Print version ISSN 0034-7094
Rev. Bras. Anestesiol. vol.52 no.1 Campinas Jan./Feb. 2002
Influence of midazolam and clonidine premedication on hypnosis level after anesthetic induction with propofol and alfentanil in children. Bispectral index monitoring *
Influencia de la medicación pré-anestésica con midazolam y clonidina en el nivel de hipnosis después de inducción anestésica con propofol y alfentanil en niños. Monitorización por el índice bispectral
Eliana Marisa Ganem, TSA, M.D.I; Norma Sueli Pinheiro Módolo, TSA, M.D.II; Pedro Thadeu Galvão Vianna, TSA, M.D.III; Yara Marcondes Machado Castiglia, TSA, M.D.III
IProfessora Adjunta Livre Docente
do CET/SBA da FMB UNESP
IIProfessora Assistente Doutora do CET/SBA da FMB UNESP
IIIProfessor (a) Titular do CET/SBA da FMB UNSP
BACKGROUND AND OBJECTIVES: Premedication
is an anesthetic adjuvant which decreases both perioperative anxiety and the
need for high anesthetic concentrations, in addition to producing amnesia and
contributing to hemodynamic stability. Midazolam and clonidine are among preanesthetic
drugs indicated for children. This study aimed at evaluating whether preanesthetic
midazolam or clonidine influences hypnosis in children induced with propofol
METHODS: Participated in this study 30 patients aged 2 to 12 years, physical status ASA I, undergoing elective surgeries, who were divided into 3 groups: G1- without premedication, G2 - oral midazolam (0.5 mg.kg-1), and G3 - oral clonidine (4 µg.kg-1), both administered 60 minutes before anesthesia. All patients received alfentanil (30 µg.kg-1), propofol (3 mg.kg-1), and atracurium (0.5 mg.kg-1). BIS values were evaluated before anesthesia induction (M1) and after tracheal intubation (M2). Analysis of variance was the statistical method used for age, weight, and height, and profile analysis was used for BIS values, considering significant p < 0.05.
RESULTS: In comparing the same moment (M1 or M2) among the three groups there were no significant differences. When comparing the two moments of a same group, M1 values were higher than M2 values in all groups.
CONCLUSIONS: Midazolam and clonidine premedication have not influenced hypnosis level of propofol and alfentanil in children.
Key Words: HYPNOTICS: alfentanil, propofol; MONITORING: bispectral index; PREANESTHETIC MEDICATION: clonidine, midazolam
JUSTIFICATIVA Y OBJETIVOS: La medicación
pré-anestésica (MPA) es adjuvante de la anestesia y diminuye tanto
la necesidad de concentraciones elevadas de anestésicos, como la ansiedad
perioperatoria, produciendo amnesia y contribuyendo para la estabilidad hemodinámica.
De entre las drogas administradas en la MPA de niños, se encuentran el
midazolam y la clonidina. El objetivo de esta pesquisa fue evaluar si la MPA
con midazolam y clonidina ejerce influencia en el nivel de hipnosis, evaluado
por el BIS, en niños después inducción anestésica con propofol
MÉTODO: Participaron del estudio 30 pacientes, con edades entre 2 y 12 años, estado físico ASA I, sometidos a cirugías electivas, que fueron distribuidos en 3 grupos: G1 sin MPA, G2 - midazolam (0,5 mg.kg-1) y G3 - clonidina (4 µg.kg-1), por vía oral, 60 minutos antes de la cirugía. Todos los pacientes recibieron alfentanil (30 µg.kg-1), propofol (3 mg.kg-1) y atracúrio (0,5 mg.kg-1). Se evaluó el valor derivado del BIS antes de la inducción de la anestesia (M1) y después de la intubación (M2). El método estadístico utilizado fue la análisis de variancia para edad, peso y altura, y análisis de perfil para el BIS, siendo el valor de p < 0,05 considerado significativo.
RESULTADOS: Cuando se comparó el mismo momento (M1 o M2) entre los tres grupos, no fueron observadas diferencias estadísticamente significativas. Cuando se compararon los dos momentos de un mismo grupo, M1 fue mayor que M2 en los tres grupos.
CONCLUSIONES: La MPA con midazolam y clonidina no influenció el nivel de hipnosis en niños inducidos con propofol y alfentanil.
Premedication is an anesthetic adjuvant which decreases both perioperative anxiety and the need for high anesthetic concentrations, in addition to producing amnesia and contributing to hemodynamic stability 1. Midazolam - a water-soluble benzodiazepine, effective in reducing anxiety and widely used 2 - and clonidine - an a2-adrenergic agonist providing preoperative sedation 3 - are among preanesthetic drugs administered in children for decreasing perioperative anesthetic concentrations 4.
