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Print version ISSN 0034-7094
Rev. Bras. Anestesiol. vol.52 no.1 Campinas Jan./Feb. 2002
Sedation levels of oral preanesthetic clonidine and midazolam. Clinical and electroencephalographic bispectral analysis *
Níveles de sedación determinados por la clonidina y midazolam en la medicación pré-anestésica. Evaluación clínica y eletroencefalográfica bispectral
Leandro Gobbo Braz, M.D.I; Pedro Thadeu Galvão Vianna, TSA, M.D.II; José Reinaldo Cerqueira Braz, TSA, M.D.II; Maria Zoé Turchiari de Mello, M.D.III; Lídia Raquel de Carvalho, M.D.IV
IME1 do CET/SBA da FMB
UNESP. Bolsa de Inciação Científica da FAPESP
IIProfessor Titular do CET/SBA da FMB UNESP
IIIEnfermeira Chefe da SRPA da FMB UNESP
IVProfessora Assistente Doutora do Departamento de Bioestatística do Instituto de Biociências de Botucatu, UNESP
BACKGROUND AND OBJECTIVES: This study
aimed at evaluating clonidine - an a2-agonist
- and midazolam - a benzodiazepine - sedative effects in preanesthetic medication
by clinical and electroencephalographic analysis.
METHODS: After institutional approval and their informed written consent, participated in this study 45 patients aged 18 to 65 years, physical status ASA I, who were randomly distributed in placebo (P), clonidine (C) or midazolam (M) groups. Patients were premedicated with oral placebo, 150 µg clonidine or 15 mg midazolam 60 minutes before anesthetic induction (n = 15 per group). Monitoring consisted of electrocardiogram (DII), non-invasive blood pressure, heart rate, oxygen saturation, respiratory rate, axillary and operating room temperature and bispectral electroencephalography to determine bispectral index (BIS). These attributes and sedation scale (1-anxious, 2-calm, 3-sleepy, 4-sleeping with reflex, 5-sleeping without reflex) were obtained at 0 (M0), 15 (M15), 30 (M30), 40 (M40), 50 (M50) and 60 (M60) minutes after medication.
RESULTS: There were no significant differences in respiratory, hemodynamic and temperature parameters. There has been a significant difference among groups in sedation scale (M60: M=C>P) and BIS (M50 and M60: M=C>P).
CONCLUSIONS: In our conditions, clonidine and midazolam have determined similar sedation levels in patients ASA I when evaluated by sedation scale and BIS. No hemodynamic and respiratory changes were observed with both drugs.
Key Words: MONITORING: depth of anesthesia, bispectral index; PREANESTHETIC MEDICATION: clonidine, midazolam; SEDATION: level
JUSTIFICATIVA Y OBJETIVOS: Verificar
el efecto sedativo de la clonidina, un a2-agonista,
y del midazolam, un benzodiazepínico, cuando utilizados en la medicación
pré-anestésica, empleandose evaluación clínica y eletroencefalográfica
MÉTODO: Después de la aprobación institucional y consentimiento escrito dado, 45 pacientes de 18 a 65 años, estado físico ASA I, fueron aleatoriamente distribuidos en los grupos placebo (P), clonidina (C) o midazolam (M), y que recibieron, respectivamente placebo, 150 µg de clonidina o 15 mg de midazolam por vía oral, 60 minutos antes de la inducción de la anestesia (n = 15 por grupo). La monitorización se constituyó de eletrocardiograma (DII), presión arterial no invasiva, frecuencia cardíaca, saturación de pulso de oxígeno, frecuencia respiratoria, temperatura axilar y de la sala de cirugía y eletroencefalograma bispectral para determinación del índice bispectral (BIS). Eses atributos y la escala de sedación (1-ansioso, 2-calmo, 3-soñoliento, 4-durmiendo con reflejo, 5-durmiendo sin reflejo) fueron obtenidos a los 0 (M0), 15 (M15), 30 (M30), 40 (M40), 50 (M50) y 60 (M60) minutos después de la medicación.
RESULTADOS: En los grupos no hubo alteración significante de los parámetros respiratorios, hemodinámicos y de temperatura. Hubo diferencia significante entre los grupos en la escala de sedación (M60: M=C>P) y en el BIS (M50 y M60: M=C>P).
