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On-line version ISSN 1806-907X
Rev. Bras. Anestesiol. vol.55 no.1 Campinas Jan./Feb. 2005
Preemptive analgesia with epidural bupivacaine and S(+)ketamine in abdominal hysterectomy*
Analgesia preemptiva con S(+)cetamina y bupivacaína peridural en histerectomía abdominal
Ferdinand Edson de Castro, M.D.I; João Batista Santos Garcia, TSA, M.D.II
IProfessor Adjunto da Disciplina de
Fisiologia da Universidade Federal do Maranhão; Anestesiologista Assistente
do HU - UFMA
IIProfessor Adjunto Doutor da Disciplina de Anestesiologia da Universidade Federal do Maranhão. Responsável pelo Serviço de Dor do Hospital Universitário (HU - UFMA)
BACKGROUND AND OBJECTIVES: This study
investigates the ability of epidural S(+)ketamine, NMDA receptor antagonist,
plus local anesthetic (bupivacaine) injection to promote preemptive analgesia
in patients undergoing total abdominal hysterectomy, when this solution is administered
before surgical incision.
METHODS: Participated in this prospective double-blind study 30 patients were randomly assigned in two equal groups. Epidural injection and catheter insertion were performed at L1-L2 interspace. Group 1 (G1) patients received 17 mL bupivacaine 0.25% plus 3 mL S(+)ketamine (30 mg), 30 min before surgical incision, followed by 20 mL saline 30 min after incision. Group 2 (G2) patients received 20 mL saline 30 min before surgical incision, followed by 17 mL bupivacaine 0.25% plus 3 mL S(+)ketamine (30 mg) 30 min after incision. General anesthesia was induced with propofol, pancuronium, O2 and isoflurane. Postoperative analgesia consisted of epidural fentanyl plus bupivacaine bolus with 4h minimal interval. If necessary, IV dipyrone supplementation was administered. Patients were evaluated for analgesia by a verbal and numeric scale (at recovery and every six hours until 24 postoperative hours). Time to first analgesic request and total analgesic requirements were recorded.
RESULTS: There were no significant differences between groups in time to first analgesic request, total analgesic consumption and numeric or verbal scale pain scores.
CONCLUSIONS: This study failed to demonstrate a preemptive effect of epidural administration of bupivacaine and S(+)ketamine in the doses tested for abdominal hysterectomy.
Key words: ANALGESIA, epidural, preemptive; ANESTHETICS: bupivacaine, ketamine
JUSTIFICATIVA Y OBJETIVOS: El presente
estudio investiga la capacidad del antagonista del receptor NMDA, S(+)cetamina,
asociado a la inyección peridural de anestésico local (bupivacaína)
en promover analgesia preemptiva en pacientes sometidas a histerectomía
total abdominal, administrando esa solución antepasadamente a la incisión.
MÉTODO: Fueron evaluadas 30 pacientes, distribuidas aleatoriamente en dos grupos de igual tamaño y estudiadas prospectivamente de forma encubierta. Inyección peridural e inserción de catéter fueron realizadas entre los interespacios de L1-L2. En el grupo I (G1, n = 15), las pacientes recibieron por vía peridural, 17 mL de bupivacaína a 0,25% sin vasoconstrictor asociados a 30 mg de S(+)cetamina (3 mL) treinta minutos antes de la incisión quirúrgica y, después de 30 minutos de la incisión, recibieron 20 mL de solución fisiológica a 0,9%. En el grupo 2 (G2, n = 15), recibieron 20 mL de solución fisiológica por vía peridural, 30 minutos antes de la incisión, fue hecha una administración de 17 mL de bupivacaína a 0,25% asociadas a 30 mg de S(+)cetamina (3 mL), treinta minutos después de la incisión. Después de la inyección peridural, se realizó anestesia general con propofol, pancuronio, O2 e isoflurano. Para analgesia post-operatoria fue usada solución peridural en bolus de fentanil asociada a la bupivacaína, con intervalo mínimo de cuatro horas. La suplementación con dipirona solamente era usada si necesario. Se evaluó la intensidad del dolor a través de escala numérica y verbal (al despertar, 6, 12, 18 24 horas después del término de la operación), el tiempo necesario para pedir por la primera vez el analgésico y el consumo total de analgésicos.
