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On-line version ISSN 1806-907X
Rev. Bras. Anestesiol. vol.56 no.2 Campinas Mar/Apr. 2006
The effect of adding subarachnoid clonidine to hyperbaric bupivacaine and sufentanil during labor analgesia*
Efecto de la adición de clonidina subaracnoidea en la bupivacaína hiperbara y sufentanil en la analgesia del parto
Mônica Maria Siaulys Capel Cardoso, TSA, M.D.I; Fabio V. Papa, M.D.II; Roberta F. Vieira, M.D.III; Mário M. Kondo, M.D.IV; Marcelo Luis Abramides Torres, TSA, M.D.V
em Anestesiologia pela FMUSP; Supervisora da Anestesia Obstétrica do HC-FMUSP;
Anestesiologista do Hospital e Maternidade Santa Joana
IIMédico Colaborador da Disciplina de Anestesiologia da FMUSP
IIIME2 da Disciplina de Anestesiologia da FMUSP
IVDoutor em Obstetrícia pelo Departamento de Obstetrícia da FMUSP
VDoutor em Anestesiologia pela FMUSP; Anestesiologista da Maternidade Pró-Matre Paulista
AND OBJECTIVES: Adding subarachnoid clonidine (an a-agonist)
prolongs the analgesic effect of the combination of sufentanil and isobaric bupivacaine
when combined during labor analgesia. The aim of this study was to compare the
quality and duration of the analgesia as well as the incidence of side-effects
after the addition of subarachnoid clonidine to hyperbaric bupivacaine and sufentanil
in a combined spinal-epidural analgesia during labor.
METHODS: Twenty-six patients, physical status ASA I in full-term pregnancy were studied. They randomly received the following in the subarachnoid space: clonidine, sufentanil and bupivacaine (n = 13) referred to as the Clon/Sufenta/Bupi Group wherein 2.5 mg of 0.5% hyperbaric bupivacaine was added to 2.5 µg of sufentanil and 30 µg of clonidine; sufentanil and bupivacaine (n = 13) referred to as the Sufenta/Bupi Group wherein 2.5 mg of 0.5% hyperbaric bupivacaine was added to 2.5 µg of sufentanil. This was a double-blind study. Evaluations of pain and side effects (nausea, vomiting, itching, low blood pressure and sedation) were conducted every five minutes for the first 15 minutes and after that, every 15 minutes up until the birth of the baby. Pain was evaluated using a visual analogic scale ranging from 0-10 cm (VAS 0 = absence of pain and 10 = unbearable pain). The study was over whenever complementary epidural anasthesia was found necessary (pain > 3 cm) or at the moment of birth. A Student t-test statistical analysis was performed and the results were significant (p < 0.05).
RESULTS: The mean pain scores at the times measured were similar for the Clon/Sufenta/Bupi and Sufenta/Bupi Groups respectively: 0 min (8.9 ± 1.6/ 7.6 ± 2.1), 5 min (3.4 ± 2.3/ 2.3 ± 3.1), 10 min (1.5 ± 2.5/ 1.4 ± 2.2) and 15 min (0.26 ± 0.8/ 1.4 ± 2.2). No differences between the Clon/Sufenta/Bupi and Sufenta/Bupi Groups, respectively, were observed regarding: the duration of the analgesia (58.8 ± 32 min / 55.4 ± 53 min), itching (4/13 and 4/12 patients), nausea (1/13 and 1/12 patients), vomiting (1/13 and 0/12 patients) and low blood pressure (2/13 and 1/12 patients). The sedative effect of clonidine was not observed in any patient. One patient from the Sufenta/Bupi group was eliminated from the study because the anaesthesia failed to take effect after 15 minutues.
CONCLUSIONS: Under the conditions observed in the study, adding a low dosage of clonidine when combined with a hyperbaric solution does not prolong the duration of the analgesia, does not improve the quality of the action and does not act as the determining factor for the occurence of low blood pressure or sedation.
