Relationship between dexmedetomidine continuous infusion and end-tidal sevoflurane concentration, monitored by bispectral analysis

Abstracts

JUSTIFICATIVA E OBJETIVOS: A associação de agentes venosos à anestesia geral inalatória proporciona melhor qualidade de analgesia e hipnose. A dexmedetomidina é um agonista específico alfa2-adrenérgico com estas características e reconhecida por proporcionar estabilidade hemodinâmica. O objetivo do estudo foi avaliar o efeito da infusão contínua de dexmedetomidina na fração expirada de sevoflurano (FEsevo) em anestesia geral, monitorizada pela análise bispectral do EEG (BIS). MÉTODO: Estudou-se, de modo prospectivo, 24 pacientes adultos, de ambos os sexos, estado físico ASA I e II, submetidos à cirurgias eletivas sob anestesia geral, monitorizados com ECG, PANI, SpO2, P ET CO2, FEsevo e BIS. Procedeu-se a indução venosa com alfentanil (30 µg.kg-1), tiopental (5 mg.kg-1) e vecurônio (0,1 mg.kg-1) e intubação traqueal. Iniciaram-se a administração de sevoflurano (manutenção do BIS entre 40 e 60), a ventilação controlada com volume corrente de 10 ml.kg-1 e a manutenção da P ET CO2 entre 35 e 45 mmHg. Na fase de manutenção da anestesia, após 60 minutos da indução anestésica (M60), foi iniciada a infusão contínua de dexmedetomidina em 2 fases: infusão inicial (1 µg.kg-1) em 20 minutos; e, infusão de manutenção (0,5 µg.kg-1.h-1). A concentração de sevoflurano foi ajustada para manter o valor de BIS entre 40 e 60. As variáveis de PA, FC, FEsevo, SpO2, P ET CO2 e BIS foram avaliadas nos momentos pré-indução (M-15), M15, M45, M75, M105 e M120. RESULTADOS: A associação da dexmedetomidina à anestesia geral com sevoflurano proporcionou redução significativa (p < 0,05) da FEsevo de M45 (1,604 ± 0,485) a M105 (1,073 ± 0,457) e de M45 (1,604 ± 0,485) a M120 (1,159 ± 0,475). As variáveis hemodinâmicas analisadas apresentaram diferenças estatisticamente significantes com p < 0,05, mas sem repercussões clínicas. CONCLUSÕES: A associação de dexmedetomidina em infusão contínua (0,5 µg.kg-1.h-1) à anestesia geral inalatória com sevoflurano, proporcionou redução da fração expiratória de sevoflurano, com estabilidade hemodinâmica.

ANALGÉSICOS; ANESTÉSICOS; ANESTÉSICOS

SCIENTIFIC ARTICLE

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 de Brasília

^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

^{Correspondence}

SUMMARY

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 (ET_sevo) 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, P_ETCO₂, ET_sevo 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 P_ETCO₂ 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, ET_sevo, SpO₂, P_ETCO₂ 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 ET_sevo 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

RESUMEN

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 (FE_sevo) 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, P_ETCO₂, FE_sevo 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 P_ETCO₂ 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, FE_sevo, SpO₂, P_ETCO₂ 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 FE_sevo 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.

INTRODUCTION

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 (ET_SEVO) during general anesthesia, monitored by EEG bispectral index (BIS).

METHODS

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 (P_ETCO₂), sevoflurane inspired fraction (IF_SEVO), sevoflurane expired fraction (EF_SEVO), 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 P_ETCO₂ 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. IF_SEVO 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), EF_SEVO, IF_SEVO, SpO₂, P_ETCO₂ 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.

RESULTS

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.

Brazilian Journal of Anesthesiology, 2004; 54: 3: 303 - 310

Relationship between dexmedetomidine continuous infusion and end-tidal sevoflurane

concentration, monitored by bispectral analysis

Edno Magalhães; Cátia Sousa Govêia; Luís Cláudio de Araújo Ladeira; Beatriz Vieira Espíndola

Brazilian Journal of Anesthesiology, 2004; 54: 3: 303 - 310

Relationship between dexmedetomidine continuous infusion and end-tidal sevoflurane

concentration, monitored by bispectral analysis

Edno Magalhães; Cátia Sousa Govêia; Luís Cláudio de Araújo Ladeira; Beatriz Vieira Espíndola

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.

Heart rate and blood pressure were not statistically different in moments M₀ to M₆₀ and M₆₀ to M₁₅₀ (Figure 1 and Figure 2).

Brazilian Journal of Anesthesiology, 2004; 54: 3: 303 - 310

Relationship between dexmedetomidine continuous infusion and end-tidal sevoflurane

concentration, monitored by bispectral analysis

Edno Magalhães; Cátia Sousa Govêia; Luís Cláudio de Araújo Ladeira; Beatriz Vieira Espíndola

Brazilian Journal of Anesthesiology, 2004; 54: 3: 303 - 310

Relationship between dexmedetomidine continuous infusion and end-tidal sevoflurane

concentration, monitored by bispectral analysis

Edno Magalhães; Cátia Sousa Govêia; Luís Cláudio de Araújo Ladeira; Beatriz Vieira Espíndola

There has been EF_sevo decrease after the association of intravenous dexmedetomidine infusion (M₀ to M₆₀ x M₆₀ to M₁₅₀) (Figure 3). Comparison of EF_sevo (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 EF_sevo decrease.

Brazilian Journal of Anesthesiology, 2004; 54: 3: 303 - 310

Relationship between dexmedetomidine continuous infusion and end-tidal sevoflurane

concentration, monitored by bispectral analysis

Edno Magalhães; Cátia Sousa Govêia; Luís Cláudio de Araújo Ladeira; Beatriz Vieira Espíndola

Brazilian Journal of Anesthesiology, 2004; 54: 3: 303 - 310

Relationship between dexmedetomidine continuous infusion and end-tidal sevoflurane

concentration, monitored by bispectral analysis

Edno Magalhães; Cátia Sousa Govêia; Luís Cláudio de Araújo Ladeira; Beatriz Vieira Espíndola

DISCUSSION

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% EF_sevo 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 EF_sevo 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 EF_sevo decrease.

REFERENCES

Submitted for publication June 06, 2003

Accepted for publication September 23, 2003

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• 12. Nunes RR, Cavalcante SL - Influência da dexmedetomidina na concentração expirada do sevoflurano. Avaliação pelo índice bispectral, taxa de supressão e análise espectral da potência do eletroencefalograma. Rev Bras Anestesiol, 2002;52: 133-145.

Correspondence to

Dr. Edno Magalhães

SQS 113 Bloco C Aptº 406

70376-030 Brasília, DF

*

Received from Hospital Universitário de Brasília, Universidade de Brasília (UnB), DF

Publication Dates

• Publication in this collection
  02 July 2004
• Date of issue
  June 2004

History

• Received
  06 June 2003
• Accepted
  23 Sept 2003