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On-line version ISSN 1806-907X
Rev. Bras. Anestesiol. vol.57 no.3 Campinas May/June 2007
Assessment of the cognitive effects of inhalational induction with sevoflurane associated or not with nitrous oxide. a comparative study in adult volunteers*
Evaluación de los efectos cognitivos de la inducción inhalatoria con sevoflurano con o sin la asociación con el óxido nitroso. estudio comparativo en adultos voluntarios
Cláudia Regina Fernandes, TSAI; Josenília Maria Alves Gomes, TSAII; Raulysson Almeida do Amaral CordeiroIII; Kayline de Souza PereiraIII
em Anestesiologia pela Universidade de São Paulo; Responsável
pelo CET/SBA Hospital Universitário Walter Cantídio da
IIDoutora em Clínica Cirúrgica pela Faculdade de Medicina de Ribeirão Preto, SP; Chefe do Serviço de Anestesiologia do Hospital Universitário Walter Cantídio da UFC; Co-Responsável pelo CET/SBA Hospital Universitário Walter Cantídio da UFC
IIIME2 CET/SBA Hospital Universitário Walter Cantídio da UFC
AND OBJECTIVES: Anesthetic induction with inhalational agents using a facemask
has gained attention since the introduction of sevoflurane. At the same time,
the influence of adding nitrous oxide on the pattern of induction and recuperation
deserves attention, especially regarding recovery of the cognitive function.
The objective of this study was to evaluate the cognitive effects of inhalational
anesthetic induction with sevoflurane alone or associated with nitrous oxide
METHODS: Twenty adult volunteers, ASA physical state I, without a history of psychiatric disorders or prior use of benzodiazepines, were enrolled in the study. After answering the Mini-Mental State Examination (MMSE), Group I received 5% sevoflurane until a bispectral index (BIS) of 60 was achieved. Group II received nitrous oxide in increments of 10% until it achieved 50% followed by the administration of sevoflurane until a BIS of 60 was achieved. Arterial blood pressure, heart rate, pulse oxymetry, SEF 95% (Spectral Edge Frequency), induction time, and anesthetic recovery time were evaluated.
RESULTS: Time of induction showed no differences between both groups. Group II showed greater hemodynamic stability and smaller SEF 95% values when BIS achieved 60. The time for recovery of cognitive function was similar in both groups, as well as the incidence of nausea and vomiting. There were no cases of apnea. Group II demonstrated greater incidence of psychomotor agitation during induction.
CONCLUSIONS: Sevoflurane alone or in association with nitrous oxide is an adequate option for inhalational anesthetic induction or outpatient sedation in adults, maintaining spontaneous ventilation, and providing a fast recuperation of the cognitive function.
Key Words: ANESTHESIA, General: inhalation; ANESTHETICS, Gases, Votalile: nitrous oxide, sevoflurane; CENTRAL NERVOUS SYSTEM: cognition; SEDATION: inhalation.
Y OBJETIVOS: La inducción con agentes inhalatorios vía máscara
facial ha venido siendo objeto de un creciente interés desde la introducción
del sevoflurano. Al mismo tiempo el influjo de la adición de óxido
nitroso merece gran atención en lo que se refiere al estándar
de la inducción y de la recuperación, sobre todo, a la completa
recuperación de la función cognitiva. El objetivo de este estudio
fue el de evaluar los efectos cognitivos de la inducción anestésica
inhalatoria con sevoflurano de modo aislado o asociado al óxido nitroso
MÉTODO: Se estudiaron 20 voluntarios adultos, estado físico ASA I, sin enfermedades psiquiátricas o previa utilización de benzodiazepínicos. Después de haber sido sometidos al cuestionario Mini Examen del Estado Mental (MEEM), el Grupo I recibió sevoflurano en la concentración de 5% hasta que fuese alcanzado el índice bispectral (BIS) de 60. El Grupo II recibió óxido nitroso en concentraciones crecientes con incremento de 10% hasta 50% cuando se le administró entonces el sevoflurano hasta que fuese alcanzado el BIS de 60. Fueron anotados valores de presión arterial, frecuencia cardiaca, oximetría de pulso, SEF 95% (Spectral Edge Frequency), tiempo de inducción y el tiempo de recuperación anestésica.
