Nitrous oxide action on the central nervous system: electrophysiological study as a sole agent or a coadjuvant

Abstracts

JUSTIFICATIVA E OBJETIVOS: O óxido nitroso é o agente anestésico inalatório mais utilizado em todo o mundo. Seu mecanismo de ação é bastante discutido, com base em resultados experimentais e em evidências clínicas. O objetivo deste estudo é avaliar a ação eletrofisiológica deste fármaco no Sistema Nervoso Central através de monitorização específica. MÉTODO: Foram estudados vinte e cinco pacientes de ambos os sexos, com idades entre 6 e 25 anos, submetidos à cirurgia ortopédica ou plástica reparadora, os quais foram monitorizados com índice bispectral do eletroencefalograma (BIS) e potencial evocado somatossensitivo (PESS) durante a anestesia. Foram realizados registros basais do BIS e do PESS, bem como após o uso do óxido nitroso em fracionais alveolares (FA) de 30%, 50% e 66%. Em seguida o óxido nitroso era descontinuado e administrado aleatoriamente isoflurano ou desflurano em 0,5 CAM e 1 CAM. Mantinha-se 1 CAM do determinado agente e o óxido nitroso era novamente administrado nas mesmas concentrações anteriores. RESULTADOS: O óxido nitroso quando utilizado como agente único, produz uma redução no BIS que, embora seja estatisticamente significante, não expressa um estado de hipnose. Esta redução também ocorre quando utilizado como agente coadjuvante mas sem importância clínica. Como agente único, o óxido nitroso deprimiu significantemente a amplitude das ondas cerebrais, sem promover aumento na latência. O isoflurano e desflurano reduziram a amplitude e aumentaram a latência das ondas cerebrais. A associação do óxido nitroso a estes agentes, intensificou ainda mais estes efeitos nas ondas corticais. Não houve alteração significativa das ondas periférica e medular do PESS. CONCLUSÕES: O óxido nitroso tem uma pequena ação hipnótica, que não é captada completamente pelo BIS. Tem ação acentuada nas estruturas corticais, tanto como agente único como associado ao isoflurano e desflurano, o que pode explicar o seu bom efeito analgésico.

ANESTÉSICOS; ANESTÉSICOS; MONITORIZAÇÃO; MONITORIZAÇÃO

SCIENTIFIC ARTICLE

Nitrous oxide action on the central nervous system. Electrophysiological study as a sole agent or a coadjuvant ^*

Acción del óxido nitroso en el sistema nervioso central. Estudio eletrofisiológico como agente único y como agente coadyuvante

Verônica Vieira da Costa, M.D.^I; Renato Ângelo Saraiva, TSA, M.D.^II

^IAnestesiologista do Hospital Sarah Brasília

^IICoordenador de Anestesiologia da Rede Sarah de Hospitais do Aparelho Locomotor

^{Correspondence}

SUMMARY

BACKGROUND AND OBJECTIVES: Nitrous oxide is the most widely used inhalational anesthetic worldwide. Its action mechanism is broadly discussed based on results of experimental studies and clinical evidences. The purpose of this study was to evaluate, through specific monitoring, nitrous oxide electrophysiological action on the central nervous system.

METHODS: Twenty-five patients of both genders, aged 6 to 25 years, undergoing orthopedic or corrective plastic surgery, were monitored by electroencephalogram bispectral index (EEG-BIS) and somatosensory evoked potential (SEP) during anesthesia. BIS and SEP baseline values were recorded, as well as after fractional alveolar (FA) 30%, 50% and 66% nitrous oxide administration. Then, nitrous oxide was withdrawn and isoflurane or desflurane were randomly administered in 0.5 and 1 MAC. While maintaining 1 MAC of one of those agents, nitrous oxide was again administered in the same previous concentrations.

RESULTS: Nitrous oxide as sole agent caused a BIS decrease which, although statistically significant, did not represent a hypnotic state. This decrease was also observed when nitrous oxide was used as a coadjuvant agent, however without clinical significance. As sole agent, nitrous oxide significantly depressed brain waves amplitude, with no increase in onset time. Isoflurane and desflurane decreased the amplitude and increased onset time of brain waves. The association of nitrous oxide to those agents further increased these effects on cortical waves. There were no significant changes in peripheral and spinal cord SEP waves.