RESULTADOS: No hubo diferencia significativa entre los grupos con relación al tiempo para pedir analgésicos por la primera vez, al consumo de analgésicos y a los resultados de dolor por las escalas numérica y verbal.
CONCLUSIONES: No fue posible demostrar efecto preemptivo con la utilización peridural de S(+)cetamina y bupivacaína en las dosis utilizadas en histerectomía abdominal.
Some experimental dates by different authors have shown that preoperative pain treatment before surgical incision could prevent spinal cord neuronal hyperexcitability secondary to peripheral stimulation, which is related to hyperalgesia. Proponents of this technique, later called preemptive analgesia, have also found a marked decrease in postoperative pain length 1,2.
Excitatory neurotransmitters, acting through N-Methyl-D aspartate (NMDA), have been related to the development and maintenance of pathological pain states after tissue injury, especially hyperalgesia and allodynia 3.
This observation has encouraged the evaluation of NMDA receptor antagonists in different pain models. Ketamine is one of the few NMDA antagonists available for clinical practice. In addition, it has analgesic properties unrelated to NMDA receptors, such as activation of descending monoaminergic inhibitory system involved in the modulation of nociceptive processes which are in general activated by systemic opioids 4,5.
Several studies have been performed with local anesthetics, opioids, anti-inflammatory drugs and medications such as ketamine by different administration routes to obtain preemptive effects, however with conflicting results 7.
This study aimed at checking whether epidural injection of S(+)ketamine plus bupivacaine in patients submitted to total abdominal hysterectomy would have preemptive analgesic effect.
After the Medical Ethics Committee approval and their written consent, participated in this study 30 female adult patients, physical status ASA I or II, submitted to elective total abdominal hysterectomy. All patients were operated in the Hospital Materno Infantil, Universidade Federal do Maranhão (UFMA).
This was a randomized, double-blind study with two equal groups. Groups (1 or 2) were assigned to sealed envelopes prepared before beginning of study and opened approximately one hour before anesthesia, after explaining the whole procedure to be performed by the anesthesiologist who had no additional involvement with the patient. The researcher in charge was blind to the drawn group until study completion.
Exclusion criteria were counterindication for epidural puncture, such as infection at puncture site, uncorrected hypovolemia, patient's refusal, coagulation disorders, anatomic abnormalities, technical difficulties and patients with cardiac, coronary or hypertensive diseases.
Group I patients (pre-incision group) (n = 15) received epidural 17 mL of 0.25% bupivacaine plus 30 mg S(+)ketamine (3 mL) 30 minutes before surgical incision, and 20 mL saline 30 minutes after incision.
Group 2 patients (post-incision group) (n = 15) received epidural 20 mL saline 30 minutes after incision, and 17 mL of 0.25% bupivacaine plus 30 mg S(+)ketamine (3 mL) 30 minutes after incision.
Monitoring during anesthesia consisted of cardioscope, pulse oximetry and noninvasive blood pressure. Hydration was achieved with lactated Ringer's after venous puncture with Teflon 18G catheter. Patients were not premedicated.
Epidural puncture was performed at L1-L2 interspace through loss of resistance to air technique followed by above-described solutions injection, catheter insertion and fixation.
All patients were submitted to general anesthesia after epidural injection. Anesthesia was induced with propofol (2.5 mg.kg-1) and neuromuscular block with pancuronium (0.1 mg.kg-1). After tracheal intubation anesthesia was maintained with O2 and isoflurane.
At the end of surgery, patients were observed in the PACU and then referred to the ward. Need for analgesics in all cases during the first 24 hours was evaluated, being administered 4 mL of 0.25% bupivacaine and 1 mL fentanyl (50 µg) via epidural catheter as soon as patient would refer pain (as from emergence), in minimum intervals of 4 hours. Nursing team was specifically trained for this purpose and all patients were previously informed that they should ask for analgesics even for mild pain. Intravenous 30 mg.kg-1 dipyrone was administered when there was need for analgesic supplementation before 4 hours. Total analgesic consumption in 24 hours has been recorded.Pain was evaluated by verbal scale and numeric scale in the following moments:
(M0) - at emergence; (M6) - 6 hours after the end of surgery; (M12) - 12 hours after the end of surgery; (M18) - 18 hours after the end of surgery; (M24) - 24 hours after the end of surgery.
