Midazolan por vía espinal o endovenosa como coadyuvante de la anestesia regional con lidocaína/fentanil en pacientes sometidos a procedimientos quirúrgicos lumbares de pequeño porte

OBJETIVOS: el presente estudio visa evaluar la utilidad de la administracion del benzodiazepinico midazolan por via venosa o espinal en pacientes sometidos a procedimientos quirurgicos de pequeno porte sobre anestesia regional con lidocaina y fentanil. METODOS: despues de la aprobacion del Comite de Etica en Investigacion Formal, 40 pacientes fueron evaluados de forma doble-ciego y prospectivo, siendo divididos de forma aleatoria uno de los cinco grupos del estudio (n=8). Los pacientes fueron pre-medicados con midazolan o solucion fisiologica (volumen final 4 mL) por via venosa. La anestesia espinal fue administrada con el paciente sentado, utilizandose 75 mg de lidocaina, 33 mg de fentanil o 500 mg de midazolan diluidos en solucion fisiologica (0.9%), siendo el volumen final administrado por via intratecal 3 mL. Fueron evaluados: el tiempo de latencia, el de bloqueo motor, el de analgesia, lo grado de sedacion y de ansiedad. El p 0.05). Tanto la administracion de fentanil intratecal o midazolan intratecal resultaron en aumento del tiempo de analgesia (p<0.01). En relacion a los resultados subjetivos, el Grupo 1 actuo como Control, siendo los pacientes alertas, pero con cierto grado de ansiedad, mientras los pacientes que recibieron midazolan estuvieron alertas y no ansiosos. CONCLUSIONES: los pacientes que recibieron midazolan intratecal permanecieron alertas y con capacidad de concentracion, presentaron menor latencia para anestesia y mayor tiempo de analgesia.


RESUMEN
Objetivos: el presente estudio visa evaluar la utilidad de la administración del benzodiazepínico midazolan por vía venosa o espinal en pacientes sometidos a procedimientos quirúrgicos de pequeño porte sobre anestesia regional con lidocaína y fentanil.Métodos: después de la aprobación del Comité de Ética en Investigación Formal, 40 pacientes fueron evaluados de forma doble-ciego y prospectivo, siendo divididos de forma aleatoria uno de los cinco grupos del estudio (n=8).Los pacientes fueron pre-medicados con midazolan o solución fisiológica (volumen final 4 mL) por vía venosa.La anestesia espinal fue administrada con el paciente sentado, utilizándose 75 mg de lidocaína, 33 mg de fentanil o 500 mg de midazolan diluidos en solución fisiológica (0.9%), siendo el volumen final administrado por vía intratecal 3 mL.Fueron evaluados: measured.P<0.05 was considered significant.Results: the addition of midazolan to the intrathecal injection in the absence of fentanyl was the only procedure which caused a statistically significant reduction in LT (p<0.002) and TT10 (p<0.001).Intrathecal midazolan increased the blockade time both with (p<0.05) and without (p<0.02)intrathecal fentanyl, but, when given intravenously, this effect failed to reach statistical significance (p>0,05).Both intrathecal fentanyl and midazolan increased the duration of analgesia (p<0.01).With respect to the subjective measures, group 1 served as the control group, demonstrating an alert, fully awake patient who was able to concentrate but showed some anxiety.Conclusions: while all additional treatments resulted in a relaxed patient, only those given intrathecal midazolan remained fully awake, alert and able to concentrate.Intrathecal fentanyl with saline premedication or intravenous midazolan premedication resulted in decreased alertness and inability to concentrate, as well as sleepiness, which was more extreme in the case of those patients given intravenous midazolan.

INTRODUCTION
Lamina V-type neurons on the spinal dorsal horn, which responded to the bradykinin injection into femoral artery, were studied neurophysiologically in spinal transected cats by the tungsten microelectrode method.It has been demonstrated that the separated and combined antinociceptive effects of fentanyl, clonidine and midazolan, administered intrathecally, can produce reduction in response to noxious stimuli.Fentanyl (25 micrograms), clonidine (30 micrograms) and midazolan (1 mg), separately, suppressed noxious evoked activity at the spinal level.On the other hand, fentanyl (5 micrograms), clonidine (5 micrograms) and midazolan (0.5 mg) produced no significant suppression of the evoked activity.However, the combinations of drugs at lower doses produced supra-additive suppressive effects, which were reversed by each antagonist (naloxone, yohimbine and flumazenil).These findings suggest that, when two of these drugs are combined at sub-analgesic doses, a significant synergistic interaction is exerted.Therefore, the use of these drugs in combination can reduce the total amount of any drug required for analgesia in the spinal cord and also reduce the side effects of these agents [1][2][3][4] .
In order to clarify some of these issues, the present study was designed to evaluate the usefulness of intravenous and intrathecal midazolan as an adjunct to intrathecal ligdocaine with or without intrathecal fentanyl.

