SciELO - Scientific Electronic Library Online

vol.51 issue4Agonistas α2 -adrenérgicos: perspectiva atualEffects of analgesic intrathecal sufentanil and 0.25% epidural bupivacaine on oxytocin and cortisol plasma concentration in labor patients author indexsubject indexarticles search
Home Pagealphabetic serial listing  

Services on Demand




Related links

  • On index processCited by Google
  • Have no similar articlesSimilars in SciELO
  • On index processSimilars in Google


Revista Brasileira de Anestesiologia

Print version ISSN 0034-7094

Rev. Bras. Anestesiol. vol.51 no.4 Campinas  2001 



Effect of nitrous oxide on the induction and recovery times of halothane and sevoflurane in pediatric patients*


Influência do óxido nitroso na velocidade de indução e de recuperação do halotano e do sevoflurano em pacientes pediátricos


Influencia del óxido nitroso en la velocidad de inducción y de recuperación del halotano y del sevoflurano en pacientes pediátricos



Maria Angela Tardelli, TSA, M.D.I; Nilza Mieko Iwata, TSA, M.D.II; José Luiz Gomes do Amaral, TSA, M.D.III; Roberto Manara Victório Ferreira, M.D.IV; Luciano Borges Rocha, M.D.IV

IProfessora Adjunta da Disciplina de Anestesiologia, Dor e Terapia Intensiva Cirúrgica da UNIFESP/EPM
IIProfessora Assistente da Disciplina de Anestesiologia, Dor e Terapia Intensiva Cirúrgica da UNIFESP/EPM
IIIProfessor Titular da Disciplina de Anestesiologia, Dor e Terapia Intensiva Cirúrgica da UNIFESP/EPM
IVEx-ME2 do CET/SBA da Disciplina de Anestesiologia, Dor e Terapia Intensiva Cirúrgica da UNIFESP/EPM





BACKGROUND AND OBJECTIVES: The use of different MAC multiples of sevoflurane and halothane, and the different effect of N2O on the MAC of these agents in children, are usually argued as the reason for the same induction and recovery times of these agents which have different blood solubilities. This study evaluated the induction time to different MAC multiples and the recovery time of anesthesia maintained with a fixed expired concentration (1 MAC) of halothane or sevoflurane, associated or not to N2O, in children under epidural caudal anesthesia.
METHODS: Participated in this study 63 children allocated in 4 groups according to the anesthetic drug used. Group 1 = Halothane; Group 2 = Halothane plus N2O; Group 3 = Sevoflurane; Group 4 = Sevoflurane plus N2O. All children were submitted to caudal epidural blockade. Mask Induction was started with 1 MAC of halogenate followed by 0.5 MAC increments at every three respiratory movements until a maximum of 3 MAC was obtained. The following parameters were recorded: heart rate, systolic and diastolic blood pressure, inhaled agent expired fraction and times for induction, recovery and response to commands.
RESULTS: Duration of surgery did not differ significantly among groups. The times to eyelash reflex loss, end of induction, emergence and oriented responses for groups 1 and 2 were longer than for groups 3 and 4 (p < 0.001) without significant differences between groups 1 and 2 and between groups 3 and 4. There were no differences in heart rate and systolic and diastolic blood pressure.
CONCLUSIONS: In the age range studied and with the anesthetic technique used, induction and recovery times were different between the halothane and the sevoflurane group, but did not differ when nitrous oxide was added to the halogenate.

Key words: ANESTHESIA, Pediatric; ANESTHETICS, Gaseous: nitrous oxide, Volatile: halothane, sevoflurane


