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Print version ISSN 0034-7094
Rev. Bras. Anestesiol. vol.57 no.2 Campinas Mar./Apr. 2007
Side effects of subarachnoid and epidural sufentanil associated with a local anesthetic in patients undergoing labor analgesia*
Efectos adversos del sufentanil asociado al anestésico local por las vías subaracnoidea y peridural en pacientes sometidas a la analgesia de parto
Isabel C.F. SalemI; Fernanda B. FukushimaII; Giane NakamuraIII; Fábio Ferrari, TSAIII; Laís C. NavarroIII; Yara Marcondes Machado Castiglia, TSAIV; Eliana Marisa Ganem, TSAV
do 5° Ano de Medicina da FMB UNESP; Bolsa de Iniciação
IIME3 (2003) do CET/SBA da FMB UNESP
IIIMédico do CET/SBA do Departamento de Anestesiologia da FMB UNESP
IVProfessora Titular do CET/SBA do Departamento de Anestesiologia da FMB UNESP
VProfessora Adjunta do CET/SBA do Departamento de Anestesiologia da FMB UNESP
OBJECTIVES: The association of an opioid with a local anesthetic improves
the quality of labor analgesia and reduces the risk of systemic toxicity of
the local anesthetic. However, opioids are not devoid of side effects. The aim
of this study was to compare the side effects of subarachnoid sufentanil associated
with bupivacaine to those caused by epidural sufentanil associated with ropivacaine
in the doses used in the Anesthesiology Department in pregnant women undergoing
METHODS: Sixty pregnant women, ASA physical status I and II, ages between 15 and 42 years, at term and with healthy fetuses, undergoing labor analgesia were enrolled in this study. They were randomly divided in two groups: G1 combined spinal epidural anesthesia 0.5% bupivacaine (2.5 mg) and subarachnoid sufentanil (5 µg); G2 Epidural Block 0.2% ropivacaine (20 mg), and epidural sufentanil (10 µg). Complementary doses of 0.2% ropivacaine (12 mg) were administered whenever necessary, and 1% ropivacaine (50 mg) was administered for labor resolution. Patients were evaluated after analgesia (M1) regarding the presence of hypotension, maternal bradycardia, pruritus, nausea, vomiting, respiratory depression, and sedation. They were also evaluated postoperatively (M2) regarding the presence of nausea, vomiting, pruritus, sedation, urinary retention, and pain. Newborns were evaluated by the Apgar score. The test t Student, Mann-Whitney test, and Chi-Square test were used for the statistical analysis.
RESULTS: Both groups were similar regarding age, weight, height, duration of labor after analgesia, Apgar score of the newborns, hypotension, maternal bradycardia, nausea, vomiting, pruritus, and urinary retention. Sedation was more frequent in patients in G2 at M1 (50%), which was statistically significant.
CONCLUSION: Subarachnoid or epidural sufentanil, in the doses used in this study, associated with local anesthetics, had the same effect on the duration of labor after analgesia and in the Apgar score of newborns. Sedation was the most frequent side effect in patients receiving epidural sufentanil.
Key Words: ANALGESIA, Obstetric: labor; ANALGESICS, Opioids: sufentanil; ANESTHETICS, Local: bupivacaine, ropivacaine; ANESTHETIC TECHNIQUES, Regional: combined subarachnoid and epidural, epidural; COMPLICATIONS: bradycardia, hypotension, nausea, pruritus, vomiting, sedation.
JUSTIFICATIVA Y OBJETIVOS:
La asociación del opioide con el anestésico local mejora la calidad
de la analgesia de parto y reduce el riesgo de toxicidad sistémica por
el anestésico local. Los opioides, sin embargo, pueden determinar efectos
colaterales. El objetivo de esta investigación fue comparar los efectos
adversos determinados por el sufentanil, administrado por vía subaracnoidea,
asociado a la bupivacaína, con aquel determinado por el sufentanil por
vía peridural, asociado a la ropivacaína, en las dosis utilizadas
en el Servicio de Anestesia, en embarazadas sometidas a la analgesia de parto.
