Print version ISSN 0034-7094
Rev. Bras. Anestesiol. vol.51 no.6 Campinas Dec. 2001
Plain 0.5% levogyrous bupivacaine versus 0.5% bupivacaine enantiomeric mixture (S75-R25) in epidural anesthesia for varicose vein surgery*
Bupivacaína levógira a 0,5% pura versus mezcla enantiomerica bupivacaína (S75-R25) a 0,5% en anestesia peridural para cirugía de várices
José Delfino, M.D.I; Nilton Bezerra do Vale, M.D.II
IProfessor de Anestesiologia
da Universidade Federal do Rio Grande do Norte, Natal, RN
IIProfessor de Farmacologia e Anestesiologia da Universidade Federal do Rio Grande do Norte, Natal, RN
BACKGROUND AND OBJECTIVES:
The cardiotoxic effect of racemic bupivacaine (50:50) is still the major safety-related
variable for regional blocks requiring higher concentrations and volumes. Recent
animal studies suggested that the manipulation of racemic bupivacaine enantiomers
could contribute for a better therapeutic efficacy by decreasing its potential
toxicity. This study aimed at evaluating the efficacy of 0.5% bupivacaine enantiomeric
mixture (S75-R25) as compared to plain S(-100%) bupivacaine in lumbar epidural
anesthesia for varicose vein surgery.
METHODS: Participated in this randomized double-blind study 30 female patients aged 15 to 65 years, physical status ASA I or II scheduled for elective lower limb varicose vein surgery, who were allocated into two groups: S75-R25 Group 20 ml (100 mg) of 0.5% (S75-R25) bupivacaine; and Levogyrous Group - 20 ml (100 mg) of 0.5% plain S(-100) bupivacaine without adjuvants. Characteristics of sensory and motor block as well as the incidence of side effects were investigated.
RESULTS: Significant demographic differences and a longer surgical time were found in the S75-R25 Group. Faster spread and lower analgesic effects of the isomeric mixture were statistically significant. Motor block was significantly deeper in the S75-R25 Group. Side effects were negligible for both groups.
CONCLUSIONS: Fewer side effects, good patients acceptance and the lack of post-operative transient neurological symptoms point towards the safety of both solutions in lumbar epidural anesthesia for elective varicose vein surgery. The sample, however, is still small for final conclusions.
Key Words: ANESTHETICS, Local: bupivacaine, levobupivacaine; ANESTHETIC TECHNIQUES, Regional: epidural
JUSTIFICATIVA Y OBJETIVOS:
La cardiotoxicidad de la bupivacaína racémica (50:50) aún es
la grande variable relacionada a la seguridad de indicación en los bloqueos
regionales que exigen masas y volúmenes elevados. Recientes experimentaciones
en animales sugerían que la modificación de la relación enantiomérica
de la bupivacaína racémica podría contribuir para su eficacia
terapéutica y diminución de su toxicidad potencial. El objetivo del
presente estudio fue comparar la eficiencia de la mezcla enantiomerica de bupivacaína
(S75-R25) con la levógira pura S(-100) en la anestesia peridural lumbar
para cirugías de várices de los miembros inferiores.
MÉTODO: El estudio envolvió 30 pacientes del sexo femenino con edades entre 15 y 65 años, estado físico ASA I ó II, programados para cirugía electiva de várices. En test aleatorio y duplamente encubierto, los pacientes fueron divididos en dos grupos de 15: Grupo S75-R25 - 20 ml (100 mg) de mezcla enantiomerica de bupivacaína a 0,5% (S75-R25) - y Grupo Levógiro - 20 ml (100 mg) de bupivacaína levógira S(-100%) a 0,5% sin adyuvante. Fueron comparadas las características del bloqueo sensitivo y motor, bien como la incidencia de efectos colaterales.
RESULTADOS: Fueron detectadas diferencias intergrupales relacionadas a las características demográficas y un mayor tiempo quirúrgico en el grupo S75-R25. La dispersión mas rápida y la menor potencia analgésica de la mistura isomérica exhibieron significancia estadística. No hubo diferencia significativa relacionada a la ocurrencia de efectos colaterales. El grupo levógiro presentó menor relajamiento muscular.
