Poul Astrup

Oxygen Affinity and Acid-Base Status of Human Blood during Exposure to Hypoxia and Carbon Monoxide

In eight subjects exposed to hypoxia at high altitude the oxyhemoglobin dissociation curve was shifted to the right, the half saturation oxygen tension at pH 7.40 being changed from 26.7 to 30.2 mm Hg on the average. The decreased affinity of hemoglobin for oxygen appeared within 12 hours after exposure to hypoxia. The shift was confirmed in short exposure experiments using simulated high altitude in a low pressure chamber. At prolonged carbon monoxide exposure the expected shift of the oxygen dissociation curve to the left occurred, but no adaptive changes were found. The physiological implication of these differences are discussed. It is suggested that the rapid shift to the right at high altitude may be a physiological regulation.

Enhancing influence of carbon monoxide on the development of atheromatosis in cholesterol-fed rabbits

Summary Twenty-four rabbits were fed Altromin-K® plus 2 % cholesterol. Twelve animals were exposed to small concentrations of carbon monoxide and 12 animals to room air. The following observations were made: (1) The degree of visible aortic atheromatosis and the content of total cholesterol in the aortic tissue was significantly higher in the rabbits exposed to carbon monoxide than in the controls. (2) In about 3/4 of the carbon monoxide exposed rabbits the hearts displayed macroscopic focal degenerative changes and scattered haemorrhages. Only one animal in the control group showed similar changes. (3) Microscopic examinations supported the macroscopic findings, as the vascular changes and their sequelae were significantly more pronounced in the carbon monoxide exposed group. (4) The underlying biochemical and physiological mechanisms are discussed and it is suggested that the differences observed in the two groups of animals may be explained by tissue hypoxia due to a carbon monoxide-induced displacement of the oxygen dissociation curve to the left, in combination with a decreased activity of certain enzymes inhibited by carbon monoxide. (5) The relation between the experimental findings and the demonstration of often very high concentrations of carboxyhaemoglobin in smokers with cardiovascular diseases in comparison to healthy smokers is briefly discussed.

EFFECT OF MODERATE CARBON-MONOXIDE EXPOSURE ON FETAL DEVELOPMENT

Abstract The effect of moderate carbon-monoxide exposure (180 p.p.m. and 90 p.p.m. carbon monoxide in atmospheric air) on fetal development was studied in rabbits. Exposure to 180 p.p.m. carbon monoxide (16-18% carboxyhaemoglobin) during pregnancy resulted in a 20% decrease of birth-weight, and a neonatal mortality of 35% as against 1% in the control group. Exposure to 90 p.p.m. carbon monoxide (8-9% carboxyhaemoglobin) had a less pronounced effect. In women there was a negative correlation between birth-weight and carboxyhaemoglobin concentration (p

Enhancing influence of arterial hypoxia on the development of atheromatosis in cholesterol-fed rabbits

Summary Twenty-four rabbits were fed standard rabbit pellets plus 2 % cholesterol. Twelve animals were exposed to about 10 % oxygen (atmospheric air + nitrogen) and 12 animals to 21 % oxygen (atmospheric air). The following observations were made: (1) The degree of visible aortic atheromatosis and the aortic content of total cholesterol and triglycerides were significantly higher in the hypoxic rabbits, while no changes were seen in aortic phospholipids. (2) In most of the hypoxic rabbits the hearts displayed macroscopic infarct-like areas and petechiae. None of the controls showed similar changes. (3) Microscopic examinations supported the macroscopic findings, as the vascular changes and their sequellae were far more pronounced in the hypoxic group. (4) The underlying biochemical and physiological mechanisms are discussed, and it is suggested that the increased arterial accumulation of lipids is caused by an increased endothelial permeability.