MÉTODO: Participaron del estudio 60 pacientes, estado físico ASA I y II, con edad entre los 15 y los 42 años, con embarazo en tiempo y fetos saludables, sometidas a la analgesia de parto. Se distribuyeron aleatoriamente en de los grupos: G1 Doble bloqueo bupivacaína a 0,5% (2,5 mg) y sufentanil (5 µg) por vía subaracnoidea, G2 Peridural ropivacaína a 0,2% (20 mg) y sufentanil (10 µg) por vía peridural. Para dosis complementarias fue administrada ropivacaína a 0,2% (12 mg) y para resolución del parto, ropivacaína a 1% (50 mg). Las pacientes se evaluaron después de la analgesia (M1) con relación a la hipotensión arterial, bradicardia materna, prurito, náusea, vómito, depresión respiratoria y sedación. En el postoperatorio (M2), en cuanto a la presencia de náusea, vómito, prurito, sedación, retención urinaria y dolor. Los recién nacidos se evaluaron por el índice de Apgar. Para análisis estadístico, se utilizaron la prueba t de Student, Mann-Whitney y Qui-cuadrado.
RESULTADOS: Los grupos fueron similares con relación a la edad, al peso, a la altura, a la duración del período de trabajo de parto después de la analgesia, al Apgar de los recién nacidos, a la existencia de hipotensión arterial, bradicardia, náusea, vómito, prurito y retención urinaria. La sedación fue más frecuente en las pacientes de G2, en M1 (50%) con diferencia estadística significativa.
CONCLUSIONES: El sufentanil en las dosis utilizadas, administrado por vía subaracnoidea o peridural, asociado a los anestésicos locales, determinó similitud en la duración del trabajo de parto después de la analgesia y en el Apgar de los recién nacidos. La sedación fue el efecto adverso más frecuente en las pacientes que recibieron el opioide por vía peridural.
Pain represents one of the most important clinical signs of the beginning of labor and, once the diagnosis is made and the regularity of uterine contractions established, pain must be treated since it has several undesirable effects both in the mother and in the fetus.
Anxiety and pain during the phase of cervical dilation lead to maternal hyperventilation, increase in oxygen consumption and in circulating catecholamines, cortisol, and adrenocorticotrophic hormone 1. Hyperventilation causes hypocarbia, uteroplancental vasoconstriction, and deviation of maternal hemoglobin dissociation curve to the left; these effects, associated with increased maternal oxygen consumption decrease oxygen delivery to the fetus. Besides uterine vasoconstriction 1, excessive concentration of circulating catecholamines increases oxygen consumption 1 and blood lactate 1. Pain relief during labor decreases minute ventilation, oxygen consumption, concentration of circulating catecholamines, and blood lactate 1. Studies conducted after epidural anesthesia for labor analgesia demonstrated improvement in placental perfusion and a reduction in the concentration of the substances released during periods of stress, such as cortisol and b-edorphins 1.
Modern anesthetic techniques, associated with the development of new local anesthetics with decreased cardiovascular and neurological toxicity, and the addition of opioids to local anesthetics, are responsible for pain free labor with few maternal and fetal side effects 1-3.
Local anesthetics (LA) blocks sodium channels in the membrane of axons in the spinal nerve roots and in the cells of the posterior and anterior horns of the spinal cord. Opioids are agonists of pre- and post-synaptic opioid receptors in the central nervous system and in other areas of the body 4,5. These drugs, with distinct mechanisms of action, have synergistic action 6.
Adding opioids, such as fentanyl and sufentanil, to LA decreases the latency, prolongs the duration, and improves the quality of epidural anesthesia 1. This association also allows the anesthesiologist to use low concentrations of LA, decreasing the motor blockade and the risk of toxicity 1.
Another technique often used for pain relief during labor is the combined spinal-epidural (spinal block and epidural anesthesia), with the association of bupivacaine and subarachnoid liposoluble opioids (fentanyl or sufentanil) 7. The advantages of subarachnoid opioids include improvement in the quality of analgesia 8, fast onset of action 8, absence of motor blockade 8, decreased maternal/fetal exposure to drugs, and the technique is easy to perform 9. The main disadvantages of using opioids in the neuroaxis include pruritus, hypotension, temporary changes in fetal heart rate, and respiratory depression, whose incidence varies from 0.01% to 0.1% and is not significant in the absence of sedation 10.
