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Most of the signs and symptoms of carbon monoxide poisoning are due to hypoxia. The most significant neurologic and psychiatric manifestations of carbon monoxide poisoning are subacute or late sequelae, often following a period of apparent recovery from an acute episode. Carbon monoxide exposure causes oxidative stress that triggers activation of N-methyl-D-aspartate--neuronal nitric oxide synthase pathway, a key factor in the progression of carbon monoxide–mediated neuropathology. The most important diagnostic test for carbon monoxide poisoning is the direct spectroscopic measurement of carboxyhemoglobin level in the blood. Hyperbaric oxygen is an important component of the management of carbon monoxide poisoning.
• Most of the effects of carbon monoxide poisoning are due to hypoxia.
• Neurologic sequelae of carbon monoxide poisoning may be delayed in onset.
• Hyperbaric oxygen plays an important role in managing carbon monoxide poisoning.
Historical note and terminology
Humans have been exposed to carbon monoxide since they first made fire inside sheltered caves. In 300 BC, Aristotle's comment that "coal fumes lead to a heavy head and death" was a reference to carbon monoxide poisoning. In the 19th and 20th centuries, the increased burning of coal greatly increased the frequency of carbon monoxide poisoning.
Early recognition of the features of carbon monoxide poisoning. The bright red skin complexion in victims who died from charcoal fumes (much later recognized as resulting from elevated carboxyhemoglobin levels) was documented by Swiss pathologist and pharmacologist Johann Jakob Wepfer (1620-1695) in the 1600s and by French anatomist, physician, and medical historian Antoine Portal (1742-1832) in the late 1700s.
Swiss pathologist and pharmacologist Johann Jakob Wepfer (1620-1695)
Engraving (1792) by Heinrich Pfenninger. Pfenninger (1749-1815). (Courtesy of the Wellcome Collection, London, England. Public domain mark. Restored, edited, and matted by Dr. Douglas J Lanska.)
Baron Antoine Portal: French anatomist, physician, medical historian, and founding president of the Académie Nationale de Médecine
Line engraving by J P Dupin Jr, 1782, after André Pujos (1738-1788), 1781. (Courtesy of the Wellcome Collection, London, England. Creative Commons Attribution 4.0 International License, https://creativecommons.org/licenses/by/4...
The first clinical description of coal gas poisoning (ie, carbon monoxide poisoning) was by French physician Dominique-Benoît Harmant (1723-1782) from Nancy, France, in 1775 (50).
(Source: Musée de la Faculté de Médecine. Figure restored by Dr. Douglas J Lanska.)
Early chemistry of carbon monoxide. Around 1772, English chemist Joseph Priestley (1733-1804) isolated carbon monoxide, which he called "heavy inflammable air" (14).
Portrait by Ellen Sharples (1769-1849), completed between 1794 and 1797. (Source: National Portrait Gallery, London, via Wikimedia Commons.)
Thomas Beddoes and James Watt recognized "hydrocarbonate" ("water gas" generated by passing steam over coke, which generates carbon monoxide and hydrogen) brightened venous blood in 1793. Watt suggested coal fumes could counteract the oxygen in the blood, and in 1796 Beddoes and Watt speculated hydrocarbonate has a greater affinity for animal fiber than oxygen.
English physician Thomas Beddoes (1760-1808)
Pencil drawing by Edward Bird (1772-1819). In 1799, Beddoes established the Pneumatic Institution (also referred to as Pneumatic Institute), a medical research facility in Bristol, England, to study the medical effects of gases...
Scottish inventor, mechanical engineer, and chemist James Watt (1736-1819)
Portrait painting by Carl Frederik von Breda (1759-1818). (Source: National Portrait Gallery, London, England, via Wikimedia Commons. Public domain.)
In 1800, Scottish military surgeon and chemist William Cruickshank (born circa 1740 or 1750, died 1810 or 1811) identified carbon monoxide as a compound containing carbon and oxygen.
(Born circa 1740/1750, died circa 1810/1811) (Courtesy of Wikimedia Commons. Public domain. Edited by Dr. Douglas J Lanska.)
Early concepts of the pathophysiology of carbon monoxide poisoning. German physician and physiologist Johann Joseph Dömling (1771-1803) in 1803 and English physician and geologist John Bostock (1773-1846) in 1804 suggested that blood returned to the heart loaded with carbon monoxide to subsequently be oxidized to carbon dioxide in the lung prior to exhalation.
Lithograph (1836) by WD Drummond after J Partridge. (Courtesy of the Wellcome Collection, London, England. Creative Commons Attribution 4.0 International License, https://creativecommons.org/licenses/by/4.0/deed.en.)
A half-century later, in 1854, Adrien Chenot (1803-1855) similarly suggested that carbon monoxide could remove oxygen from the blood and be oxidized within the body to carbon dioxide; sadly, Chenot died suddenly and unexpectedly in November 1855 after falling out of a window, apparently due to disorientation and nausea from experimenting with carbon monoxide poisoning.
In 1865, German-Swiss microbiologist Theodor Albrecht Edwin Klebs (1834-1913) described clinical and pathologic findings in rats exposed to carbon monoxide (62).
