While nitrous oxide gas has been used recreationally and medically for more than 200 years - originally for its euphoric and then for its pain relieving and anesthetic properties - the mechanism behind its effects on the brain has been poorly understood. A report from investigators at Massachusetts General Hospital (MGH) finds that the EEG patterns of patients receiving high doses of nitrous oxide differ significantly from those of the same patients when they had received ether-based inhaled anesthetics earlier in the procedures, findings that - along with suggesting how nitrous oxide produces its effects - also may help explain the failure of the first attempt to demonstrate anesthesia at MGH.
"Nitrous oxide is most often used today as an adjunct to potent inhaled drugs like sevoflurane, desflurane and isoflurane, which are ethers," says Emery Brown, MD, PhD, of the MGH Department of Anesthesia, Critical Care and Pain Medicine, senior author of the report that has been published online in Clinical Neurophysiology. "A common practice is to switch patients from an ether anesthetic to nitrous oxide at the end of a surgical procedure, which shifts the anesthetic state from maintenance of unconsciousness to a state of sedation from which patients can be more readily awakened. As part of our continuing investigation into the mechanisms behind general anesthesia, we analyzed EEG reading taken from 19 surgical patients during the transition from ether to nitrous oxide."
It has been believed that nitrous oxide binds to and blocks the NMDA receptor for the excitatory neurotransmitter glutamate. Low doses of nitrous oxide produce sedation and relative rapid EEG patterns that are called beta (12 to 25 Hz) and gamma (greater than 25 Hz) oscillations. The MGH team's analysis revealed that, when patients were shifted from sevoflurane to the high-dose nitrous oxide used at the end of surgery, the typical EEG pattern during sevoflurane adminstration, characterized by medium frequency alpha oscillations (8 to 12 Hz), disappeared within about 6 minutes and was replaced by a pattern of what are called slow-delta oscillations of around 0.1 to 4 Hz. The slow-delta pattern was transient and was replaced by the beta and gamma oscillations after 2 to 12 minutes, even though patients were still receiving nitrous oxide.
The identification of this slow-delta pattern as the EEG signature of high-dose nitrous oxide anesthesia fits the theory that the drug acts by blocking excitatory impulses arising from the brain stem to the NMDA receptors in the thalamus and cortex. Studies dating back to the 1930s showed that blocking the transmission of excitatory signals between the brain stem and the cortex produced similar slow-delta patterns. These patterns are also associated with slow-wave sleep, the deepest stage of normal sleep that also involves substantial inactivation of arousal centers in the brain stem. The beta and gamma patterns of low-dose nitrous oxide could explain the euphoric effects experienced at the lowest doses, since the drug's blockage of glutamate's effects could first affect inhibitory neurons and produce a paradoxical excitatory effect, while higher doses would have a broader inhibitory effect throughout the brain.
"Why the slow-delta EEG pattern is transient is part of the mystery of nitrous oxide," says Brown. "Other anesthetics will continue to produce the pattern, which is characteristic of deep sedation and unconsciousness, so long as the dosage is maintained, so exactly how the effect of nitrous on neuronal targets emerging from the brainstem ceases to be strong is the question. Right now we just don't know. But it's interesting to me that anesthesiologists are not generally aware of these oscillation because they do not use EEG to monitor patients' brain states.
"It's interesting to wonder whether the transient nature of nitrous-oxide-induced slow-delta oscillations could partially explain why the first attempt to demonstrate anesthesia here at MGH - by dentist Horace Wells who'd used nitrous oxide with several of his patients - was a complete failure," Brown adds. "Our findings suggest why these transient effects could be ideal for anesthesia management at the end of a case: patients are in a state of profound unconsciousness while surgeons close the incision but are able to be awakened more quickly since nitrous is cleared from their systems more rapidly that are ether anesthetics. They also reveal how the study of anesthetics, even in the clinical setting, can give new insights into the fundamental workings of circuits in the brain."
Brown is the Warren M. Zapol Professor of Anaesthesia at Harvard Medical School and the Taplin Professor of Medical Engineering at MIT. Kara Pavone of the MGH Department of Anesthesia, Critical Care and Pain Medicine is lead author of the Clinical Neurophysiology paper. Additional co-authors are Oluwaseun Akeju, MD, Aaron Sampson, Kelly Ling, and Patrick L.Purdon, PhD, all of MGH Anesthesia. Support for the study includes National Institutes of Health grants DP1-OD003646, DP2-OD006454 and TR01-GM104948 and a Foundation for Anesthesia Education and Research Award.
Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $760 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, transplantation biology and photomedicine.