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On-line version ISSN 1806-907X
Rev. Bras. Anestesiol. vol.56 no.4 Campinas Set./Aug. 2006
Postoperative analgesia for cesarean section. Does the addiction of clonidine to subarachnoid morphine improve the quality of the analgesia?*
Analgesia postoperatória para cesárea. ¿la adición de clonidina a la morfina subaracnoidea mejora la calidad de la analgesia?
José Francisco Nunes Pereira das Neves TSAI; Giovani Alves Monteiro, TSAII; João Rosa de AlmeidaIII; Roberto Silva Sant'AnnaIII; Rodrigo Machado Saldanha, TSAIV; José Mariano Soares de Moraes, TSAV; Emerson Salim NogueiraVI; Fernando Lima CoutinhoVI; Mariana Moraes Pereira das NevesVII; Fernando Paiva AraújoVII; Paula Brazilio NóbregaVII
pelo CET/SBA da UFJF, Membro do Comitê de Anestesia Locorregional da SBA,
Anestesiologista do Hospital Monte Sinai
IICo-responsável pelo CET/SBA da UFJF, Anestesiologista do Hospital Monte Sinai
IIIAnestesiologista do Hospital Monte Sinai
IVInstrutor do CET/SBA da UFJF, Anestesiologista do Hospital Monte Sinai
VResponsável pelo CET/SBA da UFJF, Chefe do Serviço de Anestesiologia do Hospital Monte Sinai
VIME1 do CET/SBA da UFJF
VIIGraduanda de Medicina, Estagiária do Serviço de Anestesiologia do Hospital Monte Sinai
OBJECTIVES: The mechanism of action of a2-adrenergic
analgesia has been explored for more than one hundred years. The increased duration
of the sensitive and motor blockades caused by clonidine is dose-dependent and
has antinociceptive properties. The objective of this study was to evaluate
whether the addition of 15 to 30 µg of clonidine to spinal anesthesia
for cesarean sections with 0.5% hyperbaric bupivacaine (12.5 mg) and morphine
(100 µg) improves the quality of postoperative analgesia.
METHODS: We realized a prospective, randomized study that included 60 patients divided in 3 groups: BM 0.5% hyperbaric bupivacaine (12.5 mg) and morphine (100 µg), BM15 0.5% hyperbaric bupivacaine (12.5 mg), morphine (100 µg), and clonidine (15 mg), and BM30 0.5% hyperbaric bupivacaine (12.5 mg), morphine (100 µg), and clonidine (30 µg), administered separately. In the perioperative period the use of ephedrine and the newborn's Apgar score were recorded. In the postoperative period, the pain was evaluated in the 12th h by the VAS, the length of time it took the patient to ask for analgesics, and the postoperative side effects, such as pruritus, nausea, vomiting, bradycardia, hypotension, and sedation. The values were considered significant when p < 0.05.
RESULTS: The groups were homogenous. The use of ephedrine and the evaluation by the Apgar score did not show statistically significant differences among the different groups. The pain scores and the average time to start analgesia showed differences among the groups BM and BM15/BM30, and there were no differences regarding the incidence of postoperative side effects.
CONCLUSIONS: The addition of clonidine to spinal anesthesia with 0.5% hyperbaric bupivacaine (12.5 mg) and morphine (100 µg) for cesarean section improved the quality of the postoperative analgesia without increasing the incidence of side effects. We suggest that the dose of 15 µg of clonidine should be used.
Key Words: ANALGESIA, Postoperative; ANALGESICS: clonidine, morphine; ANESTHETIC TECHNIQUES, Regional: spinal block; SURGERY, Obstetric: Cesarean section.
Y OBJETIVOS: El mecanismo de acción analgésica a2-adrenérgico
ha venido siendo investigado hace más de cien años. La clonidina
aumenta de manera dosis-dependiente la duración de los bloqueos sensitivo
y motor y tiene propiedades antinociceptivas. El objetivo de este estudio fue
el de evaluar si la adición de clonidina en las dosis de 15 y 30 µg
a raquianestesia, para cesárea, con bupivacaína hiperbárica
a 0,5% (12,5 mg) y morfina (100 µg), mejora la calidad de la analgesia
MÉTODO: Se realizó un estudio prospectivo, aleatorio con 60 pacientes y divididos en 3 grupos: BM - bupivacaína hiperbárica a 0,5% (12,5 mg) y morfina (100 µg), BM15 - bupivacaína hiperbárica a 0,5% (12,5 mg), morfina (100 µg) y clonidina (15 µg) y BM30 - bupivacaína hiperbárica a 0,5% (12,5 mg), morfina (100 µg) y clonidina (30 µg), administradas separadamente. En el perioperatorio, fueron anotados el consumo de efedrina y la evaluación del recién nacido por el índice de Apgar. En el postoperatório, el dolor se evaluó en la 12ª hora por la Escala Analógica Visual, el tiempo para la solicitación de analgésicos y efectos colaterales postoperatórios, como comezón, náuseas, vómitos, bradicardia, hipotensión arterial y sedación. Los valores fueron considerados significativos cuando p < 0,05.