CONCLUSIONES: En las condiciones utilizadas, la clonidina y el midazolam determinan niveles de sedación adecuados y semejantes en la medicación pré-anestésica de pacientes de estado físico ASA I, cuando evaluados por la escala de sedación y por el índice bispectral, sin determinar alteraciones hemodinámicas y respiratorias.
Clonidine, an a2-adrenergic agonist, was first introduced as a nasal decongestive and then as anti-hypertensive medication. However, to induce sedation, hypnosis and analgesia, it was only used by European anesthesiologists in the early 1990s as preanesthetic medication for general and spinal anesthesia. These data are thoroughly reported in a Brazilian paper published in 2000 1.
The a2-receptors may be pre or post-synaptic. Pre-synaptic a2-receptors regulate norepinephrine release and ATP through a negative feedback mechanism. Hence, they inhibit norepinephrine release when activated by a2-agonists. The activation of post-synaptic a2-receptors located in vessels smooth muscles promotes vasoconstriction. a2-receptors are found in the central and peripheral nervous system and in non-neuronal tissues, such as platelets, liver, pancreas, kidney and eyes, where they have specific physiological functions.
The a2-adrenergic receptors have several anesthesia-related mechanisms. Animal studies have shown that central a2-adrenergic receptors stimulation induces hypnosis 2, analgesia 3 and neural sympathetic activity inhibition 4. Clonidine is an a2-adrenergic used as oral preanesthetic medication which increases postoperative opioid analgesia duration 5,6 and decreases perioperative anesthetic and/or opioid consumption 7. On the other hand, clonidine attenuates hemodynamic response to tracheal intubation sympathetic stimulation 8. Due to these properties, oral clonidine is considered a good choice for preanesthetic medication.
After oral administration, clonidines absorption is fast (between 20 and 30 minutes) and almost complete (70% to 80%), reaching the highest serum peak in 60 to 90 minutes 9. As a consequence of its high liposolubility, it crosses blood-brain barrier and is widely spread in the central nervous system where it interacts with a2-adrenergics at spinal and supra-spinal levels. It shows a large distribution volume (2 L.kg-1) with elimination half-life varying from 9 to 12 hours 10. At least half the dose can be recovered unchanged in the urine and the drugs half-life may be increased in the presence of renal failure 8. The other half is metabolized in the liver into inactive metabolytes 11. It may be also rectally used in children with 95% of bioavailability 12.
The most popular oral premedication is midazolam. Thanks to its ansiolitic and amnesic properties 13,14, this benzodiazepinic drug causes minor ventilatory and hemodynamic changes and acts synergistically with inhalational and intravenous anesthetics decreasing their consumption.
Hypnotic effects of anesthetic drugs have in general been subjectively evaluated by Ramsays sedation scale 15.
Several computerized EEG methods have been used in an attempt to simplify EEGs interpretation. Those methods analyze amplitude, frequency or both, in addition to mathematical derivations of such values to represent brain activity. Bispectral EEG monitoring has been recently validated as a measure of anesthetic effects on the brain 16. The bispectral index generates a numeric value which seems to accurately indicate hypnosis depth during anesthesia 17. BIS control during anesthesia seems to optimize the amount of anesthetics used in patients. As a consequence, this may determine faster anesthetic recovery and avoid unnecessary anesthetics overdose 18.
Our study aimed at comparing the sedative effects of preanesthetic clonidine and midazolam using Ramsays 15 sedation scale and bispectral EEG to evaluate sedation.
After the Ethics Committee approval and their written informed consent, participated in this study 45 adult patients of both genders, physical status ASA I, submitted to surgical procedures. Exclusion criteria were age below 18 and above 65 years, body mass index above 30, and clinical changes, such as arterial hypertension, diabetes mellitus, heart, liver and kidney diseases, in addition to the use of ansiolitic and central nervous system depressing drugs.
During preanesthetic evaluation the day before surgery, patients were informed about the research procedures and gave their written informed consent.
Patients were randomly distributed in 3 groups: Midazolam Group (15 mg); Clonidine Group (150 µg); and Placebo Group (starch tablets). Patients were sent to the operating room where oral medication or placebo were administered 60 minutes before preparation for the surgical procedure. Patients were randomly allocated by a nurse who was blind to patients evaluation.