CONCLUSIONS: Nitrous oxide has a minor hypnotic action, which is not completely captured by EEG-BIS. It has a pronounced action on cortical structures, both as sole agent or associated to isoflurane or desflurane, which may explain its satisfactory analgesic effect.

Key words: ANESTHETICS, Gaseous: nitrous oxide, Volatile: desflurane, isoflurane; MONITORING: bispectral index, somatosensory evoked potentials

RESUMEN

JUSTIFICATIVA Y OBJETIVOS: El óxido nitroso es el agente anestésico inhalatorio más utilizado en todo el mundo. Su mecanismo de acción es bastante discutido, con base en resultados experimentales y en evidencias clínicas. El objetivo de este estudio es evaluar la acción eletrofisiológica de este fármaco en el Sistema Nervioso Central a través de monitorización específica.

MÉTODO: Fueron estudiados veinticinco pacientes de ambos sexos, con edades entre 6 y 25 años, sometidos a cirugía ortopédica o plástica reparadora, los cuales fueron monitorizados con índice bispectral del eletroencefalograma (BIS) y potencial evocado somatosensitivo (PESS) durante la anestesia. Fueron realizados registros basales del BIS y PESS, bien como después del uso del óxido nitroso en fraccionales alveolares (FA) de 30%, 50% y 66%. En seguida el óxido nitroso era descontinuado y administrado aleatoriamente isoflurano o desflurano en 0,5 CAM y 1 CAM. Se mantenía 1 CAM del determinado agente y el óxido nitroso era nuevamente administrado en las mismas concentraciones anteriores.

RESULTADOS: El óxido nitroso cuando utilizado como agente único, produce una reducción en el BIS que, aunque sea estadísticamente significante, no expresa un estado de hipnosis. Esta reducción también ocurre cuando utilizado como agente coadyuvante más sin importancia clínica. Como agente único, el óxido nitroso deprimió significantemente la amplitud de las ondas cerebrales, sin promover aumento en la latencia. El isoflurano y desflurano redujeron la amplitud y aumentaron la latencia de las ondas cerebrales. La asociación del óxido nitroso a estos agentes, intensificó aun más estos efectos en las ondas corticales. No hubo alteración significativa de las ondas periférica y medular del PESS.

CONCLUSIONES: El óxido nitroso tiene una pequeña acción hipnótica, que no es captada completamente por el BIS. Tiene acción acentuada en las estructuras corticales, tanto como agente único como asociado al isoflurano y desflurano, lo que puede explicar su buen efecto analgésico.

INTRODUCTION

Nitrous oxide is a gaseous anesthetic agent of low potency. Its minimum alveolar concentration (MAC) is 104% (± 10), which corresponds to a partial pressure of 805 mmHg (at sea level), only experimentally obtained with a hyperbaric chamber ¹ or by calculated estimates.

It is used in non-hypoxic concentrations, never above 70%. Nitrous oxide has moderate analgesic properties, weak amnesic action, minor immobilizing power and very mild hypnotic effect ^2-4. Hence, its indications as sole anesthetic agent are very limited, being used mostly a coadjuvant of more potent inhalational anesthetic to decrease their doses and, as a consequence, their side-effects.

Nitrous oxide low blood and tissue solubility (blood/gas coefficient of 0.47 and brain/blood coefficient of 1.1) ⁵ provides it with very special and desirable pharmacokinetic properties, especially as a coadjuvant, since its uptake and distribution are very fast , as well as its excretion. Its pharmacodynamic profile indicates very mild side effects, with emphasis to minimum cardiovascular and respiratory effects. In addition, it is a less soluble gas with almost no metabolization. It is widely used for being very well tolerated ^6,7.

With a MAC very close to 100%, when used as a coadjuvant drug, it should theoretically decrease main agent’s MAC in a proportion equivalent to its own the concentration being administered. For example, since halothane MAC is about 0.76%, the addition of nitrous oxide to the inhalational mixture in a 50% concentration would decrease this MAC to 0.38%.

According to the literature, this proportion of reduction of volatile anesthetic’s MAC is observed for same agents, but not to all ⁸. In addition, some electrophysiological studies have shown a linear relationship of this additive effect on certain parts of the central nervous system (CNS) ⁹, but not on all CNS structures ¹⁰.