JUSTIFICATIVA E OBJETIVOS: A utilização de múltiplos de CAM, não comparáveis, do sevoflurano e do halotano, além da diferente contribuição do N2O na CAM destes dois agentes, em pacientes pediátricos, são os fatores citados para explicar igual velocidade de indução e de recuperação destes agentes com diferentes solubilidades sangüíneas. O objetivo deste trabalho foi avaliar o tempo de indução através de múltiplos da CAM e a recuperação da anestesia mantida com concentração expirada fixa de 1 CAM de halotano ou sevoflurano, associados ou não ao N2O, em crianças sob anestesia peridural sacra.
MÉTODO: Foram estudadas 63 crianças divididas em 4 grupos de acordo com o agente inalatório utilizado para indução e manutenção da anestesia: Grupo 1: Halotano; Grupo 2: Halotano + N2O; Grupo 3: Sevoflurano; Grupo 4: Sevoflurano + N2O. Todas foram submetidas à peridural sacra. A indução sob máscara foi iniciada com 1 CAM do halogenado e incrementos de 0,5 CAM a cada 3 movimentos respiratórios até atingir 3 CAM, no máximo. Foram analisados os seguintes parâmetros: freqüência cardíaca, pressão arterial sistólica e diastólica, fração expirada dos agentes inalatórios e os tempos de indução, de emergência e de resposta a comandos.
RESULTADOS: Os tempos cirúrgicos não mostraram diferença significativa entre os grupos. Os tempos para perda do reflexo ciliar, para o término da indução, de emergência e orientação dos grupos 1 e 2 foram maiores que dos grupos 3 e 4, sem diferença entre os grupos 1 e 2 e entre os grupos 3 e 4. A freqüência cardíaca e as pressões arteriais sistólica e diastólica não diferiram entre os grupos, nos diferentes tempos considerados.
CONCLUSÕES: Nesta faixa etária, com a técnica anestésica empregada, os tempos de indução e de recuperação da anestesia foram diferentes entre os grupos do halotano e do sevoflurano, mas não apresentaram diferença com a associação de óxido nitroso.

Unitermos: ANESTESIA, Pediátrica; ANESTÉSICOS, Gasoso: óxido nitroso, Volátil: halotano, sevoflurano


JUSTIFICATIVA Y OBJETIVOS: La utilización de múltiplos de CAM, no comparables, del sevoflurano y del halotano, más allá de la diferente contribución del N2O en la CAM de estos dos agentes, en pacientes pediátricos, son los factores citados para explicar igual velocidad de inducción y de recuperación de estos agentes con diferentes solubilidades sanguíneas. El objetivo de este trabajo fue evaluar el tiempo de inducción a través de múltiplos de la CAM y la recuperación de la anestesia mantenida con concentración expirada fija de 1 CAM de halotano o sevoflurano, asociados o no al N2O, en niños bajo anestesia peridural sacra.
MÉTODO: Fueron estudiados 63 niños divididos en 4 grupos de acuerdo con el agente inhalatorio utilizado para inducción y manutención de la anestesia: Grupo 1: halotano; Grupo 2: halotano + N2O; Grupo 3: sevoflurano; Grupo 4: sevoflurano + N2O. Todos fueron sometidos a peridural sacra. La inducción bajo máscara fue iniciada con 1 CAM del halogenado e incrementos de 0,5 CAM a cada 3 movimientos respiratorios hasta llegar a 3 CAM, como máximo. Fueron analizados los siguientes parámetros: frecuencia cardíaca, presión arterial sistólica y diastólica, fracción expirada de los agentes inhalatorios y los tiempos de inducción, de emergencia y de respuesta a comandos.
RESULTADOS: Los tiempos quirúrgicos no mostraron diferencia significativa entre los grupos. Los tiempos para pérdida del reflejo ciliar, para el término de la inducción, de emergencia y orientación de los grupos 1 y 2 fueron mayores que de los grupos 3 y 4, sin diferencia entre los grupos 1 y 2 y entre los grupos 3 y 4. La frecuencia cardíaca y las presiones arteriales sistólica y diastólica no difirieron entre los grupos, en los diferentes tiempos considerados.
CONCLUSIONES: En esta faja de edad, con la técnica anestésica empleada, los tiempos de inducción y de recuperación de la anestesia fueron diferentes entre los grupos del halotano y del sevoflurano, solo que no presentaron diferencia con la asociación de óxido nitroso.




In 1992, some authors have observed that nitrous oxide (N2O) had less influence on sevoflurane MAC in pediatric patients than in adults 1,2. This result is different from that reported for halothane MAC that is equally decreased by N2O in adults and children 3,4. The association of 60% N2O to halothane decreases its MAC in 60% in adults and in children, whereas the addition of 60 % N2O to sevoflurane decreases its MAC by 60% in adults but only 24% in children 1-4. Authors refer that, in children, the association of N2O to low blood solubility halogenated agents induces less MAC changes than when added to agents with higher solubility 5.

