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Print version ISSN 0034-7094
Rev. Bras. Anestesiol. vol.58 no.6 Campinas Nov./Dec. 2008
Effects of the addition of subarachnoid clonidine to the anesthetic solution of sufentanil and hyperbaric or hypobaric bupivacaine for labor analgesia*
Efecto de la adición de clonidina subaracnoidea a la solución anestésica de sufentanil y bupivacaína hiperbárica o hipobárica para la analgesia de parto
Thaís Cristina Tebaldi, M.D.I; Luíz Marcelo Sá Malbouisson, TSA, M.D.II; Mario. M Kondo, M.D.III; Mônica M. S. C. Cardoso, TSA, M.D.IV
da Disciplina de Anestesiologia da FMUSP
IIDoutor em Ciências pela FMUSP; Médico Supervisor da Unidade de Terapia Intensiva da Disciplina de Anestesiologia da FMUSP; Especialista em Medicina Intensiva - AMIB
IIIDoutor em Obstetrícia pelo Departamento de Obstetrícia da FMUSP; Médico Ginecologista-Obstetra do HC/FMUSP
IVDoutora em Anestesiologia pela FMUSP; Médica Assistente do Serviço de Anestesiologia do HC-FMUSP; Anestesiologista do Hospital e Maternidade Santa Joana
OBJECTIVES: The addition of subarachnoid clonidine (α-agonist)
prolongs the analgesia produced by the combination of sufentanil and isobaric
bupivacaine in combined labor analgesia1. The objective of this study
was to compare the quality of analgesia and the prevalence of side effects after
the addition of subarachnoid clonidine to the anesthetic solution in labor analgesia.
METHODS: After approval by the Ethics Commission, 22 pregnant women in labor were randomly assigned to the subarachnoid administration of either 2.5 mg of 0.5% hyperbaric bupivacaine (CLON/HYPER Group; n = 11) or 2.5 mg of 0.5% isobaric bupivacaine (CLON/ISO Group; n = 11) associated with 2.5 µg of sufentanil and 30 µg of clonidine. Pain, evaluated by the Visual Analogue Scale, heart rate, and mean arterial pressure were assessed every 5 minutes during the first 15 minutes, and then every 15 minutes afterwards until delivery. The prevalence of side effects (nausea, vomiting, pruritus, and sedation) was evaluated. The study was terminated whenever the patient needed supplemental epidural analgesia (pain > 3) or upon delivery of the fetus. The Student t test, Chi-square test, Fisher exact test, and two-way ANOVA for repeated measurements were used in the statistical analysis and a p < 0.05 was considered significant.
RESULTS: Anthropometric data, duration of analgesia (70.9 ± 32.9 vs. 85.4 ± 39.5), heart rate, and the incidence of pruritus, sedation, nausea, and vomiting were similar in both groups. Mean arterial pressure was significantly lower in the CLON/ISO Group than in the CLON/HYPER Group at 15, 30, and 45 minutes (p < 0.05).
CONCLUSIONS: Under the conditions of the present study, the association of a small dose of clonidine (30 µg) with sufentanil caused a higher incidence of hypotension when the isobaric solution of the local anesthetic was used. For all other side effects, both hyperbaric and isobaric solutions showed similar behavior.
Key Words: ANALGESIA: labor; ANALGESICS: clonidine; ANESTHETIC TECHNIQUES, Regional: combined subarachnoid epidural.
Y OBJETIVOS: La adición de la clonidina subaracnoidea (α-agonista),
prolonga la acción analgésica de la combinación sufentanil
y bupivacaína isobárica en analgesia combinada para el trabajo
de parto 1. El objetivo de este estudio fue comparar la calidad de
analgesia y la prevalencia de los efectos colaterales, después de la
adición de clonidina subaracnoidea a la solución anestésica
en gestantes durante el parto.
MÉTODO: Después de la aprobación de la Comisión de Ética, 22 gestantes en trabajo de parto recibieron aleatoriamente en el espacio subaracnoideo 2,5 mg de bupivacaína hiperbárica 0,5% (grupo CLON/HIPER; n = 11) o 2,5 mg de bupivacaína isobárica 0,5% (grupo CLON/ISO; n = 11) en asociación con el sufentanil 2,5 µg y la clonidina 30 µg. El dolor evaluado por la Escala Analógica Visual, la frecuencia cardíaca y la presión arterial promedio, fueron estudiados a cada 5 minutos en los primeros 15 minutos y a continuación, a cada 15 minutos hasta el nacimiento. Fue evaluada la prevalencia de efectos colaterales (náusea, vómito, prurito y sedación). El estudio fue terminado en el momento en que se hizo necesaria la complementación analgésica epidural (dolor > 3 cm) o al nacimiento. El análisis estadístico fue realizado a través de los tests t de Student, Chi-cuadrado, Fisher y ANOVA de dos vías para medidas repetidas, considerando como significativo p < 0,05.