Key words: ANALGESIA: labor; ANALGESICS, Opioids: sufen-tanil; ANESTHETICS, Local: bupivacaine; SURGERY, Obstetrics: labor; DRUGS: clonidine; ANESTHETIC TECHNIQUES, Regional: combined subarachnoid and epidural.
Y OBJETIVOS: La adición de clonidina subaracnoidea (un a
-agonista), prolonga la acción analgésica de la combinación
del sufentanil y de la bupivacaína isobárica en analgesia combinada
para el trabajo de parto. El objetivo de este estudio fue comparar la calidad
y la duración de la analgesia y la incidencia de los efectos colaterales
después de la adición de clonidina subaracnoidea en la bupivacaína
hiperbara y sufentanil en anestesia combinada raqui-peridural durante el trabajo
MÉTODO: Fueron estudiadas 26 gestantes a término, estado físico ASA I, en trabajo de parto que recibieron, al acaso en el espacio subaracnoideo: clonidina, sufentanil y bupivacaína (n = 13), denominado Grupo Clon/Sufenta/Bupi, 2,5 mg de bupivacaína hiperbara al 0,5% asociada a 2,5 µg de sufentanil y 30 µg de clonidina; sufentanil y bupivacaína (n = 13), denominado Grupo Sufenta/Bupi, 2,5 mg de bupivacaína hiperbara al 0,5% asociada a 2,5 µg de sufentanil. El estudio fue doble ciego. El dolor y los efectos colaterales (náuseas, vómito, prurito, hipotensión arterial y sedación) fueron evaluados cada cinco minutos en los primeros 15 minutos y, a seguir, cada 15 minutos, hasta el nacimiento. El dolor fue evaluado con la escala analógica visual de 0-10 cm (VAS = 0, ausencia de dolor y 10, dolor insoportable) y el estudio fue encerrado en el momento en que se hizo necesaria la complementación analgésica peridural (dolor > 3 cm) o al alumbramiento. El análisis estadístico fue realizado con los testes t de Student y Exacto de Fisher, considerando como significativo p < 0,05.
RESULTADOS: Los promedios de dolor en los momentos - 0 min (8,9 ± 1,6/7,6 ± 2,1) 5 min (3,4 ± 2,3/2,3 ± 3,1), 10 min (1,5 ± 2,5/1,4 ± 2,2) y 15 min (0,26 ± 0,8/1,4 ± 2,2) en los grupos Clon/Sufenta/Bupi y Sufenta/Bupi fueron respectivamente parecidos. No se observaron diferencias con relación a la duración de la analgesia (58,8 ± 32 min / 55,4 ± 53 min), ocurrencia de prurito (4/13 y 4/12 pacientes), náusea (1/13 y 1/12 pacientes), vómito (1/13 y 0/12 pacientes) e hipotensión arterial (2/13 y 1/12 pacientes) en los grupos Clon/Sufenta/Bupi y Sufenta/Bupi, respectivamente. No se observó ningún efecto sedante de la clonidina en ninguna paciente. Una paciente del grupo Sufenta/Bupi fue excluida del estudio por falla total del bloqueo después de 15 minutos.
CONCLUSIONES: En las condiciones estudiadas, la adición de clonidina en dosis bajas (30 µg) y cuando asociada con soluciones hiperbaras no prolongo la duración de la analgesia, no mejoro la calidad del bloqueo ni determino la ocurrencia de hipotensión arterial y/o sedación.
The administration of low doses of subarachnoid sufentanil along with hyperbaric bupivacaine is a commonly used tecnique for labor analgesia, resulting in a fairly quick and effective installation of the analgesia. However, Yamaguchi et al.1 have shown that this technique is significantly limited by its short duration (around 90 minutes). Many times, this makes it necessary to give complementary dosages of local anesthesia by a epidural catheter in order to obtain effective analgesic effects up until the end of vaginal labor.