Nitrous oxide pharmacological characteristics are widely studied. It is not considered a complete anesthetic agent, although exhibiting analgesic and amnesic properties. It is not hypnotic and may cause a hilarious effect. It may cause excitation by acting as a depressor on CNS areas with inhibiting functions, releasing other areas with stimulating functions and triggering a typically extrapiramidal reaction. Nitrous oxide’s action mechanism on CNS structures is not thoroughly known. However, a lot is already known through evidences found in experimental studies and clinical trials ^11,12.

Nitrous oxide produces very typical clinical states, different from other inhalational anesthetics. It is possible that an electrophysiological evaluation may reveal results showing how different are its action’s on different CNS structures. The challenge of observing functional neurological changes during nitrous oxide administration is a very interesting motivation. So, the aim of this study was to objectively evaluate, thru specific monitoring, the action of such drug on CNS structures, both as sole agent or as a coadjuvant, correlating observed changes to its pharmacological effects.

METHODS

After the Hospital’s Ethical Committee approval, 25 patients of both genders, aged 6 to 25 years, physical status ASA I and II, undergoing lower limb orthopedic or corrective plastic surgeries were included in this study. Patients were premedicated with 0.8 mg.kg^-1 oral midazolam 30 minutes before surgery, with a maximum dose of 15 mg. Routine physiological and electroneurophysiological monitoring were installed in the anesthetic induction room.

Electroencephalogram with BIS was used to monitor the actions on brain cortex, with Zipprep-type electrodes (Aspect Medical System) placed on the frontal region; one electrode on each side and a third reference electrode between them. Two channels, were established (Fp1 and Fp2) plus a referential channel (Fpz), according to the International System 10-20 of the International Society of Clinical Neurophysiology (Figure 1). Fp1-Fpz was analyzed in channel 1, Fp2-Fpz in channel 2 and the “ground” placed on the pre-auricular region. BIS and both BIS channel waves were recorded from successive 2 seconds periods ¹³ and updated at every 5 seconds by a monitor A 1000 (Aspects Medical Systems, Natick, MA). Selected frequency bandwidth was set between 0.5 and 30 Hertz (Hz). Impedance was checked before every reading and remained always below 800 ohms (W). The monitor also featured an automatic artifact detection and rejection system. BIS baseline value was obtained before anesthetic induction.

Brazilian Journal of Anesthesiology, 2002; 52: 3: 255 - 271

Nitrous oxide action on the central nervous system.

Electrophysiological study as a sole agent or a coadjuvant

Verônica Vieira da Costa; Renato Ângelo Saraiva

Anesthesia was induced with 3 mg.kg^-1 propofol and 0.1 mg.kg^-1 vecuronium, followed by tracheal intubation and mechanical ventilation. All patients received epidural anesthesia between the third and fourth lumbar vertebra with bupivacaine in concentration and volume depending on patients weight, but never exceeding 3 mg.kg^-1. The purpose of that was to avoid the interference of other stimuli on the monitor. Somatosensory evoked potential (SEP) was recorded 30 minutes after propofol administration, being this first record considered the baseline value, thus avoiding artifacts generated by muscle shivering due to low operating room temperatures. SEP was monitored by a Dantek-Keypoint release 3.04 monitor (Denmark) after right median nerve stimulation with a bar-type electrode, with a cathode-anode distance of 3.5 cm. Records were obtained through surface electrodes on the following sites: Erb point, located on the right supraclavicular fossa (wave N9); over the spinous process of the second cervical vertebra (N13); over the skull, close to parietal lobe sensory cortex, contralateral to the stimulated limb (waves N19 and P22), according to the International System 10-20. The reference electrode (Fz) was placed in the top of the middle frontal region, and the “ground” electrode was placed on the right shoulder. Impedance was always kept below 5 kohms (W). Stimulation intensity was adjusted until motor response threshold was reached, characterized by the Thumb Twith. For each SEP reading, 20 constant current impulses were repeated for 0.2 miliseconds (ms), with a discharge frequency of 5.1 Hz. Filtration band was adjusted between 20 Hz (low) and 3000 Hz (high). Promediations (tracings) were duplicated and both record series were compared to evaluate their reproducibility.

Waves N9 (brachial plexus), N13 (cervical spinal cord), N19 (thalamus-cortical) and P22 (cortical) were simultaneously evaluated. Onset time was recorded in milliseconds (ms) and amplitude in microvolts (µv).