History of blood gas analysis. VI. Oximetry

Oximetry, the measurement of hemoglobin oxygen saturation in either blood or tissue, depends on the Lambert-Beer relationship between light transmission and optical density. Shortly after Bunsen and Kirchhoff invented the spectrometer in 1860, the oxygen transport function of hemoglobin was demonstrated by Stokes and Hoppe-Seyler, who showed color changes produced by aeration of hemoglobin solutions. In 1932 in Göttingen, Germany, Nicolai optically recorded the in vivo oxygen consumption of a hand after circulatory occlusion. Kramer showed that the Lambert-Beer law applied to hemoglobin solutions and approximately to whole blood, and measured saturation by the transmission of red light through unopened arteries. Matthes in Leipzig, Germany, built the first apparatus to measure ear oxygen saturation and introduced a second wavelength (green or infrared) insensitive to saturation to compensate for blood volume and tissue pigments. Millikan built a light-weight car “oximeter” during World War II to train pilots for military aviation. Wood added a pneumatic cuff to obtain a bloodless zero. Brinkman and Zijlstra in Groningen, The Netherlands, showed that red light reflected from the forehead could be used to measure oxygen saturation. Zijlstra initiated cuvette and catheter reflection oximetry. Instrumentation Laboratory used multiple wavelengths to measure blood carboxyhemoglobin and methemoglobin is cuvette oximeters. Shaw devised an eight-wavelength ear oximeter. Nakajima and coworkers invented the pulse oximeter, which avoids the need for calibration with only two wavelengths by responding only to the pulsatile changes in transmitted red and infrared light. Lübbers developed catheter tip and cuvette fiberoptic sensors for oxygen tension, carbon dioxide tension, and pH.

ULTRASTRUCTURAL INTIMAL CHANGES IN THE RABBIT AORTA AFTER A MODERATE CARBON MONOXIDE EXPOSURE

Abstract 1. (1) Eight rabbits were fed a normal diet and placed in exposure chambers. Four were exposed to 0.018 vol. % carbon monoxide for 2 weeks, while the other 4 served as controls and were exposed to atmospheric air. At the end of the study tissue from arch and thoracic aorta was taken for transmission and scanning electron microscopy. 2. (2) The luminal aortic coats of the experimental animals showed pronounced changes, characterized first of all by a severe edematous reaction with extensive swelling, formation of subendothelial blisters, and plaque formation. Furthermore, the myointimal cells showed vacuolation and occasionally the endothelial cells showed severe degeneration with cytolysis and condensation. Apart from actual plaque formation, the surface structures were markedly swollen and irregular. Occasionally spotty or streaky lesions occurred, where the normal folding architecture had changed into a characteristic “cobblestone-like” picture formed by protruding, grossly edematous endothelial cells. 3. (3) The results support earlier findings of toxic effects of low concentrations of carboxyhaemoglobin on the arterial walls, thereby provoking increased endothelial permeability and formation of edema, leading to changes indistinguishable from early atherosclerosis.

REVERSAL OF RABBIT ATHEROMATOSIS BY HYPEROXIA

Summary Twenty-four rabbits were fed standard rabbit pellets plus 2 % cholesterol. Twelve animals were exposed for 10 weeks to 28 % oxygen (atmospheric air + oxygen) and 12 animals to 21 % oxygen (atmospheric air). The degree of visible aortic atheromatosis and the aortic content of total cholesterol, phospholipids and triglycerides were significantly lower in the hyperoxic rabbits. Microscopic examinations supported the macroscopic findings.

Effects of Carbon Monoxide on Myocardium Ultrastructural Changes in Rabbits After Moderate, Chronic Exposure

Sixteen rabbits were placed in exposure chambers: eight were continuously exposed to 180 ppm of carbon monoxide and eight were exposed to atmospheric air for 2 weeks. The myocardial ultrastructure of all the rabbits was examined. In rabbits exposed to carbon monoxide, local areas of partial or total necrosis of the myofibrils and degenerative changes of the mitochondria were found. Extra- and intracellular edema, increases in the number of ribosomes and lipofuscin granules, and reparative fibrotic changes also occurred. Varying degrees of injury were noted in the blood vessels. Capillary edema, but never total stenosis, was seen in some areas. Stasis and occasional small perivascular hemorrhages were typical on the venous side; on the arterial side the characteristic picture was one of endothelial swelling, formation of subendothelial edema, and degenerative changes of the myocytes. The present study supports the hypothesis that chronic exposure to low levels of carboxyhemoglobin can produce myocardial damage and account for the increased risk of myocardial infarction and sudden death seen in heavy cigarette smokers.