The incidence of side effects is decreased by reducing the dose of the subarachnoid opioid 11. When 5 µg of sufentanil was associated with subarachnoid bupivacaine in the technique of combined spinal-epidural, the quality of analgesia was preserved and the incidence of side effects was minimal 12.
The aim of this study was to compare the side effects of the association of subarachnoid sufentanil and bupivacaine with those caused by the association of epidural sufentanil and ropivacaine, in the doses used in the Anesthesiology Department, in pregnant women undergoing labor analgesia.
After approval by the Ethics Committee on Clinical Research and signing of the informed consent, 60 pregnant women, between 15 and 42 years old, ASA physical status I and II, with full term pregnancies, healthy fetuses without fetal distress, who underwent labor analgesia participated in this study. Patients with current or past gastric complaints, those who used alcohol or drugs, patients with psychiatric disorders, and patients who received meperidine during labor were excluded. Patients were randomly divided in two groups that differed regarding the anesthetic technique used:
- Group 1 (combined spinal-epidural): 0.5% bupivacaine (2.5 mg) + subarachnoid sufentanil (5 µg)
- Group 2 (epidural): 0.2% ropivacaine (14 mg) + epidural sufentanil (10 µg)
Complementary doses: epidural 0.2% ropivacaine (12 mg) in both groups. Dosage for labor resolution: epidural 1% ropivacaine (50 mg)
After the indication of labor analgesia, which in the Hospital das Clínicas de Botucatu is done when the cervical dilation is equal to 6 cm, Ringer's lactate (8 to 10 mL.kg-1) infusion was initiated and patients were monitored with an electrocardioscope in the DII derivation, sphygmomanometer, and pulse oxymeter.
In Group 1, an epidural puncture was performed with the patient in the sitting position, by the median approach, in the L3-L4 space with a Touhy 80/18 needle and an epidural catheter was inserted, followed by a subarachnoid puncture in the L2-L3 space with a 25G Quincke needle and the administration of 5 µg of sufentanil and 2.5 mg of bupivacaine. In patients who needed further doses for analgesia, a test dose of a local anesthetic (1% lidocaine 30 mg and adrenaline 1:200,000) was administered to confirm it was properly placed. It was followed by 6 mL (12 mg) of 0.2% ropivacaine.
In Group 2, the epidural puncture was performed using the same technique as in Group 1 and, after the test dose, 10 mL (20 mg) of 0.2% ropivacaine and sufentanil (10 µg) were administered. Whenever patients needed additional doses of anesthetic due to pain, the complementary dose of 0.2% ropivacaine, 6 mL (12 mg), was administered.
For labor resolution, 5 mL of 1% ropivacaine were administered.
Determination of side effects was done in two moments: M1 the period of labor after analgesia, and M2 24 hours after analgesia.
The period of time from analgesia until the patient left the delivery room was considered as the period of labor after analgesia, and the presence of hypotension (at least a 20% drop in blood pressure), bradycardia (heart rate below 60 beats per minutes), pruritus, sedation, nausea, vomiting, and respiratory depression was evaluated every 10 minutes.
The Apgar scores of the newborns were determined.
In case of hypotension, the patient was initially treated by moving the uterus to the left and increasing the rate of the IV infusion. If those measures were ineffective, ephedrine was administered. Pruritus would be treated with propofol (10 mg), and nausea with ondansetron (4 mg).
In the first 24 hours after analgesia, patients were oriented to request the presence of an anesthesiologist if they developed pruritus, nausea, and pain, when they would receive the medication established in the protocol.
In the postoperative period, 24 hours after analgesia (M2), patients were evaluated by another anesthesiologist who was present during the anesthesia to determine whether the patients experienced pain, nausea, vomiting, pruritus, sedation, and urinary retention. These events were evaluated during an interview, with no prior knowledge of which group the patient belonged to.