RESULTADOS: No hubo diferencia entre el tiempo de inducción en los dos grupos. El Grupo II presentó una estabilidad hemodinámica mayor y un menor valor del SEF 95% al momento del BIS = 60. El tiempo para la recuperación de la función cognitiva fue igual en los dos grupos, como también lo fue la incidencia de náuseas y vómitos. No se verificó la incidencia de apnea. El Grupo II presentó mayor incidencia de agitación psicomotora durante la inducción.
CONCLUSIONES: El sevoflurano aisladamente o en asociación con el óxido nitroso constituyó la opción adecuada para la inducción inhalatoria o la sedación ambulatorial en adultos, con el mantenimiento de la ventilación espontánea, proporcionando una rápida recuperación de la función cognitiva.
Intravenous induction is currently the most common technique of anesthetic induction used. However, induction with inhalational agents using a facemask has been gaining attention. This renewed interest is attributed mainly to the introduction of sevoflurane. Sevoflurane is a halogenated agent with an agreeable odor, which allows an inhalational induction with a rapid increase in the alveolar concentration of the anesthetic due to its low coefficient of blood liposolubility. The fast recuperation is another important characteristic of this drug, due to its low metabolization (2% to 3%) 1. Besides, according to some clinical studies 2,3, inhalational induction with sevoflurane is fast and associated with the safe maintenance of spontaneous ventilation and with a low risk of agitation associated with stage 2. Such characteristics, associated with little salivation, support the use of this technique with sevoflurane for laryngoscopy to confirm the diagnoses of difficult airways on the physical exam 4,5.
Nitrous oxide (N2O) is commonly used as an adjuvant anesthetic agent in general anesthesia and in sedation for medical and odontological procedures. It has an important analgesic component when administered in concentrations greater than 30% 6.
The bispectral index (BIS) 7 quantifies the relationship among the several frequency bands of the electroencephalogram (EEG). This type of assessment was validated as a quantifiable measure of the hypnotic effect of anesthetic drugs 8,9. The Spectral Edge Frequency (SEF 95%) derives from electroencephalographic monitoring and reflects the predominant spectral power 10.
The complete recovery of consciousness after an anesthetic procedure means to recover the cognitive capacity that involves behavioral functions, such as physical ability, perception, and data acquisition. The effects of anesthetics on cognitive function can be responsible for the delay of the patient to resume his/her regular functions.
The objective of this study was to evaluate the cognitive effects of inhalational anesthetic induction with sevoflurane alone or associated with nitrous oxide in adults.
The study protocol was approved by the Ethics Committee of the Hospital Universitário Walter Cantídio. The study population was composed of 20 volunteers between 18 and 30 years old, of both genders, ASA physical state I, who agreed to sign the informed consent. Exclusion criteria included body mass index below 21 and greater than 25, prior use of benzodiazepines, psychoactive drugs, psychiatric disorders, and smoking.
Volunteers were admitted to the hospital on the day of the procedure and did not receive any premedication. The Mini-Mental State Examination (MMSE) was used to evaluate the cognitive function 11-12. The degree of hypnosis was monitored by the BIS. The Ramsay sedation scale was used to determine the degree of sedation 13.
The BIS electrodes were placed in the frontal region. Reading was initiated after the impedance test, when it was below 2 kW. The bispectral index (BIS) and the waves of the two channels of the BIS were registered at successive 2-second periods and updated every five seconds by the BIS monitor (BIS XP, Aspect Medical System, USA). A frequency band between 0.5 and 30 Herz (Hz) was chosen. Impedance was verified before each determination and was always below 800 ohms. The automatic artifact detection and rejection system of the monitor was used. Basal BIS was obtained before anesthetic induction 14.