RESULTADOS: Los grupos CLON/HIPER y CLON/ISO fueron similares con relación a los datos antropométricos, duración de la analgesia (70,9 ± 32,9 vs. 85,4 ± 39,5), frecuencia cardíaca, incidencia de prurito, sedación, náusea y vómitos. En el grupo CLON/ISO hubo una disminución significativa de la presión arterial promedio con relación al grupo CLON/HIPER en los momentos 15, 30, y 45 minutos (p < 0,05).
CONCLUSIONES: En las condiciones estudiadas, la adición de clonidina en baja dosis (30 μg), asociada al sufentanil, determinó una mayor incidencia de hipotensión cuando se administró con soluciones isobáricas de anestésico local. Con relación a los demás efectos colaterales, las soluciones hiperbáricas e isobáricas se comportan de manera similar.
The administration of small doses of subarachnoid sufentanil associated with hyperbaric 2 and isobaric bupivacaine is frequently used in labor analgesia, promoting fast onset of effective analgesia. However, Cardoso et al. 3 demonstrated that the short duration of analgesia (around 90 minutes) is the main limitation of this technique. Thus, the administration of supplementary doses of the local anesthetic through the epidural catheter to obtain adequate analgesia until delivery is often necessary.
In obstetric anesthesia, and especially in the subarachnoid space, the interest on the use of analgesics that block pain by distinct mechanisms of action has increased, since their association allows for the reduction in the dose of each one, obtaining better analgesia with a reduction in side effects.
D'Angelo et al. 1 demonstrated that the addition of 50 µg of subarachnoid clonidine, an α-agonist, prolonged the analgesic effects of the combination of subarachnoid sufentanil and isobaric bupivacaine for labor analgesia. However, Cardoso4 reported that the addition of 30 µg of clonidine to hyperbaric bupivacaine was not effective in prolonging analgesia.
The specific gravity of solutions affects significantly their dispersion in the subarachnoid space, producing anesthesia with clinically different behaviors. Cardoso et al. 3 demonstrated that the administration of sufentanil and hyperbaric bupivacaine (hyperbaric solution) was associated with a greater latency for the development of the blockade and lower prevalence of adverse effects than the administration of the same dose of sufentanil associated with isobaric bupivacaine (hypobaric solution). Thus, it is clear that in labor analgesia the change in the specific gravity of a solution containing equal proportions of the local anesthetic and opioid can determine analgesia with clinical distinct behavior.
The objective of this study was to compare the quality of analgesia and incidence of side effects resulting from the addition of subarachnoid clonidine to the anesthetic solution (low doses of sufentanil and hyperbaric or isobaric bupivacaine) in pregnant women undergoing combined spinal-epidural block for pain relief during the first stage of labor.
After approval by the Research Project Analysis Commission of the Hospital das Clínicas of the Faculdade de Medicina da USP (CAPPesq), a randomized, prospective study with 22 pregnant women at term, physical status ASA I or II, with cervical dilation < 6 cm, was conducted. The size of the study population was calculated to detect a 10 mmHg reduction in mean arterial pressure between the groups that received hyperbaric and isobaric bupivacaine. For such, it was considered a mean arterial pressure of 80 mmHg 45 minutes after the blockade with a standard deviation of 10% in the hyperbaric group, and 70 mmHg with a standard deviation of 10% in the isobaric group, a study power of 80% and p value of 0.05. It was demonstrated that it would be necessary at least 10 patients in each group.
Patients with obstetric or fetal anomalies and those who had already received systemic analgesics before the regional block were excluded from the study. Patients were randomly divided in two groups (11 patients in each group) and received the subarachnoid administration of:
- CLON/HYPER Group: 2.5 mg of 0.5% hyperbaric bupivacaine associated with 2.5 µg of sufentanil, and 30 µg of clonidine.
- CLON/ISO Group: 2.5 mg of 0.5% isobaric bupivacaine associated with 2.5 µg of sufentanil, and 30 µg of clonidine.
Anesthetic solutions used were prepared by an anesthesiologist not involved with the care of the patient.
After monitoring with electrocardioscope, non-invasive blood pressure, and pulse oximetry, patients received 250 mL of crystalloid solution (Ringer's lactate). Patients were placed on a sitting position for the combined spinal-epidural at the L2-L3 or L3-L4 space, with a single puncture (needle through the needle), using an 18G Tuohy needle to locate the epidural space, and a 27G Whitacre needle to locate the subarachnoid space. The anesthetic solution was administered only after passive reflux of spinal fluid through the needle was observed, followed by the introduction of the epidural catheter.