Considering the halogenated agents solubility, the depth of anesthesia should change faster with sevoflurane 5. However, there is no consensus among authors that induction and emergence times are faster in children anesthetized with sevoflurane than with halothane 6-12. Factors such as the different effect of N2O on sevoflurane and halothane MAC and the use of non-comparable MAC multiples, have been suggested to explain such results.

This study evaluated children within a narrow age range submitted to minor infra-umbilical procedures under caudal epidural anesthesia, associated to inhalational general anesthesia. The induction time to different MAC multiples and the recovery time of anesthesia maintained with a fixed expired concentration of 1 MAC of halothane or sevoflurane, associated or not to N2O, were evaluated.



After the Hospital São Paulo Ethics Committee approval, participated in this study 63 children aged 2 to 6 years, weighing no more than 25 kg, physical status ASA I and II, submitted to postectomy or inguinal herniorraphy. Patients received general anesthesia associated to caudal epidural anesthesia and were randomly distributed in four groups, according to the inhalational agent administered for anesthesia: Group 1: halothane; Group 2: halothane + 50% N2O; Group 3: sevoflurane; Group 4: sevoflurane + 50% N2O. No child was premedicated.

Patients were monitored with pulse oximetry, cardioscope, non-invasive blood pressure and gas analyzer. Before anesthesia, the Jackson-Rees system was saturated with the anesthetic mixture so that halogenate inspired concentration would be equal to 1 MAC for this age range (0.9% for halothane and 2.5% for sevoflurane).

Induction with a mask was started with 1 MAC of the halogenate followed by 0.5 MAC increments at every 3 respiratory movements until a maximum of 3 MAC.

Time to eyelash reflex loss and time for eyeball centralization, myosis and regular breathing were recorded at every 10 seconds, being the latter considered as the end of the induction. The halogenate expired concentration was maintained at 1 MAC from this point until the end of anesthesia. Following, the venous puncture was performed and lactated Ringer’s solution was started. Next, children were placed in the lateral position and a caudal epidural anesthesia was induced with 0.75 of 0.25% bupivacaine without vasoconstrictor.

Heart rate, systolic and diastolic blood pressure were monitored throughout the procedure and recorded at the following moments:

a) 1 minute before induction (BI);

b) at the end of induction (EI);

c) after caudal epidural anesthesia (AC);

d) 1 minute after surgical incision (SI);

e) 5 minutes after surgical incision (5SI);

f) at the end of surgery (ES);

g) 10 minutes after anesthetic agent withdrawal (10AW).

Anesthetic agents were withdrawn at the end of the procedure and the child ventilated with 100% oxygen. Children were stimulated with painless stimuli at every 10 seconds.

Emergence time (time for first movements) and time to respond to commands (eye opening, handshaking) were recorded, as well as any adverse event during anesthesia.

Data was analyzed by Analysis of Variance or Kruskal-Wallis test, when convenient, to check differences between means, and by the Chi-square test to check frequency differences.



Demographic data is shown in table I.

Mean age and weight were higher in group 2 as compared to group 1 (p < 0.05). No differences in the mean age and weight for groups 2, 3 and 4 were observed (Table I). Anesthesia and surgery duration was not significantly different among groups (Table II). The mean time to eyelash reflex loss was of 140.3 ± 40.2 seconds in Group 1; 157.4 ± 30.7 seconds in Group 2; 103.0 ± 22.1 seconds in Group 3 and 87.5 ± 25.2 seconds in Group 4. The mean induction time was of 397.2 ± 118.8 seconds for Group 1; 371.2 ± 105.3 seconds for Group 2; 185.0 ± 28.7 seconds for Group 3 and 199.9 ± 165.8 seconds for Group 4. The induction times of Groups 1 and 2 were significantly longer than those for Groups 3 and 4 (p < 0.001). No significant differences between Groups 1 and 2 and Groups 3 and 4 (Figure 1 and Figure 2) were observed.

Mean emergence time was of 346.9 ± 192.7 seconds for Group 1, 294.7 ± 84.6 seconds for Group 2, 153.3 ± 66.4 for Group 3 and 169.3 ± 67.6 for Group 4. Mean orientation time was of 705.0 ± 297.1 seconds for Group 1, 513.2 ± 101.8 sec for Group 2, 344.0 ± 193.7 seconds for Group 3 and 339.0 ± 219.7 seconds for group 4. Values for Groups 1 and 2 were significantly longer than for groups 3 and 4 (p < 0.001). There were no significant differences between groups 1 and 2 and groups 3 and 4 (Figure 3 and Figure 4).