Other monitoring parameters included: non-invasive blood pressure, cardioscope in the DII and V5 derivations, pulse oxymetry, and analysis of inspired and expired gases through a multiparametric monitor.
After the cognitive test (MMSE), volunteers were placed horizontally, in the dorsal decubitus, and asked to maintain their eyes closed and to breathe slowly, allowing the determination of resting hemodynamic and BIS parameters. This was followed by the anesthetic induction using a face mask, with a special device to prevent leaking, connected to a circular system with CO2 absorber, which allowed spontaneous pulmonary ventilation. The first step of induction consisted of the desnitrogenation with 3 liters of oxygen for five minutes. The inhalational agent was then instituted according to the protocol of the group to which the patient was randomly allocated. The same administration technique of the inhalational agents was used in both groups, in which the patients were requested to take deep and slow breaths until they lost consciousness.
Volunteers were randomly assigned to two groups: Group I SEVO inhalational induction with sevoflurane; Group II SEVO + N2O inhalational induction with sevoflurane preceded by the administration of 50% N2O.
In the SEVO group, patients received 5% inspired concentration of sevoflurane, which was maintained until a BIS value of 60 was achieved. At this moment, the administration of sevoflurane was discontinued, but 100% oxygen administration was maintained until the patient responded to his/her name (score 3 of the Ramsay scale) and maintained hemodynamic and ventilatory parameters within normal limits.
In the SEVO + N2O, patients received nitrous oxide in increments of 10% until the expired concentration of nitrous oxide reached 50%. At this moment, the administration of nitrous oxide was continued and the administration of sevoflurane was initiated at a constant inspired concentration of 5%, which was maintained until a BIS of 60 was achieved, when the administration of the inhalational agents was discontinued but the administration of 100% oxygen was maintained until the patient responded to his/her name (score 3 of the Ramsay scale) and hemodynamic and ventilatory parameters were within normal limits.
Data were gathered at three moments: M1 Baseline, i.e., values measured before the administration of the study agents; M2 When BIS achieved 60 in both groups; M3 When the patient awakened, score 3 of the Ramsay scale.
The parameters studied at each moment were the following: a) Electroencephalogram BIS and SEF 95%; b) Hemodynamic blood pressure and heart rate.
When completely awakened, immediately after achieving a score 2 in the Ramsay scale (calm, cooperative, oriented), patients were submitted once again to the MMSE questionnaire.
The following data were also recorded: time of induction (length of time from the beginning of the administration of sevoflurane until a BIS of 60 was achieved) and recovery time, the length of time from awakening (score 3 of the Ramsay scale) until MMSE scores were obtained; afterwards, the patient was discharged from the recovery room.
The data were presented as mean and standard deviation. The Analysis of Variance and Tukey test were used to compare the parameters at the different moments, M1, M2, and M3. The t test was used to analyze the results of the MMSE, induction and recovery times, as well as the demographic data (age, weight, and height). Values of p < 0.05 were considered significant.
Twenty volunteers were enrolled in the study. In the sevoflurane group, one patient did not conclude the study due to hypertension before beginning the administration of sevoflurane. In the group that received nitrous oxide, the procedure was discontinued in three patients before the expired concentration of 50% of N2O was achieved due to severe psychomotor agitation.
The incidence of vomiting after awakening, 20%, was similar in both groups. There were no cases of apnea. No changes in pulse oxymetry were observed. Both groups were similar regarding age, weight, and height.
The analysis of the systolic blood pressure (SBP) revealed a significant reduction in the sevoflurane group at M2 (p < 0.001), i.e., when BIS achieved 60, and this reduction was sustained until M3, when BIS had returned to baseline values. The group receiving the combination of nitrous oxide and sevoflurane showed no significant changes in SBP (Figure 1).
Heart rate showed no significant differences in both groups (p = 0.8051).
Induction time (length of time from the institution of sevoflurane until a BIS of 60 was achieved) was similar in both groups (Figure 2).
The SEF 95% was significantly lower at M2 in the group that received sevoflurane associated with nitrous oxide (Figure 3).