Sedation was evaluated by the sedation numeric scale that varies from 0 to 3, where 0 = patient awake, without clinical evidence of sedation; 1 = sleepy, responding to verbal commands; 2 = sleepy, not responding to verbal commands, but responding to light touch; and 3 = severe sedation, responding to painful stimuli. Pruritus was also evaluated using a numeric scale from 0 to 3, where 0 = absent; 1 = light pruritus, without the need to scratch; 2 = moderate pruritus, with occasional scratching; and 3 = severe pruritus, scratching constantly. Pain was evaluated by the verbal numeric scale, from 0 to 10, where 0 is the absence of pain and ten stands for maximal pain. When pain severity was greater than 3, oral cetoprophen (50 mg) was administered according to the norms established by the Obstetric Department.
Considering a 40% difference between the groups and the power of the test of 95%, the size of the study population was calculated as a minimum of 22 patients per group.
In the statistical analysis of the results, the test t Student was used for quantitative variables with normal distribution and the Mann-Whitney test for those that were not. The Chi-square test was used for qualitative variables.
Both groups were homogenous regarding the anthropometric data, duration of labor after analgesia (Table I), and Apgar score of the newborns (Table II). Only two patients in Group 1 needed complementary doses of epidural anesthetic. In both cases, a single dose was administered 90 and 110 minutes after the initial dose. Five patients in Group 2 needed complementary doses of ropivacaine, also as a single dose for each patient, 100 to 195 minutes after the initial dose.
Of the 60 patients selected for the study, eight were excluded from the analysis of the results because they had cesarean sections. Of the 52 remaining patients, 28 were in Group 1, and 24 in Group 2.
Five patients in Group 1 and four in Group 2 had an episiotomy for relief forceps.
Of the 28 patients in Group 1, 19 presented one or more side effects during the study period; three of them in M1, eight in M1 and M2, and eight in M2. Pruritus was the most common symptom in M1, affecting eight patients (six mild, and two moderate), followed by hypotension and nausea, which affected four patients (Table III). The patients with hypotension were not the same that complained of nausea. Pruritus did not require any treatment. Hypotension was treated moving the uterus to the left and increasing the infusion of IV fluids. Nausea was transitory and did not require any treatment. In M2, eight patients complained of pruritus, followed by pain and sedation, which affected six patients (Table IV).
Eighteen patients in Group 2 had one or more side effects during the evaluation period; eight in M1, seven in M1 and M2, and three in M2. Twelve patients complained of sedation in M1 (Table III) and five in M2, four of which had also complained of sedation in M1. Ten patients presented grade 1 sedation and three, grade 2 sedation. Pruritus was the second most common side effect, being classified as mild to moderate (two patients in M1 and four in M2) (Table IV), which did not require treatment. The incidence of sedation in M1 in Group 2 was greater than in Group 1, which was statistically significant (p = 0.017).
The results showed that subarachnoid or epidural sufentanil, in the doses used in this study, associated with local anesthetics had a similar behavior regarding duration of analgesia and vitality of the newborns, evaluated by the Apgar score.
The incidence of adverse effects, such as pruritus, bradycardia, hypotension, nausea, vomiting, respiratory depression, and urinary retention was also similar in both groups. Only the incidence of sedation in M1 was greater in patients who received epidural sufentanil, which was statistically significant.
The administration of sufentanil in the neuroaxis is associated with several side effects. Although some of them reflect their action in the spinal cord, others are caused by the cephalic migration and supraspinal effects 13.
Pruritus is caused by spinal and supraspinal actions 11. It is the most frequent side effect 14. Although there were no statistically significant differences, pruritus was the main complaint of 32% of the patients who underwent combined spinal-epidural and 17% of those who underwent epidural anesthesia.
These results are in agreement with those in the literature, in which the incidence of pruritus is greater after the administration of subarachnoid opioid 15. The incidence after the subarachnoid administration of sufentanil varies from 25% to 90% 11-13,16-18.
