Neuroscience & Biobehavioral Reviews, Vol. 12, pp. 311-314. o Pergamon Press plc, 1988. Printed in the U.S.A. 0149-7634/88 $3.00 + .00

Carbon Monoxide Studies at High Altitude

J. J. M c G R A T H

Department o f Physiology, School o f Medicine Texas Tech University Health Sciences Center, Lubbock, TX 79430

McGRATH, J. J. Carbon monoxide studies at high altitude. NEUROSCI BIOBEHAV REV 12(3/4)311-314, 1988.--1n high altitude areas, ambient carbon monoxide (CO) concentrations are rising because of the increasing number of new residents and tourists, and their concomitant use of motor vehicles and heating appliances. There are, however, compara- tively few studies of the acute or chronic physiological effects that may be caused by inhaling CO at high altitude. There are data supporting the concept that the effects of breathing CO at high altitude are additive, and data suggesting that the effects may be more than additive. Visual sensitivity and flicker fusion frequency are reduced in humans inhaling CO at high altitude. One provocative study suggests that the increase in coronary capillarity seen with chronic altitude exposure may be blocked by CO. We exposed male, laboratory rats for 6 weeks to 100 ppm CO, 4676 m (15,000 ft) simulated high altitude (SHA), and CO at SHA. SHA increase hematocrit ratio (Hct) and fight ventricle weight, but decreased body weight. CO increased Hct and left ventricle weight. Our results indicate that 100 ppm CO does not exacerbate the effects produced by exposure to 4676 m altitude.

Carbon monoxide High altitude Hypoxia Air pollution Smoking Carboxyhemoglobin

PRECISE estimates of the number of people exposed to CO at high altitude are not readily available. However, more than 2.2 million people live at altitudes in excess of 1524 m (5000 ft) and countless tourists sojourn in high altitude areas during the summer and winter months (18). The effects of CO at altitude on human health is made complex because 1) Residents at altitude live in a state of hypoxemia, because the partial pressure of oxygen (pO._,) in the air is reduced. In Denver, CO the pO._, is 16% lower than it is at sea level. 2) CO I~inding to hemoglobin further reduces transportation of oxy- gen to the tissues, which intensifies the hypoxemia existing at altitude.

Moreover, there are several factors that tend to exacer- bate ambient CO levels at high altitude (I0). For example, in mountain recreational communities, automobile emissions are higher; even automobiles tuned for driving at 1646 m (5,280 ft) emit almost 1.8 times more CO when driven at 2494 m (8,000 ft). Automobiles tuned for sea level driving emit al- most 4 times more CO when driven at 8,000 ft. Furthermore, automobile emissions are increased by driving at reduced speeds along steep grades under poor driving conditions. Therefore, large influxes of tourists driving automobiles tuned for sea level conditions into high altitude resort areas may drastically increase pollutant levels in general, and CO levels in particular (18). In addition, population growth in mountain areas is concentrated along valley floors; this factor com- bined with the reduced volume of air available for pollutant dispersal causes pollutants, including CO, to accumulate in mountain valleys. Finally, heating devices (space heaters and fireplaces) used for social effect, as well as warmth, also contribute to CO emissions in mountain resort areas. As a result of these factors, the National Ambient Air Quality Standards (NAAQS) for CO of 9 ppm is exceeded fre-

quently in Denver, CO (altitude 1646 m) during the winter months (8).

COHb FORMATION

The effects of altitude on COHb formation can be pre- dicted from Haldane's first principle:

(COHb) pCO - M - -

(O~Hb) pO2

where COHb= blood concentration of carboxyhemoglobin O..,Hb= blood concentration of oxyhemoglobin pCO= partial pressure of CO in blood pO2= partial pressure of 02 in blood

M= Haldane Constant

According to this principle, a given pCO will result in a higher % COHb at altitude (where pO2 is reduced) than at sea level. Thus, Collier and Goldsmith (4) calculate that humans, exposed to 8 ppm CO will have equilibrium COHb levels of 1.4% at sea level and 1.8% at 3660 m (11,741 ft). Inter- estingly, these workers calculate an increase in COHb at altitude even in the absence of ambient CO (due to endoge- nous production of CO).