Regular monitoring consisted of ECG, non-invasive blood pressure (BP), hemoglobin oxygen peripheral saturation (SpO₂), end expired CO₂ partial pressure (P_ETCO₂) and nasopharyngeal temperature, as well as inspired and end expired concentration (alveolar) of inhaled agents through an anesthetic gas analyzer. After baseline SEP recording, nitrous oxide was introduced until an alveolar fractional concentration (AF) of 30% was reached. After 5 minutes, a new SEP was recorded. While SEP was being registered, BIS values on the screen were recorded as well with mean values being calculated. At the same time, the other physiological variables values were also registered. Then, nitrous oxide concentration was increased to 50% and 66%, following the same recording procedures. Next, nitrous oxide was withdrawn and isoflurane or desflurane were randomly introduced until an AF of 0.5 MAC. After 10 minutes BIS, SEP and other variables were once again recorded, the same being repeated after bringing AF to 1 MAC. With the patients at 1 MAC of their respective agents, nitrous oxide was reintroduced in the same concentrations (30%, 50% and 66%) and the same procedures were performed again, in the previous sequence and time intervals.

Student’s t and Chi-square tests were used for statistical analysis of demographics. Bonferroni’s method was used to compare cardiovascular, respiratory and temperature variables between different nitrous oxide and other agents concentrations. Exploratory data analysis (mean and standard deviation) was used to evaluate the significance of neurophysiological changes, followed by the method of repetitive measures (modified Fisher’s test), considering statistically significant p < 0.05.

RESULTS

Twenty-five patients were given initially nitrous oxide as sole agent, which was then temporarily withdrawn. After that, 13 patients were given isoflurane and 12 desflurane, according to the above mentioned sequence. There were no differences in gender, age, physical status and weight between the group receiving nitrous oxide and isoflurane and the group receiving nitrous oxide and desflurane (Table I).

Brazilian Journal of Anesthesiology, 2002; 52: 3: 255 - 271

Nitrous oxide action on the central nervous system.

Electrophysiological study as a sole agent or a coadjuvant

Verônica Vieira da Costa; Renato Ângelo Saraiva

There were no significant changes in physiological variables during nitrous oxide administration in different concentrations. Stability was maintained with sevoflurane and desflurane, with a mild trend to decrease those values, but with no statistical or clinical significance. Mean P_ETCO₂ values varied from 39 to 33 mmHg, reaching lower values in the isoflurane group, but also with no statistical significance. There were no significant temperature changes as well (Table II and Table III).

Brazilian Journal of Anesthesiology, 2002; 52: 3: 255 - 271

Nitrous oxide action on the central nervous system.

Electrophysiological study as a sole agent or a coadjuvant

Verônica Vieira da Costa; Renato Ângelo Saraiva

Brazilian Journal of Anesthesiology, 2002; 52: 3: 255 - 271

Nitrous oxide action on the central nervous system.

Electrophysiological study as a sole agent or a coadjuvant

Verônica Vieira da Costa; Renato Ângelo Saraiva

EEG-BIS Monitoring of Nitrous Oxide, Isoflurane and Desflurane Effects on the Brain Cortex

BIS value decreased 23.8% when 30% nitrous oxide was used as a sole agent, reaching statistical significance (p < 0.001). As concentration increased to 50% and 66%, BIS values were kept stable, with only a slight trend to increase (Figure 2). After nitrous oxide withdrawal (AF close to zero) and 0.5 MAC isoflurane achieved, there was a 42.6% BIS decrease as compared to baseline, with statistical significance (p < 0.001). When the concentration was increased to 1 MAC, BIS had a further drop to 66.17% of baseline (p < 0.001).

Brazilian Journal of Anesthesiology, 2002; 52: 3: 255 - 271

Nitrous oxide action on the central nervous system.

Electrophysiological study as a sole agent or a coadjuvant

Verônica Vieira da Costa; Renato Ângelo Saraiva

With 0.5 MAC desflurane, there was a 46.9% BIS reduction (p < 0.001), and a 67.93% decrease when concentration was increased to 1 MAC (p < 0.001).

With 1 MAC isoflurane and nitrous oxide readministration in increasing concentrations (30%, 50% and 66%), there was a mild BIS decrease of 3.26%, 5.59% and 10.96%, respectively. At the same time, desflurane group showed a BIS reduction of 9.95%, 16.67% and 24.73%, respectively. BIS decrease was higher in patients where nitrous oxide was associated to desflurane compared to those where nitrous oxide was associated to isoflurane. Prior to nitrous oxide reintroduction, isoflurane and desflurane produced a sudden and squared wave form BIS decrease (Figure 3). When nitrous oxide was associated to those potent agents, BIS reduction was smoother, with a trend to stabilization from 50% concentration on.