EEG-derived bispectral index is a quantifiable measurement of the hypnotic effects of anesthetic drugs in the central nervous system 5,6. Represented by a numeric scale from 100 (awaken) to 0 (isoelectric EEG) it shows, for anesthesia induction, maintenance and recovery in children, the same values found in adults, making it feasible for pediatric use.
This study aimed at evaluating by BIS whether premedication with midazolam and cloinidine would influence hypnosis levels in children induced with propofol and alfentanil.
After the Clinical Research Ethics Committee approval and the consent of parents or guardians, participated in this study 30 patients of both genders, aged 2 to 12 years, physical status ASA I, submitted to elective surgeries. Patients were randomly distributed in 3 groups (G1, G2 and G3) according to the presence, absence or type of preanesthetic medication.
After an 8-hour fast, G1 patients received no premedication, G2 patients were premedicated with 0.5 mg.kg-1 oral midazolam and G3 patients received 4 µg.kg-1 oral clonidine (maximum dose of 150 µg.kg-1), 60 minutes before being referred to the operating room. In the operating room, after installing a venous access, 4 ml.kg-1.h-1 lactated Ringers in continuous infusion was started and monitoring consisted of ECG in DII, non-invasive blood pressure, pulse oximetry, digital thermometer and Bispectral Index. Anesthesia was induced with alfentanil (30 µg.kg-1) and propofol (3 mg.kg-1). Atracurium (0.5 mg.kg-1) and manual ventilation with 100% oxygen (O2) were used to help tracheal intubation. Next, tracheal intubation was performed and capnography was installed. Heart rate (HR), systolic (SBP) and diastolic (DBP) blood pressure, oxygen saturation (SpO2) and BIS were evaluated before anesthetic induction (M1) and after intubation, which was performed 3 minutes after induction (M2). Aiming at comparing groups and statistically studying results, HR, SBP, DBP and BIS were evaluated at M1 and M2.
Analysis of variance was adopted for age, weight and height, and profile analysis was used for HR, SBP, DBP and BIS, considering significant p < 0.05.
The three groups were homogeneous in weight, age and height (Table I). There were no statistically significant differences in SBP, DBP, HR and BIS when comparing the same moment (M1 or M2) among groups (G1, G2 and G3) (Table II).
When comparing moments within a same group, SBP and DBP for G1 and G3 were statistically higher in M1. HR was identical in both moments for all groups. BIS values were lower in M2 for all groups (Table II).
In our study, premedication with midazolam or clonidine has not influenced BIS-evaluated hypnosis level in children after anesthetic induction with propofol (3 mg.kg-1) and alfentanil (30 µg.kg-1).
Midazolam was chosen because it is the routine drug in our hospital, and clonidine for its desirable sedative effects 3,8. Clonidine acts by activating locus coeruleus a2-adrenergic receptors, suppressing their activity and resulting in increased inhibitory interneurons, such as those found in the gamma aminubutiric acid (GABA) way, determining central nervous system (CNS) depression 9. In a previous study in children premedicated with 0.5 mg.kg-1 midazolam and 4 µg.kg-1 clonidine identical levels of sedation and decreased anxiety were seen when clinical parameters were used to evaluate both medications 8.
Our study has evaluated patients by BIS values and it was observed that the presence and type of medication have not influenced hypnosis levels since BIS values were similar to those observed in non-premedicated children.
Although the lack of data on oral clonidine bioavailability in children 9, studies have shown that sedation is already present 30 minutes after 4 µg.kg-1 oral clonidine and is intensified at 60 minutes 3. And 60 minutes was the interval between premedication and referral to the operating room, that is, enough time for the drug to be fully active.
The moment immediately after laryngoscopy and tracheal intubation was chosen to evaluate hypnosis level determined by propofol and alfentanil induction dose because such maneuvers trigger major stimuli and may lead to an increase in blood pressure, heart rate and circulating catecholamines in pediatric patients 10 when induction is inadequate to block such stimuli. Clonidine (4 µg.kg-1) have prevented adverse hemodynamic effects caused by tracheal intubation, probably by decreasing circulating catecholamine levels 10. Alfentanil, for its fast onset, high safety margin and excellent hemodynamic stability is widely used for anesthetic induction in short pediatric procedures. In therapeutic doses, it determines analgesia, sedation and ansiolysis 11.