(Source: US National Library of Medicine via Wikimedia Commons.)
The interaction of carbon monoxide and hemoglobin. In 1857, French physiologist Claude Bernard (1813-1878) showed that carbon monoxide produces hypoxia by reversible combination with hemoglobin (11). In his memoirs, beginning in 1846 and published in 1857, Bernard notably concluded that carbon monoxide "prevents arterial blood from becoming venous."
Lithograph by Alexandre Laemlein (1813-1871). (Source: Bibliothèque interuniversitaire de Santé, Paris. Licence Ouverte 1.0, https://en.wikisource.org/wiki/Open_Licence_v1.0. Illustration restored by Dr. Douglas J Lanska.)
In 1858, German physiologist and chemist Felix Hoppe-Seyler (1825-1895) independently published similar conclusions to Bernard’s and also developed the first analytical method to detect carboxyhemoglobin. The first quantitative analysis method for carbon monoxide poisoning was developed by German public health physician Josef von Fodor (1843-1901) in 1880.
German physiologist and chemist Felix Hoppe-Seyler (1825-1895)
(Source: Wikimedia Commons. Public domain.)
German public health physician Josef von Fodor (1843-1901)
(Unknown author. Public domain. Photograph restored and edited by Dr. Douglas J Lanska.)
The strong affinity of carbon monoxide for hemoglobin, first suspected by Bernard, was confirmed by Scottish physician and physiologist John Scott Haldane (1860-1936) in 1895 (43; 44).
(Source: Corbis Archives via Wikimedia Commons. Public domain.)
Haldane showed that rats survived carbon monoxide poisoning when placed in oxygen at a pressure of two ATA (ATA means a pressure reading in technical atmosphere units ["at"], which are referenced to a perfect vacuum [absolute]). Haldane suggested that introducing oxygen to organisms subjected to carbon monoxide poisoning might improve the condition (43; 44), which he elaborated on in subsequent publications (44; 45; 47; 46).
In 1896, in an extremely influential report, Haldane presented his assessment of the causes of death in colliery explosions (ie, explosions in coal mines) (46). In what was then a very novel finding, Haldane concluded that most of the deaths in several devastating British mine explosions were attributable to carbon monoxide poisoning and not asphyxia from inadequate oxygen or traumatic effects of the explosions (47). In the only color plate in his official report, Haldane contrasted the color of a solution of normal blood, normal blood shaken with coal gas (containing a mixture of hydrogen, methane, carbon monoxide, and ethylene), and the blood of one of the fatalities; the progressively saturated red color was due to increasing content of carboxyhemoglobin.
A solution of normal blood (top), normal blood shaken with coal gas (containing a mixture of hydrogen, methane, carbon monoxide, and ethylene) (middle), and the blood of one of the fatalities of a coal mine explosion in Britain...
Subsequently, in 1912, the binding of hemoglobin and carbon monoxide was described in more detail by British physiologist Claude Gordon Douglas (1882-1963), JS Haldane, and Haldane's son, John Burdon Sanderson Haldane (nicknamed "Jack" or "JBS") (28). They constructed hemoglobin-carbon monoxide dissociation curves, illustrating how the amount of inspired oxygen is related to the saturation of hemoglobin with carbon monoxide.
JBS Haldane, circa 1937, pictured in front of a poster of the Spanish Republican 5th Regiment
(Source: Biblioteca Virtual de Defensa of the Spanish Government via Wikimedia Commons. Creative Commons CC0 1.0 Universal Public Domain Dedication [CC0].)
Dissociation curves of carbon monoxide-hemoglobin in the presence of air (20.9% O2) at a temperature of 38 degrees C
Although the curve for each individual is a rectangular hyperbola, the percentage saturation with a given percentage of carbon monoxide varies for different individuals and across species. However, the dissociation curves are n...
Dissociation curves of carbon monoxide-hemoglobin in the presence of a constant percentage of carbon monoxide and varying percentage of oxygen at atmo...
The points determined lie on the rectangular hyperbolas drawn through them until the dotted portions of the curves are reached for mice with very low percentages of oxygen and carbon monoxide. "The existence of the hump points ...
Dissociation curves of carboxy-hemoglobin in absence of oxygen, at 38 degrees C and with various pressures of CO2
The different curves are almost identical if the scale on which the abscissae of each are plotted is altered by a suitable constant. Thus, the effect of varying proportions of CO2, (and presumably of acidity or alkalinity in ge...
Haldane and colleagues found that when a solution of hemoglobin (enclosed in red blood corpuscles or free) is saturated in the presence of a gas mixture containing oxygen and carbon monoxide, the ratio of oxyhemoglobin to carboxy-hemoglobin is proportional to the relative partial pressures of oxygen and carbon monoxide but varies across individuals and species. The ratio is not altered by the presence of CO2 or of reduced hemoglobin, nor by dilution, but is appreciably altered by temperature.
In 1927, JBS Haldane further determined that carbon monoxide not only disrupts hemoglobin's oxygen-carrying capabilities but also poisons specific tissues (28).