Brazilian Journal of Anesthesiology, 2002; 52: 3: 255 - 271

Nitrous oxide action on the central nervous system.

Electrophysiological study as a sole agent or a coadjuvant

Verônica Vieira da Costa; Renato Ângelo Saraiva

Nitrous Oxide, Isoflurane and Desflurane Effects on Peripheral Nerve, Spinal Cord and Brain, evaluated by Peripheral Nerve Somatosensory Evoked Potential - SEP

Action on peripheral nerve structure (brachial plexus) - SEP Wave N9:

Nitrous oxide as sole agent did not change amplitude and onset time with 30%, 50% and 66% alveolar fractions (AF).

Isoflurane and desflurane also did not affect amplitude and onset time when administered in AF of 0.5 and 1 MAC.

Similarly, 30%, 50% and 66% nitrous oxide AF associated to 1 MAC isoflurane or desflurane had no influence on amplitude and onset time of wave N9.

Action on Spinal Cord Structure - SEP Wave N13:

There were no significant amplitude and onset time changes with 30%, 50% and 66% nitrous oxide, as well as with isoflurane or desflurane at 0.5 and 1 MAC.

Action on Thalamus-brain Structure - Wave N19:

Nitrous oxide decreased its amplitude in 10.76% at 30% AF compared to baseline. With 50% AF, the decrease was 29.57%, and 28.09% with 66% AF (p < 0.001). There was no change in onset time with those concentrations (Figure 4 and Figure 5).

Brazilian Journal of Anesthesiology, 2002; 52: 3: 255 - 271

Nitrous oxide action on the central nervous system.

Electrophysiological study as a sole agent or a coadjuvant

Verônica Vieira da Costa; Renato Ângelo Saraiva

Brazilian Journal of Anesthesiology, 2002; 52: 3: 255 - 271

Nitrous oxide action on the central nervous system.

Electrophysiological study as a sole agent or a coadjuvant

Verônica Vieira da Costa; Renato Ângelo Saraiva

Isoflurane promoted an 18.93% amplitude decrease at 0.5 MAC (p= 0.303) and 16.18% at 1 MAC (p = 0.42) compared to baseline. Onset time had a 3.72% increase at 0.5 MAC and 11.84% at 1 MAC. Such changes, however, were not statistically significant.

Desflurane reduced amplitude in 19.21% at 0.5 MAC (p = 0.37) and 20% at 1 MAC (p = 0.42) compared to baseline. Onset time increased 5.90% at 0.5 MAC and 14.60% at 1 MAC compared to baseline. Those changes were also not statistically significant.

The association of 1 MAC isoflurane to 30%, 50% and 66% nitrous oxide decreased amplitude even further to 29.92% (p = 0.137), 37.64% (p = 0.067) and 58.20% (p = 0.014), respectively. Onset time showed no further increase.

One MAC desflurane associated to 30%, 50% and 66% nitrous oxide also produced a further decrease in amplitude, to 48.72% (p = 0.005), 51.36% (p = 0.024) and 60.50% (p = 0.010), respectively. Onset time increase was intensified when 66% nitrous oxide was associated (20.13%), with no statistical significance though (p = 0.24).

Action on Brain Structure - Wave P22:

Nitrous oxide decreased its amplitude in 35.54% at 30% AF, 38.52% at 50% AF and 46.48% at 66% AF, compared to baseline (p < 0.001). There were no changes in onset times (Figure 6).

Brazilian Journal of Anesthesiology, 2002; 52: 3: 255 - 271

Nitrous oxide action on the central nervous system.

Electrophysiological study as a sole agent or a coadjuvant

Verônica Vieira da Costa; Renato Ângelo Saraiva

Isoflurane at 0.5 MAC decreased amplitude in 18.81%, while at 1 MAC this decrease reached 58.59%, compared to baseline, both changes statistically significant (p = 0.017 and p = 0.014, respectively). Onset time increased 4.78% at 0.5 MAC and 14.14% at 1 MAC compared to baseline. Such changes were not statistically significant though.