The following variables were compared between groups: age, weight, height, body mass index (BMI), surgery length and intercurrences. The following parameters were evaluated after surgery: pain evaluation through verbal and numeric scale, time elapsed for first analgesic request, total analgesic consumption, side effects and complications. Parametric and non-parametric tests were used for statistical analysis of results, taking into consideration the nature of studied variables. The following tests were applied: Student's t, Mann-Whitney, Kolmogorov-Smirnov, chi-square for contingency tables and Friedman's Analysis of Variance by Posts.Notwithstanding the application of non-parametric tests, tables show mean and standard deviation to give an Idea of values variability. Null hypothesis rejection level was set to 0.05 or 5% (p < 0.05) for all tests.
Demographics data (age, weight, height and body mass index) are shown in table I and are expressed in mean ± standard deviation. Statistical analysis has not shown significant differences between groups. Total surgery length has varied from 50 to 115 minutes (mean ± SD: 87.66 ± 17.40 min) for the pre-incision group (G1) and from 55 to 136 minutes (76.66 ± 25,32 min) for the post-incision group (G2) without statistically significant difference (p = 0.0889).
Time for first analgesic supplementation has varied from 0 to 185 minutes (median: 38.33 min) for group 1 and from 0 to 270 minutes (median: 58.33 min) for group 2, without significant difference (p = 0.3712).
There have been no significant differences between groups in the number of epidural analgesic solution bolus (0.25% bupivacaine - 4 mL + fentanyl 50 µg - 1 mL) and the number of supplementations with intravenous dipyrone (30 mg) requested by each patient (Table II).
There have also been no differences in total number of epidural analgesic solution bolus and total number of supplementations with intravenous dipyrone (30 mg) accumulated in the following moments: M0 - M6, M6 - M12, M12 - M18 e M18 - M24 hours, as shown in table III.
The following intercurrences were observed: hypotension (one patient from each group), hypertension (G1 = 1, G2 = 3 patients), bleeding (G2 = 1 patient), arrhythmia (G1 = 1 patient, G2 = 2 patients) and vomiting (3 patients from each group). There has been no consciousness level change.
Several studies on preemptive analgesia have been conducted, but many do not follow the model in which the intervention before painful stimulation has significantly higher, lower or equal effect as compared to the same intervention after pain stimulation by the same route and with the same dose.
Our study was performed according to an analgesic proposal in which drugs were administered before and after painful stimulation in the same dose and by the same route, as described by Mcquay, and considered the preemptive analgesia model by several authors 8,9.
Participated in this study two groups of female patients submitted to total abdominal hysterectomy, operated by the same surgical team under the same anesthetic technique, without statistically significant differences in age, weight, height and BMI. Total surgery length was also similar for both groups.
Total abdominal hysterectomy was chosen for being a medium-size procedure promoting intense nociceptive stimulations, and for being commonly associated to severe postoperative pain.
Propofol and isoflurane, which are unrelated to preemptive effects according to several authors, were used for anesthetic induction and maintenance, respectively 10-12.
Opioids were avoided in this study because they could have prevented or attenuated central sensitization, thus leading to questionable results 13-16.
A sub-anesthetic ketamine dose, defined as intravenous or epidural bolus below 1 mg.kg-1, was related to analgesic effects, as compared to a higher dose with psychomimetic symptoms and dissociated analgesia 17. Authors have concluded that sub-anesthetic ketamine doses associated to local anesthetics or opioids significantly improve pain scores decreasing the need for other drugs and the hyperalgesic area around the surgical wound.
Ketamine may act on several receptor systems, including opioids (µ, d, k) and cholinergics (muscarinic and nicotinic), involving the monoaminergic system and also exhibiting local anesthetic effects by blocking sodium channels 18-20. All those interactions are likely to mediate analgesic effects not specifically related to NMDA system, and may contribute to postoperative pain relief after epidural administration. Ketamine has anti-hyperalgesic effect.
Kawamata et al. 21 have explained in an experimental study part of ketamine analgesic effects. Authors have measured intraperitoneal and subarachnoid ketamine effects in rats with and without inflammation. The involvement of the monoaminergic system was evaluated through the administration of specific antagonists and CSF microdialysis techniques. In the absence of inflammatory reaction, ketamine has promoted antinociceptive effect through the activation of descending monoaminergic inhibitory system.