In a study with pregnant women who underwent analgesia by the combined spinal-epidural technique with 5 µg or 10 mg of sufentanil, it was observed that reducing the dose of the opioid did not change the severity of the pruritus 13.
Some authors 11 observed that the incidence of hypotension and sedation was reduced using 5 µg, compared with 10 µg, of sufentanil administered in the subarachnoid space. Similar results were observed with doses of sufentanil ranging from 2.5 to 10 µg 18.
Similar to what happens with the analgesic effect, there seem to be a threshold above which sufentanil produces pruritus regardless of the dose administered 13.
It is still unclear whether pruritus is produced by the cephalic migration of the drug in the spinal fluid and subsequent interaction with the nucleus of the trigeminal nerve in the medulla 19, or if type 3 serotonin receptors are involved, since they are abundant in the dorsal horn of the spinal cord 19.
Fourteen percent of the patients who underwent combined spinal-epidural experienced hypotension, which is similar to the incidence reported by other authors 7,11,12.
Hypotension caused by subarachnoid and epidural sufentanil depends on the dose of the opioid, as well as on the association with the local anesthetic and its dose.
Several studies with pregnant women demonstrated that the incidence of hypotension with the association of bupivacaine (2.5 mg) and subarachnoid sufentanil (10 µg) varied from 11% 7 to 43% 11. Adding 7.5 µg of sufentanil to bupivacaine (2.0 mg) caused hypotension in 15% of the patients, while the incidence decreased between 5% to 9% adding 5 µg to bupivacaine (1.25 mg) 11,12.
Using a non-invasive method of thoracic bioimpedance to monitor the central hemodynamics in pregnant women undergoing combined spinal-epidural, which included the subarachnoid administration of sufentanil (10 µg), 10% of the patients developed hypotension without changes in central cardiovascular parameters 20.
It is well established that hypotension secondary to the subarachnoid administration of sufentanil for labor analgesia is secondary to the immediate and profound analgesia caused by the technique, leading to the immediate decrease in the concentration of circulating catecholamines 21.
Fourteen percent of the patients in Group 1 complained of nausea in M1 and 12% of the patients in both groups presented this complaint in M2.
The incidence of nausea in pregnant women after the administration of subarachnoid sufentanil with doses ranging from 1 µg to 10 µg varied from 0% to 35% 7,11,12,18,21.
When sufentanil (10 µg) was associated with 0.2% ropivacaine and administered in the epidural space for labor analgesia, 20% of the patients complained of nausea 23.
In the postoperative analgesia of abdominal surgeries, the continuous infusion of epidural sufentanil led to vomiting in 33% of the patients 24.
When associated with bupivacaine in the treatment of post cesarean section pain, sufentanil caused nausea in 12% of the patients 25.
However, some studies did not demonstrated vomiting in patients who received up to 30 µg of epidural sufentanil for the treatment of post cesarean section pain 25.
Opioids can cause nausea and vomiting because they stimulate the chemoreceptor area of the trigger zone on the floor of the fourth ventricle, reflecting its characteristic of partial agonist of dopaminergic receptors in the chemoreceptor zone. The blood-brain barrier is more permeable in this area than in other regions of the brain 26.
Fifty percent of the patients who received epidural sufentanil presented sedation. These results are higher than those found in the literature.
Vertommen et al. 27 observed that only 8% of the patients receiving epidural bupivacaine (12.5 mg) and sufentanil (10 µg) for labor analgesia presented mild somnolence.
Somnolence was also reported by 30% of the patients who underwent cesarean sections and received epidural sufentanil (30 µg) 28.
Other authors, who administered a continuous infusion of 0.1% ropivacaine (10 mL) associated with sufentanil (2 µg.mL-1) for labor analgesia, observed somnolence in 25% of the patients 29. It was observed that the sedation caused by sufentanil is more pronounced than the one caused by fentanyl 24.
In postoperative analgesia of abdominal surgeries, the continuous infusion of epidural sufentanil (5 µg.h-1) promoted light sedation in the first four hours of infusion 24. In the present study, the greater incidence of sedation was observed in M1 and it was also premature in the first three hours after the administration of sufentanil.