COMPARTIMENTAL SHIFTS

Studies by Luomanmaki and Coburn (12) suggest that CO may pose a special threat at altitude. These workers report that during hypoxia, in anesthetized dogs, CO shifts out of the blood and into the tissue. In experiments using 14CO,

311

312 McGRATH

they observed that radioactivity did not change when arterial oxygen tension increased from 50 to 500 ppm CO. However, 14CO activity decreased to 50% of control levels when arterial pO~ decreased below 40 mmHg; 14CO shifted back into the blood when arterial pO~ returned to normal. Because there was no significant difference between splenic and central venous 14CO radioactivity either before or after the 14CO shift, these workers excluded the possibility that the a4CO had been sequestered in the spleen.

Luomanmaki and Coburn also studied the shift of CO out of the blood during hypoxia by administering CO into a rebreathing system and measuring the rate at which blood COHb increased. They reasoned that if the partition of CO between vascular and extravascular stores remained con- stant, the increase in blood COHb should be proportional to the amount of CO administered. They found that COHb in- creased at a constant rate up to a saturation of 50%. With additional CO, there was a decrease in the rate at which COHb increased; this suggests that proportionally greater amounts of CO were entering the extravascular stores. At 50% COHb (corresponding to an arterial pO2 of 80 mmHg) the rate of COHb formation became nonlinear. Agostoni et al. (I) presented a theoretical model supporting these obser- vations; they developed equations predicting that decreasing venous pO,. causes CO to move out of the vascular com- partment and into skeletal and heart muscle. This increases the rate at which carboxymyoglobin (COMb) is formed in the tissues.

Thus, the available evidence suggests that CO moves into the extravascular compartment during hypoxemia, causing the COMb/COHb ratio to increase. During heavy smoking (COHb levels of 10%), as much as 30% of cardiac myoglobin may be saturated with CO (3). Presumably, cardiac myoglobin would be even more saturated with CO at altitude because of the attendant arterial hypoxemia.

CARDIOVASCULAR EFFECTS

There are studies comparing the cardiovascular responses to CO with those to altitude, but there are relative few studies of the cardiovascular responses to CO at altitude. Forbes et al. (7) reported that CO uptake increased during light activity at 4877 m (16,000 ft). The increased CO uptake was caused by altitude hyperventilation stimulated by de- creased arterial oxygen tension and not by diminished barometric pressure.

Pitts and Pace (20) reported that pulse rate increased in response to the combined stress of altitude and CO. The subjects were 10 healthy men who were exposed to simu- lated altitudes of 2182, 3117 and 4676 m (7,000, 10,000 and 15,000 fi) and inhaled 3,000 or 6,000 ppm CO to obtain COHb levels of 6 or 13%, respectively. The mean pulse rate during exercise and the mean pulse rate during the first 5 minutes after exercise were correlated with and increased with the COHb concentration and the simulated altitude. The authors stated that the response to a 1% increase in COHb level was equivalent to that obtained by raising a normal group of men 104 m (335 It) in altitude. However, this relationship was stated only for a range of altitudes from 2182 to 3117 m (7,000 to 10,000 ft) and for increases in COHb up to 13%.

Weiser et al. (21) studied the effects of CO on aerobic work at 1610 m (5165 ft) in young subjects inhaling 100% CO to achieve COHb levels of 5%. They reported that this level of COHb impaired work performance at altitude to the same extent as it did at sea level. Breathing CO during submaximal

TABLE 1 APPROXIMATE PHYSIOLOGICALLY EQUIVALENT ALTITUDES AT

EQUILIBRIUM WITH AMBIENT CARBON MONOXIDE CONCENTRATIONS*

Physiologically Equivalent Altitude Ambient Carbon at Actual Altitude of: Monoxide Concentration 5,000 1,524 10,000 3,048 (ppm) 0 ftt 0 mt ft m ft m

0 0 0 5,000 1,524 10,000 3,048 25 6,000 1,829 8,300 2,530 13,000 3,962 50 10,000 3,048 12,000 3,658 15,000 4,572

100 12,300 3,749 15,300 4,663 18,000 5,486

*National Research Council, 1977. tSea level.

exercise caused small but significant changes in cardiores- piratory function; the working heart rate increased and the postexercise left ventricular ejection time shortened, but not to the same extent as when filtered air was breathed. CO lowered the anaerobic threshold and, at work rates heavier than the anaerobic threshold, increased minute ventilation; the increased ventilation was caused by increased blood lactate.