To evaluate sedation and drug effects on cardio-respiratory tract and temperature, the following attributes were studied:
a) Hemodynamic: heart rate (HR - bpm); systolic (SBP - mmHg) and diastolic (DBP - mmHg) blood pressure; and mean blood pressure (MBP - mmHg);
b) Respiratory: respiratory rate (RR - mpm) and oxygen saturation (SpO2 - %);
c) Sedation level: evaluated by computerized EEG or bispectral index (BIS) and Ramsays sedation scale 15, called sedation level (SL) according to the following levels:
- anxious and agitated 1
- cooperative and calm 2
- sleepy 3
- sleeping, awakens with mild stimuli 4
- sleeping, awakens with vigorous stimuli 5
d) Temperature: axillary (AT - oC) and room (RT - oC)
The following intervals were studied: 0 (control) - immediately before drug or placebo administration; and 15, 30, 40, 50 and 60 minutes after drug or placebo administration.
Bispectral index was obtained from the microprocessed EEG numeric scale. BIS determined hypnosis intensity in a scale of 100 to 0, where 100 represented maximum alertness and zero maximum CNS depression, with burst suppression episodes defined as periods when EEG activity was suppressed. During anesthesia, BIS values between 50 and 60 were considered ideal for adequate hypnosis levels.
For EEG, 4 electrodes were placed on patients frontal and pre-auricular region (AT1-FPZ, AT2-FPZ), after skin cleaning with foliating solution and ether.
Non-invasive measurements of systolic, diastolic and mean blood pressure, heart rate, axillary and operating room temperature and oxygen saturation, in addition to ECG in DII, were performed.
Profile analysis was used to compare HR, SBP, DBP, MBP, RR, SpO2, AT and RT in different groups along the study because variables presented a normal distribution. Friedman and Kruskall Wallis tests were used for sedation level and BIS to compare time and groups intervals, respectively, since they did not present a normal distribution. Tukey test was used to compare groups for age, height and weight. Chi-square test was used to compare percentages according to gender.
Significance level was 5% (p < 0.05).
There has been no significant difference in gender among groups (Chi-square test).
HR, SBP, DBP, MBP, RR, SpO2, AT and RT have not shown significant differences in different groups along the study. The same was true when those attributes were compared among groups.
BIS values in midazolam and clonidine groups have differed from placebo values in moments 50 and 60 minutes (p < 0.05). BIS was decreased in placebo and clonidine groups as from 15 and 30 minutes, respectively, and was maintained in the following moments. There has been a significant and progressive BIS decrease in the midazolam group as from 15 minutes (Table III and Figure 1).
Sedation level was higher in clonidine and midazolam groups in moment 60 minutes as compared to placebo. There has been an increase in the clonidine group at 15 and 30 minutes and the values were maintained constant in the following moments. There has been a progressive increase in the midazolam group as from 30 minutes (Table IV and Figure 2).
Our study has shown a sedative and hypnotic effect of oral preanesthetic midazolam - in higher intensity - and clonidine in healthy patients. Such effects were evaluated both by sedation level (Table IV and Figure 2) and BIS (Table III and Figure 1). In the placebo group, all moments evaluated have differed from the control period, showing a placebo effect in preanesthetic sedation. Although being 25 years old, Ramsays scale is still the best subjective evaluation method for sedation levels 19.
On the other hand, patients of all groups have shown wide individual variation in sedative response. That is why sedation levels of clonidine and midazolam as compared to placebo were only statistically different at 60 minutes (Table IV and Figure 2). BIS levels in the placebo group have also shown statistically significant differences between control and remaining moments (Table III and Figure 1). Placebo group BIS, however, was only statistically different from clonidine and midazolam groups at 50 and 60 minutes after preanesthetic medication. During this time, hypnotic effects were more intense in the midazolam group, although a significant hypnotic effect also seen in the clonidine group. The possible explanation for such performance among groups might have been an increased stress level caused by anesthesia and surgery proximity. At this point, drugs were responsible for the difference in sedation intensity between the placebo group and other groups.
