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Nitrous and Nitric Oxides

August 3, 2015

Mathematics, like physics and chemistry, is subdivided into many specialties. Generally, practitioners in any one of these has only a cursory understanding of what's happening in the others. While most inorganic chemists can render the periodic table of the elements from memory, this would be a hard task for an organic chemist. Likewise, condensed matter physicists can't recite the members of the particle zoo discovered by their particle physics counterparts.

Likewise, mathematics is fragmented into many fields. You can view a list of the fields of mathematics on the arXiv topic page. While most mathematicians are knowledgeable just in their specialty area, Paul Erdős was a true "poly-math," since he made contributions to so many fields of mathematics.

As was his custom, Erdős mostly collaborated with others, thereby inspiring the concept of the Erdős number, which is the "collaborative distance" between Erdős and another person. A coauthor of a paper with Erdős has an Erdős number of one, while a coauthor of a coauthor with Erdős has an Erdős number of two, etc.

Paul Erdos and Terence Tao in 1985Paul Erdős and ten year old Terence Tao in 1985.

Tao, whose work I presented in a previous article, has an Erdős number of two.

(Via Wikimedia Commons.)

While Erdős was facile in many areas of mathematics, he was often confronted with a procedural problem when talking with colleagues. Mathematics is like a Tower of Babel in which each specialty has its own nomenclature. Nomenclature is important, since it provides a shorthand way of expressing deep concepts. By asking his colleagues to define their jargon, he was able to see the mathematics lurking in a problem. Although he likely didn't admit it, this was also the Erdős' method of professional development in which his colleagues were his teachers.

Chemists have a nomenclature for naming some of the simple inorganic compounds. Compounds formed from cations at their lowest valence are "-ous," and compounds with the next highest valence are "-ic." That's why we have ferrous chloride, FeCl2, a.k.a. iron(II) chloride, and stannous chloride, SnCl2, a.k.a. tin(II) chloride, but also ferric chloride, FeCl3, a.k.a. iron(III) chloride, and stannic chloride, SnCl4, a.k.a. tin(IV) chloride.

The same is true for two principal oxides of nitrogen, nitrous oxide, N2O and nitric oxide, NO. Nitrous oxide is familiar to everyone as "laughing gas." Nitrous oxide, a once common anesthetic in dentistry, has an euphoric effect that lends itself well to comedy. There's a 1914 Keystone Studios film called Laughing Gas, in which Charlie Chaplin is both an actor and the director.[1]

Chemical Recreations - Nitrous Oxide, engravingAn engraving entitled, "Chemical Recreations." This shows nitrous oxide inducing laughing and dancing.

English chemist, Joseph Priestley (1733-1804), discovered nitrous oxide in 1772, and named it phlogisticated nitrous air. He prepared it by heating iron filings and nitric acid.

(Illustration from Wellcome Images, a website operated by Wellcome Trust, a global charitable foundation based in the United Kingdom, via Wikimedia Commons.)

Although nitrous oxide has been used as an anesthetic since the 1880s, the affect of nitrous oxide on brain function has surprisingly never been thoroughly studied. Now, a team of scientists from Massachusetts General Hospital (Boston, Massachusetts), Harvard Medical School (Boston, Massachusetts), and the Massachusetts Institute of Technology (Cambridge, Massachusetts), have used electroencephalography (EEG) to study the key brainwave changes that occur in patients on nitrous oxide.[2-3]

Nitrous oxide is commonly administered near the completion of surgery as a way to keep a patient unconscious while a primary ether anesthetic clears from the patient's system.[2-3] It's administered, also, in combination with an ether anesthetic during surgery as a way to reduce the ether dose.[3] The research team measured brain activity by the EEG technique in which six electrodes are placed on the forehead to measure the brain's electrical activity. The brain's voltage signals are a result of the collective activity of brain neurons communicating with each other.[3]

Nineteen patients were studied. They received general anesthesia using sevoflurane, an ether anesthetic, combined with oxygen and air.[2] When the anesthesia was transitioned to nitrous oxide, the brain's alpha oscillations (8–12 Hz) associated with sevoflurane dissipated within about six minutes, to be replaced by a highly-coherent large-amplitude slow-delta oscillation (0.1–4 Hz) that persisted for about three minutes.[2] Such delta waves are characteristic of deep sleep, but the delta waves induced by nitrous oxide had twice the amplitude.[3]

Brainwave spectra under an ether and nitrous oxide anesthetic.EEG spectra under a sevoflurane ether (blue) and nitrous oxide (red) anesthetic. The excess of low frequency delta waves is clearly see.