CONCLUSIONES: La reducción de la incidencia de efectos colaterales, la receptividad del método por los pacientes, la ausencia de sintomatologia neurológica transitoria pós-operatoria apuntan para la aplicación segura de ambas las soluciones en anestesia peridural lumbar para cirugía de várices de los miembros inferiores. La casuística, entretanto, no es aún suficiente para permitir conclusiones definitivas.
Racemic bupivacaine (50:50) cardiotoxic effects were, until recently, the major safety-related variable for regional blocks requiring high concentrations and volumes. Currently there are two relatively safe alternatives: S(-) ropivacaine and S(-) bupivacaine. Both act on biological membranes, preferably on specific receptors within frequency-time dependent sodium channels of the neuronal membrane1,2.
Their intrinsic vasoconstricting effect would assure lower absorption as from injection site with decreased plasma levels3. Different liposolubility levels of both drugs would also have an important role determined by the presence of propyl and butyl radicals in their respective molecules because a higher number of carbon atoms is directly related to higher liposolubility. So, S(-) bupivacaine molecule's butyl would be more potent than S(-) ropivacaine's propyl, with the corresponding advantages4,5.
However, although safer for being less cardiotoxic, both drugs cause less muscle relaxation and are not equipotent as compared to the same concentrations of their corresponding racemic mixtures. Of course, levogyrous anesthetics are effective for regional blocks without adjuvants in wall surgeries, but are not so effective in intra-cavity surgeries6,7.
Recent animal studies have suggested that changing racemic bupivacaine's enantiomeric relation could contribute for its efficacy in addition to decreasing its potential toxicity8,9.
Our study aimed at comparing the efficacy of bupivacaine enantiomeric mixture (S75-R25), with plain levogyrous bupivacaine S(-100) in lumbar epidural anesthesia for lower limb varicose vein surgery.
After the Hospital's Ethics Committee approval, participated in this double-blind randomized study 30 female patients aged 15 years or above, physical status ASA I or II, scheduled for lower limb varicose vein surgery and submitted to epidural anesthesia with racemic bupivacaine or levobupivacaine. In addition to patient's refusal, exclusion criteria were neurolo- gical, cardiopulmonary, kidney-liver and psychiatric diseases, and drug abuse. Patients were divided in two groups depending on the solution injected in the epidural space. S75-R25 Group: 20 ml (100 mg) of 0.5% bupivacaine enantiomeric mixture (S75-R25); Levogyrous Group: 20 ml (100 mg) of 0.5% plain levogyrous bupivacaine S(-100). Patients were not premedicated. In the operating room, patients were monitored with non invasive sphygmomanometer for systolic (SBP) and diastolic blood pressure (DBP), pulse oximetry for SpO2 and continuous ECG at CM5. After venoclysis and 5% glucose solution infusion, epidural block was induced with an 18G Tuhoy needle at L4-L5 interspace with the patient in the sitting position after skin and subcutaneous infiltration with 1% lidocaine without vasoconstrictor. Epidural space was identified by the loss of resistance to air technique and 20 ml (100 mg) of a bupivacaine solution previously prepared and coded by an independent anesthesiologist were slowly injected (4 ml.min-1).
To evaluate sensory and motor block, the following parameters were investigated:
a) Onset-time between end of epidural injection and lack of pain at pinprick at the sensory area corresponding to the puncture;
b) Upper sensory block highest level with no response to pinprick (2-minute interval) after three successive stimuli;
c) Cephalad spread peak time elapsed between epidural injection and time when highest sensory block was reached;
d) Surgical analgesia duration time between epidural injection and the first spontaneous non stimulated pain complaint leading to the prescription of systemic analgesics;
e) Motor block evaluation through Bromage's scale;
f) Systolic blood pressure (SBP) and heart rate (HR) changes in times scheduled in the operating room (OR): before puncture; after anesthetic injection and return to the supine position; at every 5 minutes during the first hour and at every 15 minutes after the second hour.
Adverse effects in OR and PACU were recorded: pain on injection, shivering, nausea, vomiting, bradycardia (equal to or lower than 25% of control) and SpO2 decrease (below 90%).