This effect was only seen after systemic administration. However, ketamine absorption from the epidural space to systemic circulation is fast, being impossible to rule out a supra-spinal effect by this route. In rats with peripheral inflammation, ketamine nociceptive effects are clearly independent of the monoaminergic system and are due to anti-NMDA effect. In this situation, there is antinociception regardless of the administration route 21.
Racemic ketamine is not recommended for epidural and subarachnoid administration due to the neurotoxic potential of the preservative used in its commercial preparation 22.
S(+)ketamine is produced in preservative-free solution and has been shown to be superior to the racemic mixture in several ways. Is has four times more affinity for NMDA receptors as compared to R(-) and higher analgesic potency than the racemic mixture 23.24. Fewer side effects, such as agitation and psychotic reactions have also been described 6.
There are some studies on epidural S(+)ketamine and its subarachnoid administration in continuous infusion for 24 hours has been recently described in chronic pain patient without neurological injury 25-27.
Our study has used an epidural dose of 30 mg, considered sub-anesthetic, but results indicated that ketamine through this route has not been effective to control postoperative pain, because numeric and verbal scale scores, time for first analgesic request and postoperative analgesic consumption for both pre and post-incision groups were not significantly different.
Why was epidural ketamine not effective in this study? Several answers may be proposed. First, NMDA receptors have important role in processing pain perception in the spinal segment. Particularly, these receptors prolong and amplify nociceptive response. All patients received epidural block with local anesthetics before or during surgery, which may have interfered with the action of epidural ketamine on NMDA receptors. Ketamine induces non-competitive NMDA receptor blockade, which means that receptor's channel has to be opened before the drug is bound to it. Epidural blocks with pre-synaptic inhibition of afferent nociceptive receptors could have prevented NMDA receptor of remaining open 3.
Second, and as suggested by some authors, the role of NMDA antagonists on surgical incision-induced pain could be less important than in other experimental pain models. Authors have investigated the effects of NMDA receptor antagonists on mechanical hyperalgesia in a postoperative pain model and have failed to show significant spinal effect 28.
Third, there is a more central site for ketamine anti-hyperalgesic action, which is easily reached after systemic administration. Intraperitoneal surgery also activates afferent nociceptive stimulations (sensory vagus nerve branches) and, finally, ketamine directly interferes with inflammatory reaction. Authors have shown in vitro a potent inhibitory effect of ketamine on different pro-inflammatory cytokines 29. Systemic ketamine is probably more effective than epidural ketamine for the two latter situations.
There are limited data to determine the preemptive effect of epidural ketamine. Schmid et al. 17 have observed promising ketamine effects through several routes, including epidural route. Choe et al. 30, have obtained preemptive effect with epidural ketamine plus morphine in patients submitted to gastrectomy, the same being true for Wong et al. 31 in patients submitted to knee replacement.
Moiniche, Heklet, Dahl have performed a systematic review of 80 studies on preemptive analgesia 32, including NSAIDs, intravenous opioids, parenteral NMDA receptor antagonists (intravenous and muscular), epidural analgesia (single dose or continuous infusion), caudal analgesia and local anesthesia. Intravenous ketamine studies were uniformly negative. Only two studies with dextrometorfane, another NMDA antagonist, were effective in promoting preemptive effects.
However, it is worth highlighting that there were only six ketamine studies and it seems more adequate to state that results are still inconclusive.
Only two studies on epidural ketamine alone or in association were included, and it is impossible to conclude that the drug has no preemptive effect through this route.
Pain treatment with continuous epidural injection to determine a preemptive effect extending to the postoperative period has also been surveyed. In theory, this treatment may improve the ability to decrease nociceptive impulses and central neuroplasticity, which are caused not only by surgical incision and procedure but also by postoperative inflammation. However, results have shown that the preemptive effect has been systematically negative, with the proviso that these were only eight studies. Pain intensity improvement has been observed in a small number of cases. An explanation for negative continuous epidural findings may be that notwithstanding the continuous treatment, technique has not been sufficient to prevent triggering and maintenance of central sensitization-induced injury.