Heart rate was not different among groups at the different times (Table III and Figure 5). However, were observed significant differences between the beginning and the end of induction and after epidural caudal anesthesia. Significant heart rate variations were observed at surgical incision and anesthetics withdrawal, as well as 10 minutes after it.

Systolic and diastolic blood pressures did not differ among groups. Values before induction and at 10 minutes after withdrawal of the anesthetic agent were equal, but significant differences between such values and those observed at the end of caudal epidural anesthesia, at surgical incision and 5 minutes after it, as well as after anesthetic drug withdrawal were observed (Table IV, Table V and Figure 6 and Figure 7).

Incidence of adverse events was low in all groups studied, and did not permit a statistical analysis.



The most common parameter of anesthesia depth is the minimum alveolar concentration (MAC) 13. Pediatric studies with different inhalational agents have shown that there is a variation in MAC depending on the age range 5. So, we have limited our study to children between 2 and 6 years of age in whom halothane MAC in 100% oxygen is 0.9% and sevoflurane’s is 2.5% 4,5,13.

Surgical procedures were limited to those allowing caudal epidural anesthesia in order to promote effective perioperative and postoperative analgesia, thus excluding pain as a factor interfering with time for anesthesia recovery.

Perioperative analgesia promoted by caudal epidural anesthesia allowed patients to be maintained under general anesthesia with a fixed expired concentration of halogenate in order to get a similar level of anesthesia.

The association of local-regional anesthesia to inhalational anesthesia decreases the need for halogenates 14,15.

Epidural anesthesia with lidocaine during sevoflurane anesthesia decreases sevoflurane’s MAC in 50%. This decrease is probably due to the indirect central effect of spinal deafferentation and not to a systemic effect of lidocaine or to nervous block 15. In our study, bupivacaine mass and volume were individualized considering body weight so that, in the case of blockade interfering with halogenate MAC, differences would be determined only by associated inhalational agents.

Patients were not premedicated and opioids were not used during anesthesia to avoid an additive effect on inhalational agents MAC, with the consequent interference in the parameters evaluated during induction and anesthesia recovery 3,16-18.

Previous saturation of the respiratory circuit and the increase of halogenate concentration by MAC fractions each 3 respiratory movements were planned to decrease the interference of alveolar ventilation and of the rate of increase of the inspired concentration. Such factors alter the induction velocity due to changes in the speed of increase of the alveolar concentration of inhalational agents. Such care is particularly important when two agents with different blood solubilities were compared. In this case changes in ventilation result in greater interference in alveolar concentration of the more soluble halogenate anesthetics 19.

The halogenate concentration was increased by MAC fractions and not MAC multiples avoiding inhalation of high concentrations, well above those desired for the equilibrium between alveolar and inspired fractions, that would eliminate the effect of blood solubility on induction velocity 7.

During anesthesia, a fixed halogenate expired concentration of 1 MAC was maintained because if we consider that MAC is a point in a dose-response curve (concentration-response), when two agents are compared, their curves may not be parallel. In other words, MACs (DE50) are equivalent, but their multiples or fractions may not be equivalent if the curves are not parallel 20. There are no studies showing that halothane and sevoflurane curves are parallel. So, maintaining anesthesia with an expired concentration of 1 MAC allowed us to compare the characteristics of the depressing effect of both agents, supposing that anesthetic alveolar concentrations were equipotent 21.

Sevoflurane has a lower blood solubility than halothane. So, its not surprising that shorter induction and recovery times were observed in patients anesthetized with sevoflurane than halothane in equipotent concentrations. This result contrasts with other studies where no differences have been seen in induction times between both agents 6,7. These differences might be explained by the methodology employed.

While we induced anesthesia with equipotent concentrations of the halogenated agents and increased its concentration by MAC fractions, other authors have used non equipotent concentrations and MAC multiples, what probably cancelled the effect of blood solubility differences 6,7. This explanation is based upon factors interfering with the equilibrium velocity between the halogenate alveolar and inspired fractions, and it is ratified when it is observed that when anesthesia is maintained with equipotent concentrations of halothane and sevoflurane, both mentioned studies obtained faster emergence times for sevoflurane 6.7.