(Fig. 2c of ref. 2, modified for clarity, licensed under a Creative Commons License.)

These findings stand in contrast to the brain activity observed with lower concentrations (20-40%) of nitrous oxide at which it's a sedative and not an anesthetic. At those levels, beta oscillation are found and the delta wave amplitude decreases, instead.[2-3] Says Emery Brown, a professor of Medical Engineering at MIT and an anesthesiologist at Massachusetts General Hospital,
"We literally watched it and marveled, because it was totally unexpected... Nitrous oxide has control over the brain in ways no other drug does."[3]

The reason that the delta waves are increased just at the start of dosing, and then fall-off, is unexplained. The researchers suspect a rapid habituation or desensitization process.[3] The research team is presently investigating how all principal anesthetics and anesthetic combinations affect the EEG signatures.[3]

The nitric oxide cousin of nitrous oxide also has a medical application. Inhaled nitric oxide relaxes pulmonary vessels without causing a systemic drop in blood pressure. The effect, discovered in 1999, is now used to treat about 35,000 U.S. patients in hospitals each year, some of whom are newborns with a condition called persistent pulmonary hypertension of the newborn (PPHN).[5] Nitric oxide therapy for PPHN, which takes about five days, costs about $14,000. Much of the cost arises from distribution and handling of gas cylinders, and the associated delivery and monitoring devices.[4-5]

Another team of researchers at the Massachusetts General Hospital of Harvard Medical School (Boston, Massachusetts) has developed a simple device that uses a pulsed electrical discharges to produce nitric oxide in the therapeutic range of 5-80 parts per million at carrier gas flow rates of 0.5-5 liters/minute. The nitric oxide is produced from the air, or from gas mixtures of 90% O2 and 10% N2 (see photo).

Figure captionAn electrical spark generating therapeutic nitric oxide from the air

Iridium was found to be the best electrode material for this application.

(Photo by Brian Wilson, Massachusetts General Hospital Photography Department.)[5]

The electrical spark produces potentially toxic gases, including nitrogen dioxide (NO2) and ozone (O3), but these are removed by flowing the gas through calcium hydroxide.[4-5] Iridium electrodes were found to produce the highest ratio of nitric oxide to nitrogen dioxide.[4] Other optimizations included finding the optimal timing and number of electric sparks.[5] patent applications have been filed on this system, and a startup company is looking to commercialize this.[5]


  1. Laughing Gas (1914, Charles Chaplin, Director) on the Internet Movie Database.
  2. Kara J. Pavone, Oluwaseun Akeju, Aaron L. Sampson, Kelly Ling, Patrick L. Purdon, and Emery N. Brown, "Nitrous oxide-induced slow and delta oscillations," Clinical Neurophysiology, Article in Press, DOI: http://dx.doi.org/10.1016/j.clinph.2015.06.001. This is an open access publication with a PDF file available here.
  3. Uncovering the mechanism of our oldest anesthetic, MIT Press Release, July 6, 2015.
  4. Binglan Yu, Stefan Muenster, Aron H. Blaesi, Donald B. Bloch, and Warren M. Zapol, "Producing nitric oxide by pulsed electrical discharge in air for portable inhalation therapy," Science Translational Medicine, vol. 7, no. 294 (July 1, 2015), pp. 294ff., DOI: 10.1126/scitranslmed.aaa3097.
  5. Mass. General team generates therapeutic nitric oxide from air with an electric spark, Massachusetts General Hospital Press Release, July 6, 2015.

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