METHODS
After Hospital Ethics Committee approval and written informed patient consent, 40 ASA status I and II patients, scheduled for minor orthopedic lumbar surgery, were randomly assigned to one of five groups (n=8) and the observer was blind to the treatments.All subjects were premedicated in the reception room with a total of 4 mL administered intravenously (IV).Spinal anesthesia was administered in theatre, with the patient in sitting position, using L3-4 interspace and a 25 gauge needle.The anesthetic volume of the different anesthetic combinations was 3.5 mL, injected at 1 mL/7 seconds.The patients laid down (supine position) immediately after completion of the spinal injection.The groups were divided as shown in table 1.A conservative free midazolan solution was available for this study.Standard monitoring techniques were used, including ECG, blood pressure and pulse oximetry.
The latency time for onset of the block (LT) and the time to progress to T10 sensory level (TT10), using a cold device (cotton soaked in alcohol solution), were recorded in seconds.The duration of the block (Bl) was measured as the time to reach Bromage 2 score, and the duration of effective analgesia (An) measured as the time from the intrathecal drug administration to the first need for analgesic administration in recovery room, recorded in minutes.
The subjective degree of intraoperative sedation was recorded as sleepy, slightly sleepy or fully awake.The level of alertness was subjectively analyzed by the patient demeanor, always by the same anesthesiologist.Concentration level was measured by the capacity of promptly and correctly answering direct questions, like "how old are you?";"how much do you weight?"; "how tall are you?".The correct answers had already been noted in the patient's hospital book.The degree of anxiety was also subjectively measured as anxious or relaxed.All adverse effects were recorded and specific treatments were available.All patients remained in the anesthetic recovery room until apparent complete recovery from anesthesia.Groups 4 and 5 were followed for 40 days as outpatients, in order to assess any possible adverse effect resulting from intrathecal administration of midazolan.Statistical analyses were performed with the ANOVA and the Student's two-tailed t-tests, as required.P<0.05 was considered significant.

RESULTS
The five groups did not differ statistically in ASA status, male/female ratio, age, weight and height (Table 2).The duration of surgery ranged from 45-60 minutes (p>0.05).The addition of midazolan to intrathecal injection in the absence of fentanyl was the only procedure which caused a statistically significant reduction in latency of onset and the time to progress to T10, ranging from 80±12 seconds, for the control group, to 45±5 seconds for patients who received intrathecal midazolan (p<0.002).Intrathecal midazolan increased the blockade time compared to the control group (46±7 minutes), both with 54±8 minutes (p<0.05) and without fentanyl (71±8 minutes; p<0.02), but, when given intravenously, this effect failed to reach statistical significance in the present study (p>0.05).Both intrathecal fentanyl and midazolan, by either route, also significantly increased the duration of analgesia, compared to the control group (ranging from mean of 50 minutes); 70 minutes (spinal fentanyl) to 110 minutes (spinal midazolan) (p<0.01).With respect to the subjective measures (Table 3), group 1 served as the control group, demonstrating an alert, fully awake patient who was able to concentrate, but showed some anxiety.Whi-le all additional treatments resulted in a relaxed patient, only those given intrathecal midazolan (groups 4 and 5) remained fully awake, alert and able to concentrate.Intrathecal fentanyl with saline premedication or intravenous midazolan premedication resulted in decreased alertness and inability to concentrate as well as sleepiness, which was more extreme in the case of those patients given intravenous midazolan.No intraoperative adverse effects were noted, except from five patients (two from group 2, two from group 3, one from group 4) who scratched their nose during the intraoperative period.Groups 4 and 5 were followed as outpatients for 40 days.No adverse effects were noted.

DISCUSSION
In the present study we have clearly demonstrated that co-administration of fentanyl and midazolan enhances the duration of analgesia associated with a ligdocaine spinal block.The fact that the levels and the time to achieve analgesia were not influenced by fentanyl agrees with the work of others 5,6 who used bupivacaine as local anaesthetic.The prolongation of spinal local anaesthetics action by fentanyl is also in agreement with others 5 , but this effect seems to be much greater if the local anaesthetic is ligdocaine.It is interesting to note that only intrathecal midazolan, in the absence of fentanyl, significantly reduced the latency and progress of the block.It is possible that groups 2 and 3 patients, who were sleepy and unable to concentrate, were slow to respond to the stimulus, and thus the measured latency and progress times reflected sedation rather than analgesia.However, this explanation cannot be applied to group 4 patients who were alert and able to concentrate.It is known that the lipid solubility, and thus the rate of penetration into the spinal cord, is pH dependent for both midazolan and ligdocaine.However, the ligdocaine/midazolan solution had a pH of 6.33 and the addition of fentanyl had little effect (pH=6.29), which is unlikely to explain the reduced latency observed when fentanyl was not added to ligdocaine/midazolan mixture.
The most prominent finding from the subjective data revealed that intrathecal midazolan maintains its anxiolytic action, without sedating or reducing the ability to concentrate.This is desirable when the communication between the patient and the anesthesiologist, during surgical procedures, is important.Nevertheless, studies involving midazolan must be carefully carried out, once the disposable formulation is not conservative free.In this study, the conservative free midazolan was gently prepared in our pharmacy institution.
It has been suggested that midazolan has a mild analgesic effect due to central suppression of pain perception 7 .Other workers have found that IV midazolan significantly reduces the affective and motivational component of pain, which was experienced by healthy human volunteers subjected to experimental pain 8 .This reduction in the motivational drive was suggested to be due to a central suppression 9 .However, in our study, the preservation of normal alertness, muscle tonus and respiratory rate provide some evidence that the drug is acting spinally, rather than by causing a general depression of the central nervous system.However, these observations are not objective and have qualitative end points 10 .
Studies of combinations in animals provide some information that is prerequisite to successful clinical use.However, such studies can be hampered, because many of the non-opioid drugs have marked effects on motor function, which render difficult responses to interpret in antinociceptive tests 10,11 .Nevertheless, midazolan enhancement in ligdocaine/fentanyl nociception cannot be attributed to the increase in motor deficit in this study.The IV midazolan showed no increase in ligdocaine motor effect, while enhancing its analgesic effect.In addition, although midazolan enhanced both ligdocaine motor and analgesic effects, our patients were alert, quite able to understand what was happening, to communicate and to differentiate a painful sensation even in the presence of motor block.In conclusion, putting all together, these results demonstrate selective actions on BZD and opioid receptor types, with spinal versus cortical distribution.However, a free conservative solution must be available before studies can be done to really certify its real role in anesthesia, as coadjuvant, mainly when an awake -but not anxious -patient is desirable during the procedure.