The incidence of sedation at M1 in patients who underwent combined spinal-epidural was 7%.
The incidence of sedation in pregnant women, who received combined spinal-epidural and in those who received only sufentanil or associated with a local anesthetic, varies tremendously.
Mild sedation is reported in 100% of pregnant women who received 10 µg of sufentanil in the subarachnoid space 25. Another study showed similar results with this dose 30.
Other authors reported that doses of sufentanil from 1 µg to 10 µg administered in the subarachnoid space for labor analgesia caused somnolence in 30% of the patients, regardless of the dose administered. In another study, the subarachnoid administration of 8 µg of sufentanil caused sedation in 58% of the patients 31.
When associated with bupivacaine, sufentanil (7.5 µg) caused mild sedation in 12.5% of the patients 22. After the administration of 5 µg, 5% of the patients presented this symptom 11.
Although sedation is a common side effect of opioids, the mechanism and characteristics of this phenomenon are not completely understood. In a study on the probable mechanisms of the interaction between opioids and benzodiazepines, the hypothesis of the co-localization of gamma-aminobutyric acid (GABA) receptors and opioid receptors in the central nervous system was raised, with possible cross activity and common pathways of intracellular transduction 32.
To exert their effects, opioids administered epidurally have to cross the dura mater and the arachnoid, diffuse in the cerebrospinal fluid, cross the pia mater, reach the surface of the spinal cord, and diffuse through the white matter and the gray matter to reach the opioid receptors in the dorsal horn 33.
In the epidural space, opioids can be captured by the epidural fat, absorbed into the systemic circulation, or diffuse through the dura mater into the cerebrospinal fluid 34. Since the epidural space has an extensive venous plexus, vascular absorption is intense. The epidural administration of fentanyl and sufentanil produces blood concentrations similar to the venous administration of equivalent doses 34.
Some authors demonstrated that fentanyl exerts spinal actions when administered in the epidural space 35, and several studies demonstrated that fentanyl 36 and sufentanil 37, administered in the epidural space, produced the same degree of analgesia and the same side effects as the intravenous administration. These studies emphasize the importance of the systemic absorption and subsequent cephalic distribution in the quality of analgesia and severity of side effects when lipophilic opioids are used 33.
A prospective, random, double blind study using continuous intravenous and epidural infusion of sufentanil (0.2 µg.kg-1.h-1) for postoperative analgesia of patients who underwent abdominal surgeries, observed the same levels of analgesia and incidence of side effects, such as nausea and sedation, in both study groups, although patients who received intravenous opioids had more severe sedation 37. This study showed that analgesia and side effects result from the absorption of the plasma and the redistribution to central and peripheral opioid receptors and not from the action in the spinal cord.
Opioids move rapidly from the epidural space to the cerebrospinal fluid and to the spinal cord by simple diffusion through the meninges 33. Their behavior in the subarachnoid space is determined by their lipid solubility. It has been shown that hydrophobic opioids have a high apparent volume of distribution resulting from the rapid exit from the aqueous medium of the cerebrospinal fluid to more hydrophobic spaces, such as the epidural fat 38.
Approximately 60% of the dose of sufentanil administered in the subarachnoid space traverse to the epidural space and access the circulatory system 38.
Opioids administered in the subarachnoid space probably have a spinal action, but they also diffuse to the plasma, being distributed to the brain, producing sedation and respiratory depression 33.
The results demonstrated that sufentanil, in the doses used in this study, administered in the subarachnoid or epidural space, associated with local anesthetics, had similar effects in the duration of labor after analgesia and in Apgar scores of the newborns. Regarding side effects, only sedation was more frequent in patients who received epidural opioids.
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Profa. Dra. Eliana Marisa Ganem
Depto. de Anestesiologia da FMB UNESP
18618-970 Botucatu, SP
Submitted em 03
de abril de 2006
Accepted para publicação em 05 de dezembro de 2006
* Received from CET/SBA da Faculdade de Medicina de Botucatu, Universidade Estadual de São Paulo (FMB UNESP), Botucatu, SP