Central nervous system complications of carbon monoxide poisoning. In the 1920s, particularly in Germany, Hungary, and the United States, carbon monoxide was linked to preferential damage to the internal segment of the globi pallidi, with a range of accompanying neuropsychiatric and extrapyramidal motor manifestations (101; 96; 93; 38).
From legitimate German papers issued 7/5/45. (Source: Leo Baeck Institute Archives.)
The classic bilateral lesions of the globus pallidus and diffuse subcortical demyelination were described and linked with "psychic akinesia" by the German Jewish neurologist Hermann O Pineas (1892-1969) in Berlin in 1924 (93).
Pathologic section from a fatal case of carbon monoxide poisoning reported by German physician and military hygienist Heinrich Ruge (1896-1977)
"Completely fatty small artery in a focus of softening. Details of the brain substance cannot be recognized anymore." Death occurred 10 days after poisoning. Staining with Sudan and hematoxilin (Sudan dyes, which are used to st...
Coronal section of the brain of a patient with carbon monoxide poisoning, showing necrotic areas in the globus pallidae and additional lacunes
(Source: Pineas H. Klinischer und anatomischer befund eines falles von co-vergiftung. Ein beitrag zur frage der psychomotorischen apraxie und verwandter bewegungsstörungen. Zeitschrift für die gesamte Neurologie und Psychiatrie...
"Stumbling block" commemoration for Dr. Hermann Pineas (1892) in front of Buxacher Strasse 6 in Memmingen, Germany
Photograph by Jakob Vogel on August 24, 2019. Creative Commons Attribution-Share Alike 4.0 International License, https://creativecommons.org/licenses/by-sa/4.0/deed.en.)
Pineas survived the Holocaust by hiding from Nazi persecutors under an assumed name with forged documents and twice escaping from the Gestapo in 1943. In 1946, after World War II ended, he immigrated to New York and became a clinical neurologist at a Veteran's Administration clinic from 1952 to 1969. Pineas's "psychic akinesia" resembles what was labeled subcortical dementia in the late 20th century and has since been labeled by various other terms, including "auto‐activation deficit," "hypoactive-hypoalert behavior," and "athymhormia" (69; 70; 71; 109; 68; 42; 27; 106; 72; 73; 41; 118). Psychic akinesia is due to bilateral lesions in the brainstem, basal ganglia, or the subcortical frontal lobes and is characterized by extreme passivity, apathy, blunted affect, and a profound generalized loss of self-motivation that are reversed by external stimulation.
Carbon monoxide poisoning was linked with parkinsonism by American neuropsychiatrist Roy R Grinker (1900-1993), then an attending neurologist at Cook County Hospital in Chicago (38).
American neuropsychiatrist Roy R Grinker (1900-1993)
WWII-era photograph of Lt. Col. Grinker. In World War II Grinker served at the US Army Medical Corps in North Africa, where with John P Spiegel he wrote the book Men Under Stress. Photograph cropped and edited by Dr. D...
Weigert-stained coronal brain section showing the beginning of the necrotic area of the right pallidum (n.) and the flecks of demyelination in the dee...
Abbreviations: cc., corpus callosum; Comm. ant., anterior commissure; n, necrotic area of pallidum. (From: Grinker R. Parkinsonism following carbon monoxide poisoning. J Nerv Ment Dis 1925;18:16.)
Grinker received his MD degree from Rush Medical College in 1921 and then spent a year in Europe before returning to the United States. In 1933, he returned to Europe for psychoanalytic training with Sigmund Freud. Most of his later career focused on psychiatry.
Selected 20th-century events. On his second Antarctic expedition in 1934, American naval officer and explorer Richard E Byrd (1888-1957) spent 5 winter months alone operating a meteorological station, "Advance Base," from which he narrowly escaped with his life after suffering carbon monoxide poisoning from a poorly ventilated stove. This expedition is described in Byrd's autobiography, Alone (1938).
(Courtesy of the US Library of Congress. Public domain.)
The effectiveness of hyperbaric oxygen therapy in experimental carbon monoxide poisoning in dogs and guinea pigs was demonstrated in 1942 (31). In 1960, hyperbaric oxygen therapy was first used successfully in treating human cases (107).
As a counterpoint to the improved ability to resuscitate and manage victims of carbon monoxide poisoning, carbon monoxide was also used as a method of killing. The Nazis first began using poison gas for mass murder in December 1939, when an SS Sonderkommando unit used carbon monoxide for this purpose. In the 1990s, medical suicide advocate and pathologist Jack Kevorkian (1928-2011) used carbon monoxide as a euthanasia agent.
National Press Club, Washington, DC on July 29, 1996. (Source: Kingkongphoto and www.celebrity-photos.com, https://www.flickr.com/people/362770 35@N06, from Laurel, Maryland. Creative Commons Attribution-Share Alike 2.0 Generic...
A physiological role for carbon monoxide? Carbon monoxide is produced in small amounts endogenously during the catabolism of heme, resulting in the coproduction of biliverdin and iron. Carbon monoxide is a signaling molecule that shares some chemical and biological properties with nitric oxide and is a mediator in the autonomic nervous system. Actions of carbon monoxide in the nervous system, thus, range from the physiological to the pathological.