Preanesthetic clonidine doses vary from 2 to 5 µg.kg-1. In our study, one 150 µg tablet was used, corresponding to 2.5 µg.kg-1 in an adult patient weighing 60 kilos. The good cardio-circulatory stability evaluated by heart rate and blood pressure, and the lack of respiratory depression evaluated by pulse oximetry and respiratory rate, have shown the adequacy of this clonidine dose. The same may be said for midazolam, which is normally used in oral 15 mg doses without hemodynamic and respiratory changes 20.
A study has shown bradycardia and bradypnea only with 5 µg.kg-1, that is, twice the dose used in our trial 21. The activation of pre-synaptic a2-adrenoreceptors in peripheral nervous terminations inhibits norepinephrine exocytosis partially explaining the hypotensive and bradycardia-inducing effects of such receptor agonists 4.
In spite of the evidences supporting the theory of a2-adrenergic receptors occupation, the participation of other action mechanisms in clonidines pharmacological effects is not excluded. Substantial progresses have been recently obtained in characterizing pharmacological properties and functions of imidazolinic receptors 22. The most significant progress was probably due to the identification of agmatine as an endogenous binder of imidazolinic I1 and I2 receptors 23. Some drugs, with agonist activity on receptors I1, are being used as anti-hypertensive drugs. It is believed that their action mechanism is triggered by I1 receptors activation in the central nervous system 24. I1 receptors have high affinity with several a2-adrenergic receptor agonists, including clonidine. The stimulation of I1 and a2-adrenergic receptors produces similar physiologic responses, such as hypotensive activity. It shows a good correlation between hypotension levels and the number of occupied imidazolinic receptors, but not with the number of a2-receptors 25.
A recent study has shown that during preanesthetic medication, increasing intravenous clonidine doses, from 3 to 6 µg.kg-1, cause a progressive decrease in mean BIS values, to 96 and 91, respectively 26. It must be stressed that such BIS values are higher than ours, in spite of the use of oral clonidine in lower doses. The fact that our patients were kept in a relaxing environment, without noise or excessive movement of people may explain the better results of our study.
Locus coeruleus is the major CNS region involved in the sedative effects of a2-adrenergic receptor agonists 27-29. Major ascending and descending noradrenergic ways are originated in this important area. The activation of a2 receptors in this area causes its activity suppression, resulting in increased activity of inhibiting interneurons, such as the interneuron of g-aminobutyric acid (GABA), thus determining CNS depression.
Another a2-agonists characteristic is the ansiolitic effect, comparable to benzodiazepinic drugs 30. High doses of such drug, however, may determine ansiogenic responses due to a2-receptors activation 31.
Benzodiazepinic hypnotic, sedative and ansiolitic actions are related to its interaction with GABA-mediated benzodiazepinic receptors. So, benzodiazepinic drugs act by occupying benzodiazepinic receptors modulating GABA, the most important brain inhibitory neurotransmitter. Benzodiazepinic receptors are more widely found in the olfactory bulb, brain cortex, midbrain and hippocampus, among others. With GABA receptors activation there is the opening of ion chloride channels causing those ions to enter the cell that becomes hyperpolarized and resistant to neuronal excitation 14,15.
Bispectral monitoring is easy, but the method may become expensive when original electrodes are used: Zipprep electrodes - Aspect Medical (USA). In our study, we have used electrodes originally employed in ECG monitoring, which are cheaper than original electrodes. This was possible because it has been shown that ECG electrodes have a slightly higher impedance than original electrodes, but there are no significant differences in bispectral index values 32.
To conclude, in the conditions described above, clonidine and midazolam have determined adequate and similar sedation levels in preanesthetic medication of patients physical status ASA I, when evaluated by sedation scale and bispectral index (BIS), without hemodynamic and respiratory changes.
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to Submitted for publication April 11, 2001 *
Received from CET/SBA da Faculdade de Medicina de Botucatu (FMB UNESP)
Dr. Pedro Thadeu Galvão Vianna
Deptº de Anestesiologia da FMB UNESP
Distrito de Rubião Junior
18618-970 Botucatu, SP
Accepted for publication July 18, 2001
Submitted for publication April 11, 2001
* Received from CET/SBA da Faculdade de Medicina de Botucatu (FMB UNESP)