Oxygen Affinity of Hemoglobin in Patients with Cardiovascular Diseases, Anemia, and Cirrhosis of the Liver

The partial pressure of oxygen corresponding to the 50 per cent oxyhemoglobin level of hemoglobin was determined in normal subjects and patients with cardiovascular diseases, anemias, and cirrhosis of the liver. Patients with cardiovascular diseases who did not smoke exhibited no alterations in the T50 value when compared to normal subjects. When T50 values of patients who smoked were corrected for the presence of carboxyhemoglobin in the blood, there were no differences from the normal smoking subjects T50 values similarly corrected.Carboxyhemoglobin values of cardiovascular disease patients who smoked were significantly higher than normal smokers values.Patients with anemias and cirrhosis exhibited a lower affinity for oxygen by hemoglobin than normals.

EFFECTS OF CARBON MONOXIDE EXPOSURE ON THE ARTERIAL WALLS

During discussions on the relation between tobacco smoking and the development of arteriosclerosis the attention has for many years been focused on the influence of nicotine on the cardiovascular system, whereas the CO in tobacco smoke has not been considered to have any pathogenetic importance. In animal experiments, moreover, it has not been possible to prove an atherogenic effect of nicotine by itself. In our Department at Rigshospitalet the finding of high concentrations of carboxyhemoglobin, in especially young smokers with obliterating arterial diseases, led to the initiation of experimental animal investigations on the significance of CO exposure in the development of arteriosclerosis. An injurious effect on the vascular system by even small concentrations of carboxyhemoglobin maintained for some weeks was demonstrated, thereby underlining the definite possibility of CO in tobacco smoke as an increased risk for smokers to develop arteriosclerosis, a possibility which, so far, had been disregarded. The investigations were initiated by the findings of oxyhemoglobin dissociation curves that were displaced to the left in many young smokers with peripheral or cardial arteriosclerotic Subsequent investigation^^.^ showed that the displacements were caused by high concentrations of carboxyhemoglobin in the blood, even after moderate smoking, often as high as 10 to 15 and up to 20%? Similar high values have also been reported by other investigator^.^ This led to animal experiments for evaluating the possibility of a connection between either the increased oxygen affinity or the high carboxyhemoglobin concentration and the vascular injuries. We thus constructed airtight chambers in which we placed rabbit cages, through which we could introduce various gas mixtures. These were made by mixing atmospheric air with CO, oxygen, and nitrogen, respectively. For the various series we have used different techniques described in detail else~ h e r e . 6 ~ A grouping of some of the main results is shown in TABLE 1, in which it seems that the cholesterol content of aorta in cholesterol-fed animals continuously exposed to CO for ten weeks (15% carboxyhemoglobin for eight weeks, 30% the last two weeks), on an average, was 2.5 times higher than in the control animals, which had not been exposed to CO, but which were fed cholesterol. By intermittent exposure, eight hours a day for ten weeks, to a CO gas mixture leading to 20% carboxyhemoglobin concentration, the experimental animals obtained as much as five times higher aortic cholesterol concentrations than did the control animals. In another series of experiments we exposed animals to 10% oxygen for eight weeks and obtained 3.5 times higher cholesterol concentrations in aorta walls from the experimental group than from the control group. If, on the other hand, the breathing air contained 28% oxygen, the content of cholesterol dropped to approximately half the concentration of the control animals. Macroscopically as well as microscopically there was no difference between the arterial lesions in animals exposed to CO and the animals exposed to hypoxia. Macroscopically it was easy to distinguish between the aortas from the exposed animals and from the control animals by the number and size of plaques. Similarly, the microscopic changes were more pronounced in the experimental animals, characterized by a marked lipid accumulation in intima and subintima. Also, without