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On-line version ISSN 1806-907X
Rev. Bras. Anestesiol. vol.54 no.3 Campinas May/June 2004
Relationship between dexmedetomidine continuous infusion and end-tidal sevoflurane concentration, monitored by bispectral analysis*
Relación entre la infusión continua de dexmedetomidina y la fracción expirada de sevoflurano monitorizada por el índice bispectral
Edno Magalhães, TSA, M.D.I; Cátia Sousa Govêia, TSA, M.D.II; Luís Cláudio de Araújo Ladeira, M.D.II; Beatriz Vieira Espíndola, M.D.III
IProfessor Doutor da Área de
Clínica Cirúrgica da Faculdade de Medicina da Universidade de Brasília
(UnB), Responsável pelo CET da Clínica de Anestesiologia da Universidade
IIMédica(o) Assistente da Clínica de Anestesiologia do Hospital Universitário de Brasília, Universidade de Brasília
IIIME2 do CET da Clínica de Anestesiologia da Universidade de Brasília
BACKGROUND AND OBJECTIVES: General inhalational
anesthesia associated with intravenous agents provides analgesia and hypnosis
of better quality. Dexmedetomidine is a specific a2-adrenergic
agonist with these characteristics and is known by providing hemodynamic stability.
This study aimed at evaluating the effects of dexmedetomidine continuous infusion
on end-tidal sevoflurane concentration (ETsevo) in general anesthesia,
monitored by EEG spectral index (BIS).
METHODS: Participated in this prospective study 24 adult patients of both genders, physical status ASA I and II submitted to elective surgery under general anesthesia and monitored by ECG, BP, SpO2, PETCO2, ETsevo and BIS. Intravenous anesthesia was induced with alfentanil (30 µg.kg-1), thiopental (5 mg.kg-1) and vecuronium (0.1 mg.kg-1), followed by tracheal intubation. Then, sevoflurane (to maintain BIS between 40 and 60), controlled ventilation with tidal volume of 10 mL.kg-1 and PETCO2 between 35 and 45 mmHg were started. During maintenance, 60 minutes after anesthetic induction (T60), continuous dexmedetomidine infusion was started in 2 phases: initial infusion (1 µg.kg-1) in 20 minutes; and maintenance infusion (0.5 µg.kg-1.h-1). Sevoflurane concentration was adjusted to maintain BIS between 40 and 60. BP, HR, ETsevo, SpO2, PETCO2 and BIS were evaluated in the following moments before anesthetic induction (M-15), M15, M45, M75, M105 and M120.
RESULTS: The association of dexmedetomidine to general anesthesia with sevoflurane provided statistically significant ETsevo decrease (p < 0.05) from M45 (1.604 ± 0.485) to M105 (1.073 ± 0.457), and from M45 (1.604 ± 0.485) to M120 (1.159 ± 0.475). Hemodynamic parameters have shown statistically significant differences (p < 0.05), however without clinical repercussions.
CONCLUSIONS: The association of dexmedetomidine continuous infusion (0,5 µg.kg-1.h-1) to inhalational anesthesia with sevoflurane provided end-tidal sevoflurane concentration decrease while maintaining hemodynamic stability.
Key Words: ANALGESICS: dexmedetomidine; ANESTHETICS, Volatile: sevoflurane
JUSTIFICATIVA Y OBJETIVOS: La asociación
de agentes venosos a la anestesia general inhalatoria proporciona mejor cualidad
de analgesia e hipnosis. La dexmedetomidina es un agonista específico alfa2-adrenérgico
con estas características y reconocida por proporcionar estabilidad hemodinámica.
El objetivo del estudio fue evaluar el efecto de la infusión continua de
dexmedetomidina en la fracción expirada de sevoflurano (FEsevo)
en anestesia general, monitorizada por el análisis bispectral del EEG (BIS).
MÉTODO: Se estudió, de modo prospectivo, 24 pacientes adultos, de ambos sexos, estado físico ASA I y II, sometidos a cirugías electivas sobre anestesia general, monitorizados con ECG, PANI, SpO2, PETCO2, FEsevo y BIS. Se procedió a la inducción venosa con alfentanil (30 µg.kg-1), tiopental (5 mg.kg-1) y vecuronio (0,1 mg.kg-1) e intubación traqueal. Se iniciaron la administración de sevoflurano (manutención del BIS entre 40 y 60), la ventilación controlada con volumen corriente de 10 ml.kg-1 y la manutención de la PETCO2 entre 35 y 45 mmHg. En la fase de manutención de la anestesia, después de 60 minutos de la inducción anestésica (M60), fue iniciada la infusión continua de dexmedetomidina en 2 fases: infusión inicial (1 µg.kg-1) en 20 minutos; e, infusión de manutención (0,5 µg.kg-1.h-1). La concentración de sevoflurano fue ajustada para mantener el valor de BIS entre 40 y 60. Las variables de PA, FC, FEsevo, SpO2, PETCO2 y BIS fueron evaluadas en los tiempos pré-indución (M-15), M15, M45, M75, M105 y M120.