Patients remained in horizontal dorsal decubitus, with the uterus dislodged to the left by a modified Crawford 5 wedge, for at least 15 minutes to allow for the fixation of the anesthetic in the subarachnoid space and afterwards they were cleared to be positioned according to the orientation of the obstetrician. Patients remained in bed throughout labor, and were not allowed to ambulate.
Pain, heart rate (HR), and mean arterial pressure (MAP) were evaluated every five minutes for the first 15 minutes, followed by every 15 minutes until delivery. The incidence of side effects (nausea, vomiting, pruritus, and sedation) was also evaluated. Pain was assessed with the Visual Analogue Scale (VAS) of 10 cm (0 - absence of pain and 10 - unbearable pain). If pain was greater than 3 after the initial 15 minutes, a bolus of 4 mL of increasing concentrations of bupivacaine (0.125%, 0.25%, or 0.5%) was administered every 15 minutes until pain control was achieved (VAS < 3). Hypotension, defined as a reduction in systolic blood pressure by at least 20% of baseline values, was treated with the administration of a bolus of 5 mg of intravenous ephedrine. Nausea and vomiting not related to the hypotension were treated with the intravenous administration of 10 mg of metochlopramide. Sedation was assessed by the Ramsay sedation scale, where 1 corresponds to agitated patient; 2, patient oriented and calm; 3, patient only responds to commands; 4, fast response to audible stimuli; 5, slow response to audible stimuli; and 6, absence of response to audible stimuli 6. Patients received oxytocin according to the protocol of the hospital for administration of this drug. The study was terminated whenever the patient received the first analgesic supplementation through the epidural catheter or delivery of the fetus (whichever came first).
The study was planned to detect a 10 mmHg reduction between the groups of patients who received hyperbaric and isobaric bupivacaine associated with clonidine 2,4. For such, it was considered a mean arterial pressure of 80 mmHg after 45 minutes with a 10% standard deviation in the hyperbaric group, and 70 mmHg with a 10% standard deviation in the isobaric group, study power of 80% and p value of 0.05. It was observed that it would be necessary at least 10 patients per group (G Power 3, Heinrich-Heine-Universität, Dusseldorf, Germany). The software Sigmastat 3.11 (Systat Inc, USA) was used for the statistical analysis. The Kolmogorov-Smirnov test was used to analyze the normal distribution of the data. Student t test, Chi-square test, Fisher Exact test, or two-way ANOVA for repeated measurement, followed by the Student-Newmann-Keuls multiple comparison test were used to compare both groups, and a p < 0.05 was considered significant. Data on tables are expressed as mean ± standard deviation and as mean ± standard error in the figures.
As can be seen on Table I, age, weight, and height were similar in both groups. Dilation 45 minutes after the double block was similar in both groups, 7.1 ± 2.1 in the CLON/HYPER Group, and 7.5 ± 2.6 in the CLON/ISO Group. The duration of analgesia did not show significant changes, despite the tendency for greater duration in the group that received isobaric bupivacaine. The efficacy of the analgesia induced by the blockade was similar in both groups. Groups did not differ in the incidence of pruritus, sedation, nausea, and vomiting (Table II).
As for the hemodynamic evolution, changes in mean heart rate between the groups were not observed (Figure 1). However, the behavior of the mean arterial pressure was significantly different in both groups. As shown in Figure 2, a pronounced reduction in MAP, up to 28% of baseline levels, was observed 15 minutes after the blockade in the CLON/ISO Group. In the CLON/HYPER Group it was observed a maximal reduction of 15% in MAP. When both groups were compared, it was observed that, 15 minutes after the blockade until the end of the observation period, the mean arterial pressure in the CLON/ISO Group was significantly lower than in the CLON/HYPER Group, as can be seen in Figure 2. As expected, the administration of vasopressor was necessary in four patients of the CLON/ISO Group, while in the CLON/HYPER Group it was not necessary.
The present study demonstrated that the addition of 30 µg of clonidine to isobaric bupivacaine and sufentanil increased the incidence of maternal hypotension when compared with the association of clonidine, hyperbaric bupivacaine, and sufentanil.
This data confirms the results of prior studies by Cardoso et al. 3 who demonstrated in patients undergoing combined labor analgesia that the changes in the specific gravity of solutions changes significantly the quality of analgesia. Thus, the incidence of maternal hypotension is lower when clonidine is added to sufentanil and hyperbaric bupivacaine than when it is combined with sufentanil and isobaric bupivacaine.