In obstetric anesthesia, and particulary those in the subarachnoid space, there has been growing interest in the use of analgesic drugs that used distinct mechanisms to block pain since the combination will typically allow you to reduce the individual dosages, thereby obtaining greater analgesic effect with a lower incidence of side effects. D'Ângelo et al. 2 showed that adding 50 µg of subarachnoid clonidine, an a-agonist, prolonged the analgesic effects of the combination of sufentanil and subarachnoid bupivacaine as combined analgesia during childbirth.
The aim of this study was to compare the quality of the analgesia as well as the incidence of side effects after the addition of subarachnoid clonidine to the anesthetic solution (low doses of sufentanil and bupivacaine) in pregnant women given spinal-epidural anesthesia to relieve the pain during the first stage of labor.
After obtaining approval from the Analysis Project and Research Ethics Committe at the Hospital das Clinicas and the Medical College at USP (São Paulo University), the CAPPesq, a randomized, prospective, double-blind study was performed on 26 pregant women with no prior pathologies in their medical histories and who showed cervical dilations equal to or below 6 cm. Patients with signs of obstetric or fetal abnormalities were excluded from the protocol, as were those who had already received systemic analgesics prior to the administration of a regional anaesthetic.
Patients were monitored with an electrocardioscope, non-invansive blood pressure monitor and pulse oximeter and afterwards were given volemic expansion with 250 mL of cristaloid (Lactated ringer's). The combined spinal-epidural was given in a sitting position at the L2-L3 or L3-L4 space, by way of a single-shot, needle-through-needle approach, using na 18-gauge Tuohy for the localization of the epidural space and a 27-gauge Whitacre needle for the localization of the subarachnoid space. The anesthetic solution was only injected after obtaining liquor reflux through the spinal needle; immediately after that, the catheter was inserted into the epidural space.
The patients remained in the horizontal dorsal decubitus position, with the uterus displaced to the left with a Modified Crawford wedge 3, for at least 15 minutes in order to allow the anesthetic to fixate in the subarachnoid space. After this time, they were free to position themselves according to the obstetrician's orientation. The patients remained lying down for the entire duration of labor and were not allowed to walk. The anesthetic solutions used in the procedure were prepared by an anesthesiologist who was not in contact with the patient.
The patients were randomly divided into 2 groups, each with 13 patients. The following solutions were injected in the subarachnoid space:
Clon/Sufenta/Bupi Group: 2.5 mg of 0.5% hyperbaric bupivacaine in addition to 2.5 µg of sufentanil and 30 µg of clonidine;
Sufenta/Bupi Group: 2.5 mg of 0.5% hyperbaric bupivacaine in addition to 2.5 µg of sufentanil and 0.2 mL of saline solution.
Evaluations of pain and side effects (nausea, vomiting, itching, low blood pressure and sedation) were conducted every five minutes for the first 15 minutes and after that, every 15 minutes up until the birth of the baby. Pain was evaluated using a visual analogic scale ranging from 0-10 cm (VAS 0 = absence of pain and 10 = unbearable pain) by an anesthesiologist who was not aware of which group the patient belonged to. After the first fifteen minutes, in cases of pain greater than 3 cm, a bolus of 4 mL was given to the patient every fifteen minutes with increasing concentrations of bupivacaine (0.125%, 0.25% or 0.5%) until the pain was manageable (i.e., less than 3 cm on VAS). Arterial hypotension, defined by a drop in systolic blood pressure of over 20% from basal blood pressure, was treated with a bolus of 5 mg of ephedrine injected intravenously. Nausea and vomiting unrelated to low arterial blood pressure were treated with one via of metochlorpropamide intravenously. To evaluate sedation, we used the Ramsay scale where: 1 - patient is agitated or anxious; 2 - patient is orientated and calm; 3 - patient responds only to commands; 4 - patient responds quickly to auditory stimulus; 5 - patient responds sluggishly to auditory stimulus; and 6 - no response to auditory stimulus 4. All patients were receiving ocitocin according to the hospital's protocols for administering this drug. The study was terminated at the time of the first complementary analgesic given through the epidural catheter or at the time of birth.
