medicina Review The History of Carbon Monoxide Intoxication Ioannis-Fivos Megas 1 , Justus P. Beier 2 and Gerrit Grieb 1,2,* 1 Department of Plastic Surgery and Hand Surgery, Gemeinschaftskrankenhaus Havelhoehe, Kladower Damm 221, 14089 Berlin, Germany; fi[email protected] 2 Burn Center, Department of Plastic Surgery and Hand Surgery, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany; [email protected] * Correspondence: [email protected] Abstract: Intoxication with carbon monoxide in organisms needing oxygen has probably existed on Earth as long as fire and its smoke. What was observed in antiquity and the Middle Ages, and usually ended fatally, was first successfully treated in the last century. Since then, diagnostics and treatments have undergone exciting developments, in particular specific treatments such as hyperbaric oxygen therapy. In this review, different historic aspects of the etiology, diagnosis and treatment of carbon monoxide intoxication are described and discussed. Keywords: carbon monoxide; CO intoxication; COHb; inhalation injury 1. Introduction and Overview Intoxication with carbon monoxide in organisms needing oxygen for survival has probably existed on Earth as long as fire and its smoke. Whenever the respiratory tract of living beings comes into contact with the smoke from a flame, CO intoxication and/or in- Citation: Megas, I.-F.; Beier, J.P.; halation injury may take place. Although the therapeutic potential of carbon monoxide has Grieb, G. The History of Carbon also been increasingly studied in recent history [1], the toxic effects historically dominate a Monoxide Intoxication. Medicina 2021, 57, 400. https://doi.org/10.3390/ much longer period of time. medicina57050400 As a colorless, odorless and tasteless gas, CO is produced by the incomplete combus- tion of hydrocarbons and poses an invisible danger. CO enters the human body through the Academic Editors: Lars P. Kamolz inhalation of flue gases and can cause tissue hypoxia due to its affinity for the hemoglobin and Bernd Hartmann molecule, i.e., about 240 times higher than that of oxygen [2]. The oxygen is replaced and carboxyhemoglobin (COHb) is formed [3]. Organs that have a high oxygen demand Received: 24 March 2021 and thus depend on high blood flow can be severely affected [4]. For example, due to its Accepted: 19 April 2021 affinity for myoglobin, which is also 60 times greater than that of oxygen, the replacement Published: 21 April 2021 of oxygen leads to cardiac depression and hypotension [5]. The exact pathophysiological mechanism is not yet fully understood. However, the toxic effect is attributed to the binding Publisher’s Note: MDPI stays neutral of CO to cytochrome oxidase and the inhibition of the electron transport chain [6]. with regard to jurisdictional claims in Intoxication with CO causes thousands of deaths each year, as shown by a large published maps and institutional affil- number of the most recent studies published to date [7–9]. A brief overview of symptoms iations. caused by CO poisoning includes nausea (40%), headache (46%), dyspnea (20%) and tachycardia (41%). Many patients also complain of dizziness and vomiting [9,10]. The diagnosis of CO intoxication involves several parameters. The basis is the measure- ment of the percentage of COHb, which can be detected by arterial blood gas examination. Copyright: © 2021 by the authors. Alternatively, non-invasive CO-oximetry can be performed, especially in a preclinical Licensee MDPI, Basel, Switzerland. setting [11]. Using these techniques, highly elevated values can be measured that differ This article is an open access article greatly from the normal ratio of carboxyhemoglobin to hemoglobin of 2–3% in non-smokers distributed under the terms and and 5-9% in smokers [12]. However, this basic diagnosis must be supported, especially conditions of the Creative Commons in severe cases, by further investigations such as thorough clinical examination, different Attribution (CC BY) license (https:// laboratory markers and radiological diagnostics [13–15]. creativecommons.org/licenses/by/ 4.0/). Medicina 2021, 57, 400. https://doi.org/10.3390/medicina57050400 https://www.mdpi.com/journal/medicina Medicina 2021, 57, x FOR PEER REVIEW 2 of 7 Medicina 2021, 57, 400 2 of 7 2. Literature Research 2.The Literature literature Research search for this review was conducted with PubMed and Google Scholar using theThe following literature keywords: search for this “carbon review monoxide was conducted intoxication with PubMed history”, and Google“inhalation Scholar injury history”using and the following “burns history”. keywords: In “carbon addition, monoxide we cross-checked intoxication history”, reference “inhalation lists from injury eligible publicationshistory” and