RESULTADOS: La asociación de la dexmedetomidina a la anestesia general con sevoflurano proporciono reducción significativa (p < 0,05) de la FEsevo de M45 (1,604 ± 0,485) a M105 (1,073 ± 0,457) y de M45 (1,604 ± 0,485) a M120 (1,159 ± 0,475). Las variables hemodinámicas analizadas presentaron diferencias estadísticamente significantes con p < 0,05, mas sin repercusiones clínicas.
CONCLUSIONES: La asociación de dexmedetomidina en infusión continua (0,5 µg.kg-1.h-1) a la anestesia general inhalatoria con sevoflurano proporcionó reducción de la fracción expiratoria de sevoflurano, con estabilidad hemodinámica.
General inhalational anesthesia associated with adjuvant intravenous agents provides better sedation, hypnosis and analgesia 1. Drugs with such effects already established in the literature include benzodiazepines and opioids 1-3. New intravenous agents are being introduced in the clinical practice. Alpha2-adrenergics have a promising potential in Anesthesiology.
Alpha2-adrenergic receptor agonists have beneficial properties when used in anesthesia. They provide better hemodynamic and adrenergic stability via sympatholytic action, sedation, anxiolysis, decreased anesthetic and analgesic consumption and attenuation of opioid-induced muscle stiffness, without marked ventilatory depressing effects. Sympatholytic action of a2-adrenergic agonists is not related to changes in neurotransmitter synthesis, storage or metabolism, and is reversible with vasoactive agents, antagonists of these receptors 4,5 or simply by withdrawing the drug.
Dexmedetomidine is a selective a2-adrenergic receptor agonist with a2:a1 selectivity higher than clonidine (1300:1 x 220:1) 6. Dexmedetomidine promotes norepinephrine plasma levels decrease, analgesia, hemodynamic stability (decreased systemic blood pressure and heart rate), anti-sialogogue effect, decreased intraocular pressure without depressing breathing 7. Pharmacokinetic properties show 1.5 hours half-life, fast onset (less than 5 minutes) and peak effect in approximately 15 minutes 7.
Dexmedetomidine in anesthesia has been related to preanesthetic medication, general anesthesia adjuvant and postoperative medication 5,6,8. As preanesthetic medication and general anesthesia adjuvant, dexmedetomidine decreases the need for anesthetics and analgesics administered for anesthetic induction and maintenance, as well as attenuates adrenergic response to tracheal intubation 5,6.
Dexmedetomidine as general inhalational anesthesia adjuvant provides synergistic pharmacological interaction with decreased inhalational anesthetic concentration and, as a consequence, lower toxicity potential and better hemodynamic stability (via sympatholytic and analgesic effects), providing sedation, analgesia and minor respiratory depression at emergence.
This study aimed at evaluating the influence of dexmedetomidine continuous infusion on end-tidal sevoflurane concentration (ETSEVO) during general anesthesia, monitored by EEG bispectral index (BIS).
After the Hospital's Ethics Committee approval and their informed consent, participated in this study 24 patients of both genders, physical status ASA I and II, aged between 18 and 50 years, submitted to elective surgeries under general anesthesia. Exclusion criteria were known kidney, liver and heart function disorders, morbid obesity and anti-hypertensive drugs.
Patients were premedicated with oral diazepam (10 mg) the day before surgery and in the surgery morning. Monitoring consisted of continuous ECG, noninvasive blood pressure (NIBP), pulse oximetry (SpO2), CO2 expired fraction (PETCO2), sevoflurane inspired fraction (IFSEVO), sevoflurane expired fraction (EFSEVO), and EEG analysis by bispectral index.
After previous oxygenation for 5 minutes, anesthesia was induced with intravenous alfentanil (30 µg.kg-1), thiopental (5 mg.kg-1) and vecuronium (0.1 mg.kg-1). Inhalational sevoflurane was started after tracheal intubation with calibrated vaporizer. Patients were mechanically ventilated with 0.95 oxygen inspired fraction (FiO2), 2.5 L.min-1 fresh gas flow and 10 mL.kg-1 tidal volume, with respiratory rate adjusted to maintain PETCO2 between 35 and 40 mmHg, using circle system with CO2 absorber.
Anesthetic depth was monitored by EEG and BIS (bispectral index), SEF 95% (spectral edge frequency 95%), SQI (signal quantity index) and SR (time percentage in the last 63 seconds when EEG has recorded amplitudes below 5 µV) were obtained with electrodes coupled to specific monitor ("Aspect"). Anesthetic depth was controlled by varying sevoflurane concentration to maintain BIS between 40 and 60. Gases were analyzed by a specific monitor.