The statystical analysis was conducted through a Variation Analysis of repeated readings, as well as one level, in which p < 0.05 was considered significant. The size of the sample per group was based on previous studies 2,9.
Both groups were similar regarding anthropometric variables such as age, weight and height, and also in terms of average initial cervical dilation (Table I).
The mean pain readings at the times measured were similar for the Clon/Sufenta/Bupi and Sufenta/Bupi groups, respectively: 0 min (8.9 ± 1.6/ 7.6 ± 2.1), 5 min (3.4 ± 2.3/ 2.3 ± 3.1), 10 min (1.5 ± 2.5/ 1.4 ± 2.2) and 15 min (0.26 ± 0.8/ 1.4 ± 2.2).
No differences between the Clon/Sufenta/Bupi and Sufenta/Bupi groups, respectively, were observed regarding: the duration of the analgesia (58.8 ± 32 min / 55.4 ± 53 min), itching (4/13 and 4/12 patients), nausea (1/13 and 1/12 patients), vomiting (1/13 and 0/12 patients) and low blood pressure (2/13 and 1/12 patients).
No patient showed signs of sedation due to clonidine, nor did we observe maternal bradycardia in any of the patients. One patient from the Sufenta/Bupi group was eliminated from the study because the anesthesia failed to take effect after 15 minutes.
This study has shown that adding 30 µg of clonidine to an anesthetic solution containing 2.5 mg of hyperbaric bupivacaine and 2.5 mg of sufentanil neither improves nor prolongs the effect of the analgesia. These results go against the results obtained by Gautier et al. 5 who found that by adding 15 µg or 30 µg of clonidine to 2.5 µg of sufentanil you could significantly prolong the effect of the analgesia, regardless of the dose of clonidine that is applied. Nevertheless, it is worth emphasizing that this study evaluated the effect of adding clonidine to a mixture that contained both a local anesthetic and an opioid, and not an opioid alone. Therefore, it is possible that adding low doses of clonidine could improve the quality of the analgesia provided by the opioid, but not when the opioid is combined with a local anesthetic.
It was also possible that clonidine could improve the quality of the analgesia when used in an isobaric or hypobaric solution, but would not play the same role in a hyperbaric solution. Cardoso et al. 6 have shown that, for analgesia during labor, changes in the baricity of a solution significanly effect the quality of the anesthetic. The addition of sufentanil in the hyperbaric bupivacaine cause more changes at the onset time of action and more or less side effects incidence than adding of the same dose of sufentanil with isobaric bupivacaine. Hence, changes in the baricity of a solution containing equal proportions of opioid and local anesthetic could result in analgesia with very different clinical behaviors.
At body temperature, clonidine is slightly hypobaric 7. Therefore, when you combine clonidine and isobaric bupivacaine, you will probably get a hypobaric solution. On the other hand, when combined with hyperbaric bupivacaine, the end result is probably a hyperbaric solution. This can be explained by the fact that the density of hyperbaric bupivacaine is very high when compared to the density of the liquor, meaning that its baricity hardly changes when other drugs were added (be they opioids or a2-agonists). Thus, 15 µg or 30 µg of clonidine may have been effective in prolonging analgesia when used with hypobaric solutions, but would not necessarily behave in the same way when used in hyperbaric solutions.
The same reasoning used to explain the apparent ineffectiveness of clonidine in prolonging analgesia during labor when used in hyperbaric solutions could also help to explain the absence of side effects in this study.