To correct possible intercurrences in OR and PACU, the following parameters were added to the protocol: increase in crystalloid infusion velocity to decrease SBP to 20% of baseline values; atropine if HR went below 60 bpm; phenylephrine if SBP went below 25% of baseline; oxygen (nasal catheter) if SpO2 went below 90%; meperidine to control shivering. Patients' level of satisfaction was obtained by subjective impressions: excellent, good and poor.
Student's t test was used for statistical comparisons between intervals (demographics, onset, duration and spread time). Fischer Exact test and Chi-square tests were used to compare non parametric measures. Significance levels were established as p < 0.05.
Demographics and procedures duration are shown in table I.
Significant differences between groups were observed in weight and surgery duration: S75-R25 Group patients were heavier and had a significantly longer surgical procedure (p < 0.05).
Analgesia onset, cephalad spread in minutes and maximum blockade levels (mode) are shown in Table II. The faster spread of the isomeric mixture was statistically significant (p < 0.05).
Variables related to analgesic effects are shown in table III: first spontaneous pain complaint, postoperative analgesics requirements and patients subjective evaluation. The isomeric mixture showed less analgesic effects (p < 0.05). The method was considered excellent by 13 S75-R25 Group patients (84.5%) and good by 10 levogyrous group patients (66.6%).
Side effects are shown in table IV. Hypotension, bradycardia, shivering, urine retention and pain on injection were not statistically significant. Different motor block levels obtained through Bromage's scale are shown in figure 1. The levogyrous group had less muscle relaxation as compared to level 3 and a higher incidence of lack of motor block - level zero (p < 0.05).
S(-) ropivacaine and S(-) bupivacaine, local anesthetics structurally related to mepivacaine, are equipotent for having similar pharmacokinetic and pharmacodynamic profiles. They are less cardiotoxic as compared to their racemic form, especially for having pKa, liposolubility, Vdss, t1/2 b and protein bindings, thus changing kinetics in the biophase and, specifically, heart depressing effects4.
The single presence of levogyrous aminoacids in the formation of sodium channels in the amyelinic fiber and in Ranvier nodes of the motor fiber would speed binding velocity (transduction) and drug versus receptor decoupling, as a function of stereoselectivity caused by a potential change in intrinsic affinity and activity, which is potentially related to less muscle relaxation as compared to dextrogyrous and racemic forms4.
Having said that, some issues become relevant. First of all, local levogyrous anesthetics are an excellent spinal block technique for surgeries not requiring major motor blocks, such as varicose vein, orthopedic surgeries and labor analgesia. In addition, some modifications could relatively safely overcome the "inconvenience" of less motor block in epidural anesthesia. At first sight, there is an increase in concentration and volume; however, higher concentrations in lower volumes or vice-versa would possibly show the same effects. The association of higher concentrations to higher volumes in an attempt to improve blockade quality would be at the expenses of increased neuro and cardiotoxicity, invalidating the specific aim of local levogyrous anesthetics10. A second possibility would be the use of combined spinal-epidural anesthesia to profit form the advantages of both methods, with decreased concentrations and volumes. The third alternative would be the intrathecal method because it allows for a high quality sensory block and an effective neuromuscular block (Bromage 3) although with longer onset and shorter duration11. Still another possibility would be the use (already implemented in practice) of levogyrous local anesthetics associated to hydro and/or liposoluble opioids because the analgesic effect exacerbation would partially decrease the need for more muscle relaxation for some intra-cavity procedures, such as cesarean deliveries6,7.
One may safely expect racemic bupivacaine (equimolar sum of levogyrous and dextrogyrous fractions) to promote a more effective blockade as a consequence of less selective and more long-lasting inhibition of gNa+ in membranes ionopher. The idea that to obtain an adequate motor block it would be necessary to increase anesthetic solution volume has been observed with lidocaine. However, it is our opinion that just a volume increase to increment myorelaxation does not seem to be the best solution for levogyrous local anesthetics. The use of 1% S(-) ropivacaine with height-adjusted volume promotes good analgesia, however with a less intense lower limb motor block, which is only adequate for abdominal wall and perineal procedures12.
There are no statistical differences in upper motor block between 20 ml of 0.75% and 1% S(-) ropivacaine (Bromage 3)13,14. The same rational is true for 20 ml of 0.5% S(-) bupivacaine15. 30 ml of S(-) bupivacaine [ 27 ml of 0.5% S(-) bupivcaine plus 3 ml opioids] have given similar results6.