The association of 50% nitrous oxide decreases halothane MAC to 0.44% and the association of 60% nitrous oxide decreases sevoflurane MAC to 2 % in children, corresponding to an additive effect of 50% for halothane and of just 24% for sevoflurane 1,4,5. So, the minor additive effect of nitrous oxide on sevoflurane MAC could explain similar induction times for both groups using sevoflurane. Considering the major additive effect of nitrous oxide in halothane MAC, it would be expected that induction times for group 2 would be longer than for group 1, what did not happen.

In the case of anesthesia recovery time, if the same reasoning is applied, emergence and orientation times would be similar for both sevoflurane groups. Between halothane groups, due to the additive effect of nitrous oxide, values of emergence times should be different, with longer times for the group where N2O was associated, since the same halothane expired fraction was maintained in both groups.

Similarly to induction, it was not possible to observe an additive effect of nitrous oxide on halothane emergence times.

Our results suggest that the additive effect of nitrous oxide on halothane and sevoflurane is fundamentally on analgesia (MAC) since parameters evaluated during anesthesia induction and recovery are related to the level of consciousness, or hypnotic properties.

Studies of the interaction between nitrous oxide and halogenates have shown an additive effect and an antagonism. The additive effect has been shown on MAC and on MAC for tracheal intubation. Nitrous oxide decreases the halogenate concentration needed to prevent movement in response to skin incision or tracheal intubation, respectively 1,4,22. The antagonism was observed when a specific response to a verbal command is demanded 23.

There are evidences that MAC is more related to anesthetic effects on the spinal chord than to hypnotic effects on the brain 24,25. Removal of the cortex and thalamus of rats did not change the amount of isoflurane needed to prevent motor response to a painful stimuli 24. This finding shows the importance of subcortical structures, as the spinal chord, in the generation of movements in response to painful stimulus during general anesthesia. Conversely, the adequate response to verbal commands seems to require an intact cortical function. The central increase in activity of the sympathetic nervous system promoted by nitrous oxide would result in halogenate antagonism in the brain 22. So, different objectives (response to verbal command or painful stimulus) may be associated to different anesthetic action sites 23.

Differences within groups in heart rate and blood pressure, although statistically significant, were variations within 20% of baseline values, without clinical significance.

Heart rate and blood pressure increases have been reported during induction with sevoflurane. This was not seen in our study, probably because we increased gradually the halogenate concentration avoiding a fast increase in alveolar fraction 7.

The lack of statistically significant differences between heart rate and blood pressure values suggests that, in such conditions, hemodynamic effects of halothane and sevoflurane, associated or not to nitrous oxide, are similar.

The lack of hemodynamic changes during surgical incision suggests that caudal epidural anesthesia has promoted adequate analgesia in all patients.

So, we may conclude that, in this age range, with the anesthetic technique used, anesthesia induction and recovery times are different for halothane and sevoflurane, but did not differ when nitrous oxide was associated, being impossible to differentiate the additional effect of nitrous oxide on halothane and sevoflurane in all parameters evaluated.



01. Kleinman S, Lerman J, Yentis S et al - Sevoflurane: minimum alveolar concentration (MAC) and hemodynamic responses in children, with and without nitrous oxide. Anesthesiology, 1992;77:A1144.         [ Links ]

02. Katoh T, Ikeda K - The minimum alveolar concentration of sevoflurane in humans. Anesthesiology, 1987;66:301-303.         [ Links ]

03. Saidman LJ, Eger II EI - Effect of nitrous oxide and of narcotic premedication on the alveolar concentration of halothane required for anesthesia. Anesthesiology, 1964;25:302-306.         [ Links ]

04. Murray DJ, Mehta MP, Forbes RB et al - Additive contribution of nitrous oxide to halothane MAC in infants and children. Anesth Analg, 1990;71:120-124.         [ Links ]

05. Lerman J, Sikich N, Kleinman S et al - The pharmacology of sevoflurane in infants and children. Anesthesiology 1994;80: 814-824.         [ Links ]

06. Naito Y, Tamai S, Shingu K et al - Comparison between sevoflurane and halothane for paediatric ambulatory anaesthesia. Br J Anaesth, 1991;67:387-389.         [ Links ]

07. Piat V, Dubois M, Johanet S et al - Induction and recovery characteristics and hemodinamic responses to sevoflurane and halothane in children. Anesth Analg, 1994;79:840-844.         [ Links ]