Clonidine inhibits sympathetic preganglionic activity in the spinal medula, thereby producing a reduction in arterial blood pressure 8,9. The severity of the arterial hypotension seems to be related to the level of the injection as well as with the drug dose used. It is more important when clonidine is administered in the thoracic segments, as they are closer to the sympathetic preganglionic neurons 10,11. Furthermore, the activation of the a2-postsynaptic receptors in the brain stem along with the peripheral a2-presynaptic receptors contribute towards an even greater reduction in arterial blood pressure by reducing sympathetic activity. Large doses of clonidine (of up to 200 µg) are said to be more often linked to hypotension, probably because the rostral migration of the drug to the thoracic and brain stem levels would be facilitated, especially when administered in hypobaric solutions. Hence, administering clonidine in a hyperbaric solution would not lead to the occurence of side effects (arterial hypotension, bradycardia and sedation) because of the difficult rostral migration that would limit its actions in regions like the thoracic spine and brain stem. Although arterial blood pressure is one of the most common side effects associated to clonidine use, it is worthy mentioning that clonidine itself is a mixed action alpha agonist with a-1 and a-2 action. This means that extremely elevated doses of clonidine may lead to hypertension by causing vasoconstriction. Nevertheless, Filos et al. 12 showed that doses of up to 450 µg of the drug in the subarachnoid space did not cause any hemodynamic instability.
We chose to add only 30 µg of clonidine to the sufentanil and bupivacaine since research by Chiari et al. 13 showed that 30 µg of clonidine, when combined with 2.5 µg of sufentanil, resulted in analgesia during labor with a similar duration to that promoted by the administration of 100 µg or 200 µg of clonidine combined with 2 µg of sufentanil. Furthermore, Gautier et al. 5 found that adding 30 µg of clonidine to 2.5 µg of sufentanil in the subarachnoid space increased the duration of the analgesia from an mean of 104 to 145 minutes without leading to motor block. Another advantage of using these high doses is that when the drug is administered in the subarachnoid space, it will not be detected in the mother's bloodstream.
In regards to the duration of the analgesia, the study found that adding 30 µg of clonidine to 2.5 µg of sufentanil and 2.5 mg of bupivacaine did not prolong the effects of the analgesia. These findings contrast the results of the study conducted by D'Angelo et al. 2, which found that by adding clonidine to the mixture containing a local anesthetic and an opioid (50 µg of clonidine, 2.5 mg of isobaric bupivacaine and 7.5 µg of sufentanil), there was a significant increase in the duration of the analgesia, which went from an mean time of 132 ± 39 minutes (for the group that received a combination of opioid and local anesthetic) to 197 ± 70 minutes (for the group that received the combination of opioid, local anesthetic and clonidine). It is worth emphasizing, however, that the majority of studies that proved there are benefits associated with adding clonidine involved the drug being added to hypobaric solutions.
Another important finding is that, in this study, the duration times of the analgesia were much shorter than those observed by D'Angelo et al. 2. However, the method of both these studies does not only differ in the fact that they probably used solutions with different baricity. The former study eliminated patients when the birth of the child occured before the end of the analgesia's effect or before the need to complement the analgesia. This study, on the other hand, defined the duration time of the analgesia as the period before the need to have a complementary epidural or until the baby was born (whichever happened first), which probably contributed to shortening the duration time of the block. In some cases, the patient delivered the baby before it was even necessary to administer complementary analgesia.
In conclusion, the study found that adding adding 30 µg of clonidine to 2.5 mg of hyperbaric bupivacaine and 2.5 µg of sufentanil did not improve the quality or prolong the effect of the analgesia. Similarly, under these conditions, adding clonidine also did not lead to an increase in the incidence of side effects (especially hypotension and sedation).
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Dra. Mônica Maria Siaulys Capel Cardoso
Av. Dr. Enéas de Carvalho Aguiar, 255
8° Andar PAMB Divisão de Anestesia
05403-900 São Paulo, SP
for publication 27 de junho de 2005
Accepted for publication 02 de janeiro de 2006
* Received from Disciplina de Anestesiologia do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HC-FMUSP), Departamento de Ginecologia e Obstetrícia da Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, SP