RESULTADOS: Los grupos fueron homogéneos. El consumo de efedrina y la evaluación por el índice de Apgar no exhibieron diferencia estadística significativa entre los grupos. Los rangos de dolor y tiempo promedio de analgesia indicaron una diferencia entre los grupos BM y BM15/BM30 y no hubo diferencia con relación a la incidencia de efectos colaterales postoperatórios.
CONCLUSIONES: La adición de clonidina, la raquianestesia con bupivacaína hiperbárica a 0,5% (12,5 mg) y morfina (100 µg) para cesárea, mejoró la calidad de la analgesia postoperatória, sin aumentar la incidencia de efectos colaterales, siendo 15 µg de clonidina la dosis sugerida.
The mechanism of action of a2-adrenergic analgesia has been explored for over 100 years1.
Clonidine is an imidazolic compound, a partial agonist of pre-synaptic a2-adrenergic receptors with sedating and hypnotic properties2. As adjuvant of the neuroaxial techniques it increases, in a dose-dependent fashion, the duration of the blockade3 through a mechanism that affects especially the synaptic adrenergic receptors3-5, having antinociceptive properties. It can be used as an adjuvant to both systemic and spinal or epidural opioids to control the postoperative pain6-8.
The objective of this study was to evaluate whether the addition of clonidine in doses of 15 and 30 µg to spinal anesthesia for cesarean section with 0.5% hyperbaric bupivacaine (12.5 mg) and morphine (100 µg) improves the quality of postoperative analgesia.
After approval by the Ethics Committee and signing of the consent forms, a randomized, prospective study was realized with 60 patients who received spinal anesthesia for cesarean section. The subjects were divided in three groups: BM 0.5% hyperbaric bupivacaine (12.5 mg) and morphine (100 µg), BM15 0.5% hyperbaric bupivacaine (12.5 mg), morphine (100 µg), and clonidine (15 µg), and BM30 0.5% hyperbaric bupivacaine (12.5 mg), morphine (100 µg), and clonidine (30 mg). Routine monitorization (PANI, ECG, HR, and SpO2), venipuncture with an 18G catheter, and intravenous hydration with Ringer's lactate (10 mL.kg-1) were performed, as well as positioning of the patient for lumbar puncture in the left lateral decubitus or sitting position, according to the anesthesiologist's preference. Spinal anesthesia was done in the L3-L4 space with a 27G Quinck needle, and bupivacaine (1 mL.15 sec-1), morphine and clonidine were administered, separately, according to the protocol. The episodes of intraoperative hypotension were treated with ephedrine (5 mg) every 2 minutes and the dose was recorded. The newborn's Apgar score was evaluated at 1 and 5 minutes.
Twelve hours after the procedure the intensity of postoperative pain, the time it took to start analgesia, and the presence of side effects were evaluated and recorded by an observer who did not know to which group the patient belonged. The evaluation of the postoperative pain was done with the aid of the visual analogical scale (VAS) from 0 to 10 cm (0 = no pain and 10 = worst pain possible); the time of the analgesia, i.e., the length of time between the anesthesia and the patient's request for analgesia, which was done with the administration of intravenous dipyrone (15 mL.kg-1) every 6 hours; the presence of side effects (evaluated up to 12 hours postoperative) such as pruritus, nausea, vomiting, bradycardia (heart rate below 50 bpm), hypotension (reduction greater than 20% of preoperative values), and sedation (considered clinically important when the patient was not easily awaken). Patients who needed intraoperative analgesia or sedation were not included in the study.
The statistical analysis of the data was done by ANOVA (demographic data, use of ephedrine), Tau de Kendall and Spearman's Correlation (newborn's Apgar score, evaluation of postoperative pain by VAS), and Chi-square (incidence of side effects) tests. Values were considered significant when p < 0.05.
There was no difference among the groups regarding age, weight, and height (Table I).
There was no statistically significant difference in the use of ephedrine among the different groups (Table II).
The statistical analysis demonstrated that the Apgar score was similar in all groups (Table III). The evaluation of postoperative pain 12 hours after the procedure by the visual analogic scale (Table IV) and of the average time of postoperative analgesia (Figure 1) showed a statistically significant difference between the control group (BM) and the clonidine groups (BM15 and BM30).