The length of time to totalize the results of the MMSE, considered the recovery time, showed no differences between both groups (Figure 4).
The present study evaluated the inhalational induction in young adults based on BIS and comparing the quality of induction and recovery, evaluating hemodynamic parameters and SEF 95%, as well as the length of time necessary for the recovery of normal cognitive function using sevoflurane alone or associated with nitrous oxide.
The evaluation of the degree of hypnosis is traditionally done by observing clinical parameters, such as verbal response and hemodynamic changes. These parameters are qualitative and, therefore, depend on the interpretation of the observer, carrying a greater risk of failure of the evaluation. Besides, hemodynamic changes can occur without a direct relationship with the degree of hypnosis. Thus, the BIS has the advantage of not depending on patient stimulation and providing a quantitative measurement, a numerical index 8. Despite the wide utilization of the BIS as an indicator of the depth of sedation, this type of monitoring has been questioned lately, based in recent evidence that demonstrated variability in BIS scores in different depths of anesthesia, besides the possibility in variation of BIS scores according to the drug being used 15. However, Ellerkmann et al. 16, evaluating the encephalographic effects of sevoflurane by comparing two methods, BIS and entropy, concluded that both are useful to detect a variation in the depth of hypnosis in function of the concentration of sevoflurane.
A reduction in blood pressure, related to the dose of the drug used, is a common effect of potent volatile anesthetics 17. The primary mechanism by which sevoflurane reduces the arterial blood pressure with increased dosage is related to its potent effect in systemic and regional vascular resistance. This reduction in blood pressure was seen in the present study, which was more pronounced at the moment of hypnosis and continued until patients awakened. There were no important changes in heart rate when compared to baseline values, which agrees with the results of Malan et al. 18 in volunteers, which demonstrated that sevoflurane used above 1 MAC resulted in minimal or no changes in basal heart rate.
Nitrous oxide is commonly combined with potent volatile anesthetics for maintenance of general anesthesia 19. It has unique cardiovascular actions, increasing the activity of the sympathetic nervous system and peripheral vascular resistance when administered in concentrations above 40% 20. The present study demonstrated a greater hemodynamic stability, with maintenance of the arterial blood pressure when sevoflurane was associated with nitrous oxide in the absence of the surgical stimulus. When nitrous oxide is combined with volatile anesthetics in concentrations equivalent to those used alone, persistent activation of the sympathetic nervous system, increased systemic vascular resistance, and increased arterial blood pressure counteract the hypotensive effects of halogenated drugs. However, one cannot discard the possibility that part of those effects are due to the nitrous oxide itself or simply due to a reduction in the concentration of the adjunct potent volatile anesthetic 21.
One of the advantages of associating nitrous oxide to halogenated agents is a decrease in the inhalational induction time. Videira et al. 22 described that the time of induction, evaluated by clinical parameters, and the incidence of complications, such as excitation, coughing, and movements, are significantly decreased when adults undergo fast inhalation induction, associating 4% halothane with 66% nitrous oxide and 33% oxygen. This study did not demonstrate a reduction in anesthetic induction time, evaluated by the BIS, when 5% sevoflurane was associated with 50% nitrous oxide and oxygen for induction. This group also presented a higher incidence of psychomotor agitation, such as coughing, movements, and laughter. This observation agrees with the results presented by Tardelli et al. who did not demonstrate any differences in the induction and recovery times using nitrous oxide associated with sevoflurane for inhalational anesthesia of pediatric patients 23.