08. Sarner JB, Levine M, Davis PJ et al - Clinical characteristics of sevoflurane in children: a comparison with halothane. Anesthesiology, 1995;82:38-46.         [ Links ]

09. Cagnolati CA, Nunes AMM, Serzedo PSM et al - Estudo comparativo sobre sevoflurano e halotano na indução e manutenção de anestesia pediátrica ambulatorial. Rev Bras Anestesiol, 1995;45:215-223.         [ Links ]

10. Tardelli MA, Joaquim EHG, Iwata NM et al - Anestesia com sevoflurano e halotano em crianças. Rev Bras Anestesiol, 1997;47: 1-9.         [ Links ]

11. Taivainen T, Tiainen P, Meretoja OA et al - Comparison of the effects of sevoflurane and halothane on the quality of anaesthesia and serum glutathione transferase alpha and fluoride in paediatric patients. Br J Anaesth, 1994;73:590-595.         [ Links ]

12. Meretoja OA , Taivainen T, Raiha L et al - Sevoflurane-nitrous oxide or halothane-nitrous oxide for paediatric bronchoscopy and gastroscopy. Br J Anaesth, 1996;76:767-771.         [ Links ]

13. Bowdle TA, Horita A, Kharasch ED - The Pharmacologic Basis of Anesthesiology, 2nd Ed, New York, Churchill Livingstone, 1994;497:500.         [ Links ]

14. Himes RS, DiFazio CA, Burney RG - Effects of lidocaine on the anesthetic requirements for nitrous oxide and halothane. Aneshtesiology, 1977;47:437-440.         [ Links ]

15. Hodgson PS, Liu SS, Gras TW - Does epidural anesthesia have general anesthetic effects? Anesthesiology, 1999;91: 1687-1692.         [ Links ]

16. Quasha AL, Eger EI, Tinker JH - Determination and applications of MAC. Anesthesiology, 1980;53:315-334.         [ Links ]

17. Muzi M, Colinco MD, Robinson BJ et al - The effects of premedication on inhaled induction of anesthesia with sevoflurane. Anesth Analg, 1997;85:1143-1148.         [ Links ]

18. Viitanen H, Annila P, Viitanen M et al - Premedication with midazolam delays recovery after ambulatory sevoflurane anesthesia in children. Anesth Analg, 1999; 89:75-79.         [ Links ]

19. Bowdle TA, Horita A, Kharasch ED - The Pharmacologic Basis of Anesthesiology, 2nd Ed, New York, Churchill Livingstone, 1994;523:540.         [ Links ]

20. Waud BE, Waud DR - On Dose - Response curves and anesthetics. Anesthesiology, 1970;33:1-4.         [ Links ]

21. Eger II EI - On dose - response curves and anesthetics. Anesthesiology, 1971;34:202-203.         [ Links ]

22. Swan HD, Crawford MW, Pua HL et al - Additive contribution of nitrous oxide to sevoflurane minimum alveolar concentration for tracheal intubation in children. Anesthesiology, 1999;91: 667-671.         [ Links ]

23. Katoh T, Ikeda K, Bito H - Does nitrous oxide antagonize sevoflurane-induced hypnosis? Br J Anaesth, 1997;79:465-468.         [ Links ]

24. Rampil IJ, Mason P, Singh H - Anesthetic potency (MAC) is independent of forebrain structures in the rat. Anesthesiology, 1993; 78:707-712.         [ Links ]

25. Antognini JF, Schwartz KS - Exaggerated anesthetic requirements in the preferentially anesthetized brain. Anesthesiology, 1993;79:1244-1249.         [ Links ]



Mail to:
Dra. Maria Angela Tardelli
Address: Rua Hastimphilo Moura, 338/A 7C
ZIP: 05641-000 City: São Paulo, Brazil

Submitted for publication February 20, 2000
Accepted for publication February 13, 2001



* Received from CET/SBA da Disciplina de Anestesiologia, Dor e Terapia Intensiva Cirúrgica da Universidade Federal de São Paulo e Escola Paulista de Medicina (UNIFESP/EPM). Trabalho vencedor do Prêmio SBA/ABBOTT do ano de 1999

Creative Commons License All the contents of this journal, except where otherwise noted, is licensed under a Creative Commons Attribution License