In our study, SBP, DBP and HR associated to BIS were used aiming at obtaining additional clinical parameters to assure anesthetic induction quality. It was observed that SBP and DBP decreased after induction in non-premedicated patients and in those receiving clonidine. Clonidine action on the cardiovascular system may be peripheral and central. Pre-synaptic a2-adrenergic receptors activation on peripheral nervous terminations inhibiting norepinephrine exocytosis partially explains drugs hypotensive effects 12; however, the activation of pre-synaptic receptors in blood vessel muscles causes vasoconstriction 13. In the CNS, the activation of a2-receptors decreases sympathetic eflux, increasing parasympathetic nervous activity and inducing hypotension 12.
Midazolam has minor cardiocirculatory effects since benzodiazepines act in specific GABAA sites which are exclusively located in CNS post-synaptic nervous terminations 14.
However, non-premedicated children have also shown decreased SBP and DBP, showing that propofol had a fundamental action in decreasing blood pressure. Propofol causes hypotension because it relaxes vessels smooth muscles by decreasing vasoconstrictor sympathetic response 15.
In conclusion, our results suggest that premedication with 0.5 mg.kg-1 midazolam and 4 µg.kg-1 clonidine have not increased the hypnotic effects of 3 mg.kg-1 propofol associated to 30 µg.kg-1 alfentanil for anesthetic induction in pediatric patients.
01. Lichtor JL - The goals of premedication. Refresher Courses in Anesthesiology, 1995;23:141-156. [ Links ]
02. Alderson PJ, Lermam J - Oral premedication for paediatric ambulatory anaesthesia: a comparison of midazolam and ketamine. Can J Anaesth, 1994;41:221-226. [ Links ]
03. Mikawa K, Maekawa N, Nishina K et al - Efficacy of oral clonidine premedication in children. Anesthesiology, 1993;79:926-931. [ Links ]
04. Nishina K, Mikawa K, Maekawa N et al - The efficacy of clonidine for reducing perioperative haemodynamic changes and volatile anaesthetic requirements in children. Acta Anaesthesiol Scand, 1996;40:746-751. [ Links ]
05. Liu J, Singh H, White PF - Electroencephalogram bispectral analysis predicts the depth of midazolam-induced sedation. Anesthesiology, 1996;84:64-69. [ Links ]
06. Liu J, Singh H, White PF - Electroencephalographic bispectral index correlates with intraoperative recall and depth of propofol-induced sedation. Anesth Analg, 1997;84:185-189. [ Links ]
07. Denman WT, Swanson EL, Rosow et al - Pediatric evaluation of bispectral index (BIS) monitor and correlation of BIS with end-tidal sevoflurane concentration in infants and children. Anesth Analg, 2000;90:872-877. [ Links ]
08. Lavrich PS, Hermann D, Pang LM et al - Clonidine as premedicant in children. Anesthesiology, 1996;85:A1085. [ Links ]
09. Nishina K, Mikawa K, Shiga M et al - Clonidine in paediatric anaesthesia. Paediatr Anaesth, 1999;9:187-202. [ Links ]
10. Mikawa K, Nishina K, Maekawa N et al - Attenuation of the catecholamine response to tracheal intubation with oral clonidine in children. Can J Anaesth, 1995;42;869-874. [ Links ]
11. Hiller A, Saaranivaara L - Injection pain, cardiovascular changes and recovery following induction of anaesthesia with propofol in combination with alfentanil or lignocaine in children. Acta Anaesthesiol Scand, 1992;36:564-568. [ Links ]
12. De Jonge A, Timmermans PB, Van Zweiten PA - Participation of cardiac presynaptic a2-adrenoceptors in the bradycardic effects of clonidine and analogues. Naunyn Schmiedebergs Arch Pharmacol, 1981;317:8-12. [ Links ]
13. Ruffolo JA - Distribution and function of peripheral adrenoceptores on the cardiovascular system. Pharmachol Biochem Behav, 1985;22:827-833. [ Links ]
14. Stoelting RK - Benzodiazepines, em: Stoelting RK - Pharmacology and Physiology in Anesthetic Practice, 3rd Ed, Philadelphia: Lippincott-Raven Publishers, 1999;126-139. [ Links ]
15. Ronbinson BJ, Ebert TJ, OBrien TJ et al - Mechanisms whereby propofol mediates peripheral vasodilatation in humans. Sympathoinhibition or direct vascular relaxation? Anesthesiology, 1997;86: 64-72. [ Links ]
Apresentado em 16 de março de 2001 *
Received from CET/SBA do Departamento de Anestesiologia da Faculdade de Medicina
de Botucatu (FMB UNESP)
Aceito para publicação em 08 de agosto de 2001
Apresentado em 16 de março de 2001
* Received from CET/SBA do Departamento de Anestesiologia da Faculdade de Medicina de Botucatu (FMB UNESP)