Table V shows the postoperative side effects.
Drugs are added to local anesthetics to improve the quality of subarachnoid anesthesia9.
Subarachnoid clonidine has been used in doses that range from 15 to 400 µg, isolated or associated with different local anesthetics and opioids, and the anesthetic and analgesic effects are qualified and quantified in several ways5. The increase in the local anesthetic activity occurs due to the blockade of the nervous impulse in the A-delta and C fibers, the hyperpolarization of isolated neurons due to the increased potassium conductance, and the vasoconstriction mediated by post-synaptic a2-adrenergic receptors that reduces the absorption of the anesthetic, increasing the time the neural tissue is in contact with the drug1,2,10-12.
Like the lipophilic opioids, it is possible to obtain analgesia by the systemic, epidural, or subarachnoid administration of clonidine; however, analgesia is more potent after the neuroaxial administration, indicating a local action in the spinal cord, favoring the administration through this route1.
Analgesia is due to its peripheric, supra-medullary, and especially medullary action by the activation of post-synaptic a2-receptors of the noradrenergic efferent pathways, activation of cholinergic neurons mediated by acetylcholine, the release of nitric oxide, with a strong correlation between the concentration of clonidine in the CSF and the analgesic activity1,2,6,8,10,11,13,14. The analgesic action inhibits the central sensitization produced by the repeated stimulation of the afferent C fibers, resulting in the central release of substance P, neurokinin A, glutamate, and aspartate that can interact with AMPA, NMDA, and metabotropic receptors blocking the central facilitation in the spinal cord and the synaptic plasticity2.
The proinflammatory cytokines can modulate pain directly, changing the transmission of neuroactive substances such as nitric oxide, free radicals, prostaglandins, and excitatory amino acids in the microglia and astrocytes7. Interleukin-6 (IL-6), the main proinflammatory cytokine, is produced early, 2 to 4 hours after lesion of the tissue, representing the primary stimulus in the acute phase, which lasts 24 to 36 hours7. Clonidine decreases the levels of IL-6 because it decreases the activity of adenilcyclase, reducing the levels of cyclic adenosine monophosphate7. The antinociceptive action occurs for both somatic and visceral pain11,15.
During pregnancy, the interaction between high levels of endorphins with clonidine may be responsible for its benefits during labor5.
Notwithstanding the variety of doses reported in the literature, a few studies5 demonstrated that, subarachnoid doses in the range of 15 to 30 mg increased significantly the sensitive blockade, improving the quality of postoperative analgesia in gynecological surgeries, knee arthroscopies, and inguinal hernia surgery.
Our study showed that in the assessment of the postoperative pain by VAS, the levels were significantly decreased in the group BM15 when compared to the control group, BM. It also demonstrated a small reduction in the BM30 group compared to the BM15 group, but it was not statistically significant. The length of postoperative analgesia was increased in the groups that received clonidine, confirming the data found in the literature, showing that the combination of subarachnoid a2-adrenergic drugs with opioids increases the duration of analgesia1.
Clonidine caused a reduction in blood pressure, inhibiting the pre-ganglionic neural synaptic activity in the spinal cord and through its action in the brain stem16.
In obstetric anesthesia, the doses of clonidine vary from 15 to 200 µg, producing hypotension because it is slightly hypobaric at the normal body temperature, which causes rostral diffusion, especially after the subarachnoid administration with the patient in the sitting position5.
The hypotension caused by a2-agonists is easily corrected by the administration of a1-adrenergic drugs, such as ephedrine, which causes an accentuated vasoconstriction in the presence of this drug11. The use of ephedrine did not show difference among the groups, suggesting that the clonidine groups did not have a higher predisposition for the development of hypotension.
There were no differences regarding the side effects among the groups. The addition of clonidine in the doses used did not cause important systemic reactions, such as sedation, hypotension, and bradycardia that usually are associated with doses of 1 to 2 µg.kg-1 9.
With the method used in this study, one can infer that the addition of clonidine to spinal anesthesia with 0.5% hyperbaric bupivacaine (12.5 mg) and morphine (100 µg) for cesarean section improved the quality of the postoperative analgesia without increasing the incidence of side effects, and that 15 mg is the minimal effective dose.
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Dr. José Francisco Nunes Pereira das Neves
Rua da Laguna, 372 Jardim Glória
36015-230 Juiz de Fora, MG
Submitted for publication
21 de outubro de 2005
Accepted for publication 11 de abril de 2006
* Received from Hospital Monte Sinai, Hospital agregado ao CET/SBA da Universidade Federal de Juiz de Fora (UFJF), Juiz de Fora, MG.