Racemic ropivacaine and bupivacaine have shown to be beneficial in decreasing cardiotoxicity but not as much in neural blockade efficacy. So, the stereospecificity of such drugs has led us to one more method used in this study: enantiomeric mixtures with different percentages and predominance of levogyrous enantiomers, that is, balanced solutions of bupicacaine isomeric mixtures that continue to shift polarized light counterclockwise8,9. Preliminary results in sciatic nerve and catheterized jugular vein in rats with continuous ECG confirmed that different mixtures (SR±90:10, SR±80:20 and SR±75:25) have a pattern similar to racemic bupivacaine (SR50:50) both as to onset and duration, and a similar pattern to levogyrous bupivacaine S(-) 100%, as to cardiocirculatory depression5.
In our study, demographics were not uniform and statistically significant weight differences were seen between groups, in addition to longer surgical procedures. One might say that, in considering procedures of the same size and complexity, weight differences could have increased surgical duration in the isomeric group due to difficulties in performing the surgical technique in the S75-R25 Group (isomeric mixture). Any way, such findings neither invalidate results nor impair their rational because local anesthetics were injected in fixed volume and dose.
As to onset and time to reach highest spinal level, the trend for a faster spread of the isomeric mixture was well established, probably due to less intrinsic vasoconstrictor activity (Table II). It should be highlighted that the vasoconstrictor action of cocaine as a consequence of neuronal catecholamine reuptake blockade is more inherent to its levogyrous isomer4,5. As to analgesic effect evaluation by first non stimulated pain complaint, results suggest that the plain levogyrous enantiomer would have a seemly paradoxical higher potency as compared to the isomeric mixture (Table III). Curiously, Äberg has shown in nerves a prolonged effect of the S(-) isomer as compared to the R(+) isomer16. This contradiction could be explained by microvascular stereoselectivity. Isomer S(-) is more vasoconstrictor than isomer R(+) as confirmed by Aps and Reynolds17. This effect should favor a delay in uptaking and redistributing the drug in the injection site. Such in vivo evidences reinforce in vitro studies which have shown that S(-) enantiomer is intrinsically weaker in Ranvier's nodes because the vasoconstrictor effect in the epidural injection site would make difficult perineural diffusion to block saltatory conduction of myelinized fibers. This would lead us to other essential issues, such as which would be the real role of R(+) enantiomers in exacerbating anesthetic effects, or even, how stereoisomerism of such drugs would be reflected in nervous and cardiovascular transmission pharmacokinetics and pharmacodynamics. As a curiosity, tubocurarine's levogyrous or racemic isomers have a negligible blocking action on end plate nicotinic receptors; only d-tubocurarine blocks end plate sodium inflow (N1); it has also a ganglioplegic effect (N2), which would justify its hypotensive effect4.
The low incidence of side effects on both groups was not statistically significant, thus showing the clinical validity of the epidural method for extra-cavity surgeries (Table IV).
Motor block levels evaluated by Bromage scale confirmed the weaker action of levogyrous enantiomer on motor fibers (Figure 1). This allows to infer that the presence of the R(+) isomer in the studied formulation (isomeric mixture) should be important for the neuronal blocking efficacy in muscle contraction-related myelinic fibers. The high myocardial toxicity of cocaine's semi-synthetic dextrogyrous isomer is recognized since the early 30's5. The low incidence of side-effects and patients' good acceptance of the method, together with the lack of postoperative transient neurological symptoms point to the feasibility of the safe use of both solutions in lumbar epidural anesthesia for lower limb varicose vein surgeries. The highest motor block in the S75-R25 Group may be the differential favoring its use in epidural anesthesia when muscle block is the aim.
However, our sample was not enough for final conclusions due to the small number of patients. Further clinical investigations on the most different aspects are needed to validate and confirm the use of bupivacaine enantiomeric mixture (S75-R25).
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Correspondence to Submitted for publication March 27, 2001 * Received
from Clínica Materna Natal RN
Dr José Delfino
Address: Rua Prof. Antonio Fagundes, 1849
ZIP: 59054-390 City: Natal, Brazil
Accepted for publication May 22, 2001
Submitted for publication March 27, 2001
* Received from Clínica Materna Natal RN