a rostral spread reaching the hypothalamohypophyseal axle and inhibiting oxytocin release by the posterior hypophysis lobe at the central level.
Oxytocin endogenous secretion mechanisms are highly complex and were not yet fully explained. Opioid action on hypothalamohypophyseal axle (HHA) inhibiting oxytocin release was described in experimental studies in vitro 31 and in vivo in rats 32.
The presence and action of m and k opioids in the hypothalamohypophyseal axle has been widely shown, especially in Supra-Optic and Paraventricular Nuclei 33. In Supra-Optic Nuclei magnocellular neurons, the population of k receptors is larger than of m receptors and its activation promotes a decrease in electric activity and neuronal hyperpolarization inhibiting neuro-hypophysis oxytocin release 34. However, in rats in the end of gestation, a decrease in k agonists response and an increase in m receptors activity have been observed 13,35. There are evidences of m and k receptors populations in the hypophysis posterior lobe, because intra-cerebral naloxone (m selective antagonist) promotes oxytocin release 31.
Uterine activity and oxytocin plasma levels in rats during labor decreased after subcutaneous or intra-cerebral morphine, leading to a prolonged labor and showing the inhibiting action of m agonist opioids on central Fergusons reflex 36. Although an extensive literature on the modulation of opioids in oxytocin release in animals, few studies were carried out with humans, probably due to methodological and ethical difficulties in performing such experiments. With the development and major progresses in intrathecal analgesia with liposoluble opioids in the late 80s, such subject became very important.
Intravenous 5 mg morphine, administered during the first labor phase, decreases plasma oxytocin in the peripheral circulation, probably by inhibiting hypothalamohypophyseal axle release 12, establishing the first correlation between clinical and experimental trials. During the second labor phase, intravenous morphine was unable to block oxytocin release, probably due to the higher stimulus intensity and the lower analgesic efficacy of intravenous morphine during this phase 37. Inhibitory response to labor-induced oxytocin release, both of k and m agonists, depends on the number and intensity of sensory afferences 38, which confirms the possibility of oxytocin release inhibition by opioids being labor phase-dependent.
The possibility of cephalic sufentanil spread has been previously discussed. We were unable to show that sufentanil had reached the supraspinal region, but the high incidence of somnolence and pruritus and the decrease in respiratory rate in two group S patients suggest the possibility of rostral spread. The fact of analgesia not changing plasma oxytocin in group B suggests that other mechanisms, other than pain blockade, are involved in oxytocin decrease in group S and that sufentanil action site, for decreasing oxytocin levels, should be supraspinal.
Previous studies on the effect of epidural anesthesia with local anesthetics on oxytocin plasma levels had different results and conclusions. Patients receiving epidural analgesia had a decrease in oxytocin plasma levels after blockade 10, which is different from our results. In that study, however, analgesia was induced at the end of the second labor phase, when sensory afference and the consequent oxytocin release are intense and total block with local anesthetics could show a better effect in oxytocin reflex release, which is different from our method. Although without group B oxytocin decrease in our sample, there was also no increase, as it should be expected during natural labor evolution.
Labor analgesia with intrathecal opioids does not produce loss of abdominal press and does not relax pelvis muscles.
Such factors could cause rotation dystocia and prolong labor, which could explain a faster labor evolution with such technique. In spite of the seemingly labor maintenance, the effects of oxytocin levels decrease in uterine contractility and labor evolution were not the objective of this study. Uterine contractility control mechanisms are complex and partially explained. Other factors, such as decreased catecholamine plasma concentrations and number of oxytocin receptors in the myometrium may override oxytocin decrease.
Concluding, intrathecal sufentanil decreases oxytocin plasma concentrations. The possible action mechanism is the release inhibition of hypothalamohypophysial axle. The confirmation of the action mechanism and of the influence on uterine contractions needs additional studies with a specific method.
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Submitted for publication November 13, 2000 * Received
from Maternidade Mater do Hospital de Clínicas da USP, Ribeirão Preto,
Accepted for publication February 13, 2001
Submitted for publication November 13, 2000
* Received from Maternidade Mater do Hospital de Clínicas da USP, Ribeirão Preto, SP