Desflurane decreased wave amplitude in 34.13% at 0.5 MAC and 67.69% at 1 MAC compared to baseline. This last change (at 1 MAC) was statistically significant (p = 0.001). Onset time increased 7.48% at 0.5 MAC and 15.99% at 1 MAC compared to baseline, however with no statistical significance.

Isoflurane at 1 MAC associated to 30%, 50% and 66% nitrous oxide decreased amplitude even further in 7.16% (p = 0.15), 54.58% (p < 0.06) and 41.80% (p < 0.001) respectively, with statistical significance at 66% N₂O alveolar concentration. Onset time increase was intensified with 30%, 50% and 66% N₂O AF in 20.47% (p = 0.043), 22.05% (p = 0.013) and 27.24% (p = 0.066) respectively (Figure 7 and Figure 8).

Brazilian Journal of Anesthesiology, 2002; 52: 3: 255 - 271

Nitrous oxide action on the central nervous system.

Electrophysiological study as a sole agent or a coadjuvant

Verônica Vieira da Costa; Renato Ângelo Saraiva

Brazilian Journal of Anesthesiology, 2002; 52: 3: 255 - 271

Nitrous oxide action on the central nervous system.

Electrophysiological study as a sole agent or a coadjuvant

Verônica Vieira da Costa; Renato Ângelo Saraiva

The association of 1 MAC desflurane to 30%, 50% and 66% nitrous oxide decreased amplitude in 27.23% (p = 0.03), 65.65% (p = 0.05) and 67.71% (p = 0.04) respectively. Onset time increase was intensified with 30%, 50% and 66% N₂O AF in 23.91% (p = 0.005), 27.25% (p = 0.007) and 31.33% (p = 0.009) respectively (Figure 9 and Figure 10).

Brazilian Journal of Anesthesiology, 2002; 52: 3: 255 - 271

Nitrous oxide action on the central nervous system.

Electrophysiological study as a sole agent or a coadjuvant

Brazilian Journal of Anesthesiology, 2002; 52: 3: 255 - 271

Nitrous oxide action on the central nervous system.

Electrophysiological study as a sole agent or a coadjuvant

Verônica Vieira da Costa; Renato Ângelo Saraiva

DISCUSSION

Physiological results are in line with other authors confirming the stability of cardiopulmonary functions when nitrous oxide was used as a sole agent or associated to other volatile anesthetics in alveolar concentrations of 30%, 50% and 66%. In such concentrations, nitrous oxide does not act on nervous structures able to inhibit or release certain autonomic neurotransmitters which could trigger cardiovascular changes, or even inhibit respiratory automation causing alveolar hypoventilation ^12,14,15.

Minor BIS changes with nitrous oxide indicate its very mild hypnotic action.

In our study, mean BIS value dropped from baseline 97.12 to 74.00 when 30% nitrous oxide was administered. This value kept almost constant (76.64 and 77.64) when 50% and 66% nitrous oxide were administered.

There are reports in the literature indicating that BIS between 60 and 80 is associated to increased consciousness ¹⁶. So although decreased, values reached in all studied concentrations did not indicate a total hypnotic state. The initial decrease with 30% nitrous oxide could be related to residual intravenous propofol effect used for anesthetic induction. However, BIS decrease after a propofol bolus injection is much higher, indicating total hypnosis, and it takes only 8 minutes for it to increase above 60, followed by consciousness return ¹⁷. In our study, after propofol induction, there was a 30-minute interval when no anesthetics were used. BIS did not return to baseline, but reached approximately 80. This value is clearly closer to alertness than to hypnosis. Studies have shown that patients receiving 10%, 20%, 30%, 40% and 50% nitrous oxide had no BIS change ¹⁸. Another study has shown that, even with 70% nitrous oxide, there have been no significant BIS change that could characterize hypnosis ¹⁹.

Isoflurane and desflurane decrease BIS in a dose-dependent way. This shows that different from nitrous oxide those agents have an important hypnotic action. Other author has also demonstrated the same results for drugs such as propofol, midazolam and isoflurane ²⁰. There are reports on BIS increase with high isoflurane concentrations ²¹. Our study showed no BIS increase with increased isoflurane concentrations, but we did not exceed 1 MAC. Maybe this limited concentration would justify this difference in results. Regarding desflurane, there is no report in the literature using concentrations similar to ours.