The data presented demonstrated that SEF 95% was significantly lower in the nitrous oxide group. The SEF 95% shows the frequency below which are concentrated 95% of the spectral power of the EEG. Thus, SEF represents a percentage of the changes of the high frequencies present when the patient is awake to the lower hypnotic frequencies. SEF monitoring is useful in detecting brain ischemia and depth of anesthesia 24. Recent studies demonstrated a close relation between SEF 95% values and analgesia. Gurman et al. 25, evaluating patients with morbid obesity undergoing gastroplasty, demonstrated that postoperative pain was less severe in patients who maintained intraoperative SEF 95% values between 8 and 12, showing the importance of monitoring this variable derived from the EEG to maintain the intraoperative blockade of nociceptive pathways, which might influence the control of postoperative pain. Therefore, the greater reduction in SEF 95%, which was around 8 in the presence of nitrous oxide, suggests a possible advantage of the association in promoting analgesia and, consequently, at the time of induction, and greater protection against the painful stimulus produced by laryngoscopy. This data is even more relevant when associated with the information that there were no cases of apnea or a significant reduction in oxygen saturation by pulse oxymetry in this study. This suggests that this type of inhalational induction, combining sevoflurane and nitrous oxide, can be really useful in evaluating patients with difficult airways, providing safe hypnosis and analgesia while maintaining spontaneous ventilation. Nitrous oxide is a NMDA receptor antagonist 26, and other studies have also observed the potent analgesic effects of this gas, detected by parameters derived from the electroencephalogram 14,27.
Sedation with sevoflurane is a relatively new technique and the first reports demonstrated faster recovery of cognitive function when compared with midazolam 28. Cognitive impairment with delirium and confusion is a significant problem, especially in elderly patients, in the immediate postoperative period 29. Postoperative cognitive dysfunction is characterized by a reduction in memory and concentration. It is extremely frequent in the elderly undergoing large size surgeries. The pathogenesis of postoperative cognitive dysfunction is not clear; however, alcohol abuse, low basal cognitive function, hypoxia, and hypotension contribute for this type of complication 30. The choice of anesthetic can also affect postoperative cognitive function, since the residual level of volatile anesthetics could produce changes in the activity of the central nervous system 31. However, the use of anesthetics with fast clearance and negligible metabolism may be advantageous. Sevoflurane has a low blood-gas partition coefficient, contributing for a faster recovery when compared with traditional volatile anesthetics 32. Since cognitive dysfunction is more frequent, severe, and lasts longer in elderly patients, sevoflurane is the agent most indicated in this patient population 33.
The ideal clinical tool to measure cognitive function after anesthesia has not been devised yet and the right moment for this assessment has varied in several studies 34,35. In this study, we chose the MMSE because it combines high validity, reliability, and it is easy to aplly 36. This test concentrates on the cognitive aspects of the mental function, excluding questions related to mood and abnormal mental experiences. The MMSE is composed of 11 questions that focus on orientation in time and space, registration, attention, calculation, recent memory, language, and construction ability. It has a maximal score of 30 and a score below 23 indicates impaired cognitive function. According to Antony et al. 37, the MMSE has a sensitivity of 87% and a specificity of 82% to detect dementia and delirium. A study using short duration anesthetics concluded that elderly patients presented impaired cognitive function only in the first postoperative day 11.
The data presented here demonstrated a rapid recovery of cognitive function, about four minutes. However, one should consider that the duration of sevoflurane inhalation was short and that the study population consisted of young individuals who presented a low risk for severe cognitive dysfunction. However, it was possible to observe that when sevoflurane alone or associated with nitrous oxide was administered to young adults, it promoted rapid hypnotic induction, maintaining spontaneous ventilation, and a fast recovery of cognitive functions. It should be mentioned that, despite the psychomotor agitation, the addition of nitrous oxide did not influence cognitive recovery in the study population, it did not increase the incidence of nausea or vomiting, provided for greater hemodynamic stability and lower SEF 95% values.
Thus, one can conclude that sevoflurane alone or associated with nitrous oxide is an adequate option for inhalational anesthetic induction or outpatient sedation of adults, maintaining spontaneous ventilation and providing for a fast recovery of cognitive functions.
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Dra. Cláudia Regina Fernandez
Rua Marcelino Lopes, 4520, casa 09 Edson Queiroz
60834-370 Fortaleza, CE
em 30 de maio de 2006
Accepted para publicação em 22 de fevereiro de 2007
* Received from Hospital Universitário Walter Cantídio da Universidade Federal do Ceará (UFC), Fortaleza, CE