It is widely accepted that preemptive analgesia may decrease the risk of postoperative chronic pain. In an attempt to compare the effects of identical pre and post-incision treatments in longer pain periods, some authors have observed that the number of patients with chronic pain six month after surgery was significantly decreased 32. However it is clear that further data and further preemptive treatment attempts comparing patients receiving no treatment during surgeries such as prostatectomies, thoracotomies or amputations are needed.
Our study has used 17 mL of 0.25% bupivacaine plus 3 mL (30 mg) S(+)ketamine, which is an analgesic solution volume often used epidurally in association to general anesthesia to promote anesthetic stability without cardiovascular changes. However, the dermatome reached by epidural injection has not been evaluated and it is possible that this volume (20 mL) was insufficient to totally block afferent nociceptive stimulations triggered by surgical procedure. It is important to remind that adequate somatic analgesia does not necessarily translates into visceral analgesia.
Postoperative analgesia was achieved with bolus 5 mL of 0.25% bupivacaine plus 50 µg fentanyl as from the first pain complaint until 24 postoperative hours. Bolus was administered on demand at minimum 4-hour intervals, but the injection was given immediately after request to prevent as much as possible any delay in analgesic solution administration and pain intensity increase. The amount of additional analgesics was a means to evaluate preemptive analgesia. Patient-controlled analgesia (PCA) has not been used due to high costs and for not being a routine in the hospital where the study was conducted.
Analgesia was supplemented with 30 mg.kg-1 dipyrone in patients requesting analgesics before the interval of 4-hours. Dipyrone has excellent analgesic action and is not associated to postoperative bleeding because it does not significantly change thromboplastin time or platelet aggregation with the advantage of having spasmolytic action. It decreases postoperative morphine consumption and promotes adequate analgesia. Additionally, there are evidences that dipyrone has a role in central and peripheral sensitization inhibition 33-36.
It should be highlighted that pain scores in all moments were low, providing high quality analgesia with the proposed technique.
Intercurrences with the studied analgesic approach and the anesthetic technique were mild not leading to patients' dropout.
No studies were found in the literature comparing pre and post-incision administration of epidural S(+)ketamine plus bupivacaine. Our study has investigated for the first time analgesia obtained with the epidural association of S(+)ketamine and bupivacaine.
Recently, Kissin 37 has reported that the ideal preemptive analgesic approach should avoid the establishment of central sensitization by surgical incision and by the inflammatory process in the early postoperative period. Maybe neuronal plasticity induced during this period is the major reason why several comparative pre and post-incision studies have failed in evaluating preemptive analgesia value.
This model is good enough to assure the presence or absence of the effect, but not to measure its clinical value. Impulses able to start post-surgical hypersensitization may be generated in the pre-incision group, thus decreasing the difference between groups. Still, time for analgesic administration between groups results in higher plasma concentrations of these drugs in the post-incision group, which may have more pronounced effects in preventing hypersensitization in this group and, as a consequence, could decrease the difference between results.
A major aspect also to be reviewed by preemptive analgesia studies is the lack of verification of the pharmacologic effectiveness of the treatment, through direct measurement of the early nociceptive response between preemptive and control groups, measured for example, by the levels of plasma cortisol, b-endorphins, interleukins, etc. A study in this field with patients submitted to abdominal hysterectomy with epidural bupivacaine and fentanyl has found that analgesic solutions used before surgical incision have not significantly changed serum interleukin-6 levels, which is a major mediator of the acute phase of inflammatory reaction and responsible for several endocrine and metabolic changes observed in response to surgical trauma 38.
In conclusion, although having obtained negative results with a combined technique (epidural bupivacaine + S(+)ketamine), it is sure that further studies should be conducted and that new associations should be tested, including other NMDA receptor antagonists in a longer study, as from before surgical incision until the immediate postoperative period, in an attempt to obtain attenuation of responses which prolong and worsen pain, with wider analgesic coverage throughout this period.
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Dr. João Batista Santos Garcia
Address: Av. dos Holandeses, 213/701 Ponta D´Areia
ZIP: 65085-450 City: São Luís, Brazil
Submitted for publication July 5, 2004
Accepted for publication October 27, 2004
* Received from Hospital Universitário Materno-Infantil da Universidade Federal do Maranhão (HU UFMA), São Luís, MA