The association of nitrous oxide to 1 MAC isoflurane and desflurane promoted a mild BIS decrease, never beyond 10% compared to values obtained without this gas. The decrease was a little greater in patients receiving desflurane. These results are in line with a previous study where the author has found no difference in BIS when nitrous oxide was used a sole agent (70%) or associated to isoflurane, in spite of consciousness loss ¹⁹. Another author has reported that 50% nitrous oxide as sole agent caused mild sedation and no BIS change. It was, however, observed by EEG activation in certain areas, which did not affect BIS, indicating that nitrous oxide has CNS inhibitory and excitatory effects ¹⁸.

There are studies showing different nitrous oxide effects on CNS, some of which not in agreement with results found in our study. It has been reported that nitrous oxide antagonizes isoflurane depressing effects on EEG ^{9 22}. Isoflurane would produce a higher BIS value associated to nitrous oxide than when employed as sole agent ²³. Another study has shown that the addition of nitrous oxide increased a propofol induced low BIS, although the patients continued not to respond to verbal commands ²⁴, probably due to amnesia. In fact, studies about nitrous oxide effects on BIS are conflicting, possibly reflecting an inadequate algorithm used to calculate BIS from EEG. These findings question BIS efficiency as anesthetic depth monitor in patients receiving nitrous oxide as a sole agent or associated to other anesthetic agents.

In the concentrations used in this study, nitrous oxide did not inhibit neither peripheral nervous structures, such as brachial plexus, nor spinal cord. It is possible that there might has been some action on those structures, especially spinal cord, which was not captured by SEP waves N9 and N13 due to its low magnitude. One must considered that the highest concentration used corresponded to approximately 0.6 MAC of this agent. Usually, concentrations producing even mild inhibition on the spinal cord with other agents are MAC multiples (1.3 to 1.5 MAC).

Isoflurane and desflurane had also no effect on spinal cord and peripheral potentials. Their action over the stimuli conduction through peripheral nerves and spinal cord seems to be very mild and not enough to affect potentials generated in the brachial plexus and at C2 level.

These findings are similar to other results where the author has not found nitrous oxide-induced changes in subcortical potentials ⁹. In another study, the author has described a non-significant change in SEP wave N13 amplitude with nitrous oxide as sole agent or associated to isoflurane. This author, however, agrees that anesthesia has a minor effects on cervical (N13) and brachial plexus (N9) components, and that his results are not in accordance with previous observations ²⁵. It is suggested that waves N9 and N13 responses are dependent on axonal conduction rather than synaptic transmission, being such potentials less influenced by general anesthesia ²⁶.

Nitrous oxide inhibits ascending stimuli directed to the brain. This inhibition can be observed as they enter the brain structure, on evoked wave N19, as well as in the cortex by wave P22 inhibition. There was a significant decrease in these waves’ amplitude.

Wave N19 showed no onset time change. Amplitude decrease was seen in all N₂O concentrations, being more pronounced with 50%. There was also no onset time change in wave P22, and amplitude was decreased in 38.52% with 50% nitrous oxide. At 66% AF, amplitude decrease reached 46.48%, with a 12.95% further reduction compared to previous value (AF 50). It is worth remembering that amplitude decrease was not exacerbated in wave N19 when N₂O AF changed from 50% to 66%. Some authors have described nitrous oxide-induced amplitude decrease without changes in cortical waves onset time ^10,25,27. However, none of those studies has shown so close percentual changes in N19 wave amplitude with different N₂O concentrations, like our study with 50% and 66% AF. And this is the case too for very similar P22 amplitude values with the same N₂O concentrations. Maybe this was not seen in other studies because the methods were not designed for such observation: the authors have studied just one concentration, or have studied 50% AF as maximum nitrous oxide concentration.

There is a report in the literature showing that nitrous oxide depressing effect on cortical waves amplitude, evaluated by SEP, is more pronounced than isoflurane’s ^9,25. In our study, cortical wave P22 decreased more with 30%, 50% and 66% nitrous oxide than with 0.5 MAC isoflurane. Depression in wave N19 caused by 50% and 66% nitrous oxide was greater than that found with 0.5 and 1 MAC isoflurane, suggesting that nitrous oxide, in equipotent MAC doses, has a higher primary cortex depressing effect than isoflurane. This may explain the good analgesic and amnesic effect of nitrous oxide, as opposed to its weak hypnotic effect. The stimulation of subcortical endogen opioid production and the direct cortical depressing effect were proposed as mechanisms responsible for this analgesic effect ²⁸. With desflurane, brain waves amplitude reduction with 0.5 MAC was lower than those produced by 50% and 66% nitrous oxide. No study was found in the literature comparing nitrous oxide to desflurane, but according to our results, in equipotent MAC doses, nitrous oxide cortical depressing action is stronger than 0.5 MAC desflurane. This fact also reflects the mechanisms responsible for the good analgesic and amnesic effect of such agent.