Dexmedetomidine solution was prepared by diluting 2 mL of the original product presentation (200 µg by vial) in 48 mL of 0.9% saline solution, with a final concentration of 4 µg.mL-1).
During anesthesia, evaluation was performed in intervals in which the influence of intravenous dexmedetomidine infusion was observed. During the first interval (M0 to M60) - from anesthetic induction (M0) to sixty minutes (M60) - anesthesia was maintained with sevoflurane in concentrations able to maintain BIS between 40 and 60. During the second interval (M60 to M80) - sixty (M60) to eighty (M80) minutes after anesthetic induction - anesthesia was maintained with sevoflurane and 1 µg.kg-1 dexmedetomidine for twenty minutes, with sevoflurane concentration adjusted to maintain BIS between 40 and 60. During the third interval (M80 to M150) - eighty (M80) to one hundred and fifty (M150) minutes after anesthetic induction - anesthesia was maintained with 0.5 µg.kg-1.h-1 dexmedetomidine infusion, with sevoflurane concentration adjusted to maintain BIS between 40 and 60.
Patients were maintained as described until anesthetic-surgical procedure completion and remained monitored as previously described. IFSEVO was adjusted to maintain hypnotic stability until procedure completion.
At surgery completion, inhalational sevoflurane and continuous dexmedetomidine infusion were withdrawn. Atropine (0.02 mg.kg-1) and neostigmine (0.04 mg.kg-1) were administered for neuromuscular block recovery.
Systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), EFSEVO, IFSEVO, SpO2, PETCO2 and BIS were evaluated fifteen minutes before induction (M-15), at induction (M0) and every 15 minutes after anesthetic induction (M15, M30, M45, M60, M75, M90, M105, M120 M135 and M150).
Wilcoxon's, Student's t, Duncan's, ANOVA and non-parametric ANOVA tests were used for statistical analysis, considering significant p < 0.05.
Mean age was 32.77 ± 9.59 (years), mean weight was 61.72 ± 11.25 (kg) and there were 10 males and 14 females. Otological surgery was the most frequent surgical procedure (Table I). BIS, SEF 95%, SR and SQI results are shown in table II.
BIS, maintained between 40 and 60 throughout the experiment has not shown major variations (Table II) when comparing values before (M0 to M60) and after (M60 to M150) the association of intravenous dexmedetomidine continuous infusion.
There has been EFsevo decrease after the association of intravenous dexmedetomidine infusion (M0 to M60 x M60 to M150) (Figure 3). Comparison of EFsevo (Figure 4) in times M45 x M105 (p = 0.0001), M45 x M120 (p = 0.005) and M105 x M120 (p = 0.417) has shown statistically significant EFsevo decrease.
Dexmedetomidine is a selective a2-agonist with analgesic, sedative and sympatholytic effects. As compared to clonidine, it has adequate pharmacokinetic profile for continuous intravenous infusion and 1300:1 specificity for a2:a1 (clonidine = 220:1) 6. Its action mechanism involves the activation of different receptors coupled to several G protein types, according to receptor sub-group and location. Receptors are distributed in locus ceruleus, spinal cord dorsal horn and, possibly, in peripheral and supra-spinal sites 7.
There have been no bradycardia, arterial hypertension or hypotension with the described regimen of intravenous dexmedetomidine continuous infusion.
Several authors had already reported anesthetic agents consumption decrease after the association of intravenous dexmedetomidine continuous infusion. Aanta et al. have documented decreased thiopental consumption 9. The same authors have observed 47% isoflurane MAC decrease after the association of intravenous dexmedetomidine continuous infusion 10. Fragen et al. have observed 17% sevoflurane MAC decrease in patients aged 55 to 70 years 11, while Nunes et al. have observed 58.22% sevoflurane MAC decrease 12. In our study there has been mean 33.12% EFsevo decrease. So, there is some divergence as to dexmedetomidine's ability to decrease inhalational sevoflurane consumption.
Consciousness level monitoring in our study (EEG analysis), valid for hypnosis depth analysis both with sevoflurane alone or with the association of dexmedetomidine, has allowed to rule out the bias of anesthetic depth evaluation by hemodynamic parameters, which are changed by dexmedetomidine infusion because it promotes blood pressure and heart rate decreases. Consciousness level was continuously monitored with consequent safety in decreasing EFsevo without patients' emergence. It has been observed that the association of both agents has not determined inadequate anesthetic depth. BIS, SR, SQI and SEF 95% monitoring has allowed the evaluation of the influence of dexmedetomidine in hemodynamic parameters of patients submitted to dexmedetomidine/sevoflurane association.
The association of dexmedetomidine continuous infusion to general inhalational anesthesia with sevoflurane has provided hemodynamic stability and has decreased sevoflurane minimum alveolar concentration shown by statistically significant EFsevo decrease.
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Submitted for publication June 06, 2003
Accepted for publication September 23, 2003
* Received from Hospital Universitário de Brasília, Universidade de Brasília (UnB), DF