and “burns relevant history”. review In articles addition, to we identify cross-checked additional reference studies. lists Our from search eligible in the relevantpublications literature and revealed relevant review38 PubMed articles entries to identify up to additional the year 1945, studies. about Our 1850 search entries in the from 1946relevant to 1975, literature about 2035 revealed entries 38 PubMed from 1976 entries to 2000 up to and the year the 1945,current about literature 1850 entries from from 2001 to 1946 to 1975, about 2035 entries from 1976 to 2000 and the current literature from 2001 to 2020 has about 2564 entries. A time bar of the available publications on PubMed is shown 2020 has about 2564 entries. A time bar of the available publications on PubMed is shown in Figurein Figure 1. 1. 1000 900 800 700 600 500 400 publications 300 200 100 0 1900 1910 1920 1925 1929 1936 1945 1949 1953 1957 1961 1965 1969 1973 1977 1981 1985 1989 1993 1997 2001 2005 2009 2013 2017 2021 year Figure 1. A time bar of the publications on Co intoxication available on PubMed across time. Figure 1. A time bar of the publications on Co intoxication available on PubMed across time. Further, the search in PubMed revealed that there are some publications concerning the reproduction of burn medicine in antiquity [16,17] but none dealing specifically with Further, the search in PubMed revealed that there are some publications concerning CO intoxication. This, however, could be observed for the first time in the early 20th the centuryreproduction [18]. of burn medicine in antiquity [16,17] but none dealing specifically with CO intoxication. This, however, could be observed for the first time in the early 20th cen- tury3. [18]. 1900 to 1945 A total of 38 PubMed entries dealing with CO intoxications could be found in the 3. 1900period to 1945 up to 1945. The first published article from 1906 involved animal experiments. The authorsA total Nasmith of 38 PubMed and Graham entries investigated dealing with the hematology CO intoxications of carbon could monoxide be found poison- in the ing [18]. The methodology of their experiments is described in the following paragraph: period up to 1945. The first published article from 1906 involved animal experiments. The authors TwelveNasmith guinea and pigs Graham were taken, investigated six males and the six hematology females, and of placed carbon in two monoxide cages in the poisoning [18]. Thegas methodology chamber after makingof their careful experiments estimations is ofdescribed the white andin the red following blood corpuscles paragraph: and haemoglobin. Gas was then allowed to mix with the air drawn through the chamber until Twelvethe mixture guinea waspigs of were such taken, a strength six thatmales 250/0 and of si thex females, haemoglobin and ofplaced the guinea-pigs in two cages was in the gas chambersaturated after with making carbon careful monoxide. estimations of the white and red blood corpuscles and haemo- globin.The Gas authors was discoveredthen allowed that to carbonmix with monoxide the air drawn prevents through the normal the chamber supply until of oxygen the mixture to thewas tissue of such and thusa strength disrupts that the 250/0 metabolism of the haem of cells.oglobin They concludedof the guinea-pigs a massive was toxic saturated effect of with CO.carbon The guineamonoxide. pigs that lived constantly in a diluted carbon monoxide atmosphere during thisThe experiment authors discovered showed a reduced that carbon oxygen monoxi transportde capacityprevents of the the normal blood. However, supply of their oxygen to theorganisms tissue and were thus able disrupts to compensate the metaboli for the lacksm ofofoxygen cells. They by increasing concluded the hemoglobina massive toxic concentration and the number of erythrocytes. Furthermore, they found that the effect of effect of CO. The guinea pigs that lived constantly in a diluted carbon monoxide atmos- carbon monoxide on increasing the number of erythrocytes was similar to the effect of high pherealtitudes during [18 this]. experiment showed a reduced oxygen transport capacity of the blood. However, their organisms were able to compensate for the lack of oxygen by increasing the hemoglobin concentration and the number of erythrocytes. Furthermore, they found that the effect of carbon monoxide on increasing the number of erythrocytes was similar to the effect of high altitudes [18]. Medicina 2021, 57, 400 3 of 7 Another article from this period described the problems of military mining in cases when explosive charges do not detonate completely and continue to burn. Thus, very highly concentrated CO vapors were produced, which could have devastating consequences in a narrow mine [19]. The symptoms of CO