The addition of nitrous oxide to isoflurane and desflurane produced significant changes, especially in waves N19 and P22 amplitudes, with minor onset time change of the latter. These results are in line with other authors who have shown that the association of 60% nitrous oxide significantly decreases cortical waves amplitude ^28-31. In our study, the association of nitrous oxide to isoflurane decreased even more brain waves amplitude. Wave N19 amplitude reduction became more intense as higher nitrous oxide AF were administered. In the other hand, maximum P22 decrease was reached at 50% N₂O AF. So, would there be a limit nitrous oxi- de concentration from which this gas could no further exacerbate amplitude decrease promoted by 1 MAC isoflurane in this wave? With desflurane, waves N19 and P22 showed a steeper decrease between baseline and 50% nitrous oxide. From this point on, the reduction became negligible (Figure 9 and Figure 10). The increase in N₂O AF did not result in proportional brain waves depression, what might be attributed to the existence of a “ceiling effect”. Obviously new studies are needed in this direction.

Our study found a greater P22 onset time increase when nitrous oxide was associated to 1 MAC isoflurane and desflurane. It has been reported that when 60% nitrous oxide were associated to 0.6 MAC isoflurane, only a mild additional wave N19 onset time increase was seen, besides that previously promoted by isoflurane itself. The author has found just 1 millisecond onset time increase, which was not clinically significant ²⁵. Onset time is seldom used as a criteria for perioperative monitoring due to its low sensitivity ³². However, we observed a further wave P22 onset time increase with N₂O addition in all studied concentrations. These findings are in agreement with a previous study where the authors have described an even higher cortical waves onset time increase after the addition of nitrous oxide (60% AF) to sevoflurane ³³.

There are reports in the literature on SEP changes caused by P_ETCO₂ variations ³⁴, hypothermia ³⁵, hyperthermia ³⁶ and surgical stimulation ²⁷. In our study, patients were under epidural anesthesia and had no significant P_ETCO₂ or temperature changes. So, all BIS and SEP changes may be attributed to nitrous oxide, as well as to isoflurane and desflurane at certain moments.

While producing a marked decrease in cortical potentials amplitude, N₂O almost does not change BIS, being even able to increase it. It is possible that its actions include a cortical-thalamic inhibition enhancement and an excitatory reduction ³⁷. However, it has already been reported a nitrous oxide-induced activation in certain brain cortical areas captured by EEG ³⁸, which might be attributed to a direct brain cortex stimulating effect generating spontaneous bursts, parallel to a reduction in sensory information transmission to the cortex by thalamic nucleus blockade. This results in decreased brain waves amplitude. It has also been observed that nitrous oxide-induced stimulation of reticular centers may be responsible for brain area activation seen on EEG ³⁹.

In conclusion, it was demonstrated that nitrous oxide causes minor changes in spontaneous stimuli reaching brain cortex and captured by EEG. It mildly changes spinal cord and peripheral potentials when used as a sole agent or associated to isoflurane and desflurane. Nitrous oxide significantly decreases cortical potentials amplitude as sole agent or associated to isoflurane and desflurane, reflecting in its strong analgesic and weak hypnotic effect.

ACKNOWLEDGEMENTS

The authors acknowledge the neurophysiologic team: Alexandre Cardoso Almeida, MD and Maria Dorvalina Silva, MD, and the technicians Josias Francisco de Macedo, Joselda Mara Viera Lobo, Raimunda Nonata Melo Rosendo and Renata Rodrigues dos Santos, from Hospital Sarah, Brasilia; and especially the statistician Marcio Correa de Mello for supporting this study.

REFERENCES

Submitted for publication August 15, 2001

Accepted for publication November 8, 2001

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*

Received from Hospital Sarah Brasília, DF

Publication Dates

• Publication in this collection
  18 Oct 2005
• Date of issue
  June 2002

History

• Accepted
  08 Oct 2001
• Received
  15 Aug 2001