It is possible to refer to hypobaric clonidine since clonidine is hypobaric at body temperature 7. Therefore, the combination of clonidine and isobaric bupivacaine most likely results in a hypobaric solution. On the other hand, when clonidine is associated with hyperbaric bupivacaine, it probably results in a hyperbaric solution. This can be explained by the fact that the density of hyperbaric bupivacaine is very high when compared to that of the spinal fluid and the addition of adjuvant drugs (opioids or α2-agonists) changes only slightly the specific gravity.
Clonidine reduces the blood pressure by inhibiting the pre-ganglionic sympathetic activity in the spinal cord 8,9. The severity of hypotension seems to be related to the level of the injection and the dose administered. Hypotension is more pronounced when clonidine is administered in the thoracic segments because it is closer to sympathetic pre-ganglionic neurons 10,11. Besides, activation of post-synaptic α2 receptors in the brain stem and peripheral pre-synaptic α2 receptors would contribute to reduce the blood pressure even further by reducing the sympathetic activity. Similarly, high doses of subarachnoid clonidine are more likely to be associated with hypotension, probably by facilitating the rostral dispersion of the drug into thoracic levels and the brain stem.
However, it has been observed that even small doses of subarachnoid clonidine (30 µg) in hypobaric solutions can potentially cause hypotension. This shows the importance of the mechanism of rostral dispersion of clonidine in which even small doses of this α-agonist reaching the brain stem causes important maternal hypotension.
This data does not support the results of Filos et al. 12, who demonstrated that doses of up to 450 µg of subarachnoid clonidine did not cause hemodynamic instability. But Filos 12 evaluated the analgesic efficacy and hemodynamic changes of several doses of subarachnoid clonidine without associated opioids or local anesthetics in the immediate postoperative period of patients undergoing cesarean sections. Both the solutions used and the group of patients evaluated varied.
In the present study it was decided to associate only 30 µg of clonidine to sufentanil and bupivacaine because Chiari et al. 13 demonstrated that the duration of this dose of clonidine associated with 2.5 µg of sufentanil produced labor analgesia similar to that produced by 100 or 200 µg of clonidine associated with 2 µg of sufentanil. Based on this data, it was decided to use the dose of 30 µg.
In obstetric analgesia the multimodal approach is always advantageous. Using small doses of drugs from distinct pharmacologic groups one usually obtains the maximal performance of each drug with a decrease in the incidence of side effects. It also decreases the exposure of the fetus to several drugs. The dose used in the present study, i.e., 30 µg, administered in the subarachnoid space is not detected in the maternal blood.
As for the duration of analgesia, it was observed that the addition of 30 µg of clonidine and 2.5 µg of sufentanil to 2.5 mg of isobaric or hyperbaric bupivacaine did not increase significantly the duration of anesthesia. This data does not support the results reported by D'Angelo et al. 1, who also added clonidine to the mixture of local anesthetic and opioid (50 µg of clonidine, 2.5 mg of isobaric bupivacaine, and 7.5 µg of sufentanil) observing a significant increase in the duration of analgesia that went from a mean time of 132 ± 39 minutes (opioid and local anesthetic group) to 197 ± 70 minutes (clonidine, opioid, and local anesthetic group). However, it should be mentioned that D'Angelo 1 used almost twice the dose of clonidine of the present study.
Both studies differ not only by probably having used solutions with different specific gravity, but also because, in the first study, patients whose delivery occurred before the end of analgesia or needed supplementation were excluded. In the present study, duration of analgesia was defined as the period from the blockade until the need for supplemental epidural analgesia or the delivery (whichever came first), which probably contributed to reduce the mean duration of the blockade. In some cases, delivery occurred even before the need for analgesic supplementation.
To conclude, the addition of 30 µg of clonidine to the anesthetic solution containing 2.5 µg of sufentanil and 2.5 mg of isobaric or hypobaric bupivacaine did not improve the quality or the duration of labor analgesia when injected in the subarachnoid space. However, the addition of clonidine to sufentanil and isobaric bupivacaine increased the incidence of maternal hypotension.
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Correspondence to: Submitted em 22
de janeiro de 2007 *
Received from Centro Obstétrico do Hospital das Clínicas (HC)
da Faculdade de Medicina da Universidade de São Paulo (FMUSP), São
Dra. Mônica Maria Siaulys Capel Cardoso
Av. Dr. Enéas de Carvalho Aguiar, 255 - 8º andar
PAMB - Divisão de Anestesia
05403-900 São Paulo, SP
Accepted para publicação em 24 de agosto de 2008
Submitted em 22
de janeiro de 2007
* Received from Centro Obstétrico do Hospital das Clínicas (HC) da Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, SP