PSYCHOPHYSIOLOGICAL EFFECTS

Most physiological data on the effects of combined CO- altitude exposure comes from psychophysiological studies, and it is from these studies that the concept of physiological equivalent altitudes is derived (Table 1).

McFarland et al. (15) reported that changes in visual sen- sitivity occur at a COHb concentration of 5% or at a simu- lated altitude of approximately 2438 m (8,000 ft). Later, McFarland (14) expanded on the original study and pointed out that a pilot flying at 1870 m (6,000 ft) breathing 0.005% CO in air is at an altitude physiologically equivalent to ap- proximately 3741 m (12,000 ft). McFarland states that the visual acuity test is so sensitive that even the effects of small quantities of CO absorbed from cigarette smoke are clearly demonstrable. The saturation of the blood with CO in sub- jects inhaling smoke from three cigarettes at 2338 m (7,500 ft) caused a loss of visual sensitivity equal to that occurring at 3117-3429 m (10,00(O11,000 ft). The initial report was con- firmed by Halperin et al. (9), who also observed that re- covery from the detrimental effects of CO on visual sensitiv- ity lagged behind elimination of CO from the blood.

Combined exposure to altitude and CO decreases flicker- fusion frequency (FFF), i.e., the critical frequency in cycles per second at which a flickerin~ light aooears to be steady (11). Whereas mild hypoxia [that occurring at 2805-3741 m (9,000--12,000 ft)] alone impairs FFF, COHb levels of 5-10% decrease the altitude threshold for onset of impairment to 1559-1870 m (5000--6000 ft).

The psychophysiological effects of CO at altitude are a particular hazard in high performance aircraft (6). Acute ascent to altitude increases ventilation via the stimulating effects of a reduced pO~ on the chemoreceptors. The increased ventilation causes a slight increase in blood pH and leftward shift in the oxyhemoglobin dissociation curve. Although such a small shift would probably have no physiological significance under normal conditions, it may take on physiological importance for aviators required to fly

CARBON MONOXIDE STUDIES AT HIGH ALTITUDE 313

TABLE 2 EFFECTS OF 18,000 ft ALTITUDE AND CO ON HEART WEIGHT/BODY WEIGHT RATIOS (HW:BW), HEMATOCRIT RATIOS (Hct), RIGHT (RVT) AND LEFT (LVT)

THICKNESS AND LEFT VENTRICULAR CAPILLARITY (LV CAPS)*

HW:BW Hct RVT LVT LV Caps ALT:CO (10 -a) (%) (ram) (ram) (/ram 2)

Ambient 2.4 +- 0.04 56 1.4 - 0.1 3.3 - 0.2 2293 ± 59 18K:0 3.6 -+ 0.08 84 2.1 - 0.1 3.9 - 0.2 3087 - 176 18K:50 3.5 - 0.15 81 2.1 ± 0.1 4.0 _ 0.2 2499 - 88 18K:I00 3.6 - 0.12 82 2.2 - 0.1 4.2 _ 0.3 2381 ± 88 18K:500 3.9 - 0.26 83 1.7 - 0.2 4.6 - 0.2 2617 ± 147

ANOVA <0.05 <0.05 <0.05 <0.05 <0.05

*From (13).

under a variety of operation conditions and to perform tedi- ous tasks involving a multitude of cognitive processes. The leftward shift of the oxyhemoglobin dissociation curve may be further aggravated by the persisting alkalosis caused by hyperventilation resulting from anxiety. The potential for this effect has been reported by Pettyjohn et al. (19), who reported that respiratory minute volume may be increased by 110% during final landing approaches requiring night vision devices. Thus, the hypoxia-inducing effects of CO inhalation would accentuate the cellular hypoxia caused by stress and altitude-induced hyperventilation.

CHRONIC STUDIES

There have been few studies of the long-term effects of CO at altitude. McGrath (16) exposed rats housed in altitude chambers for 6 weeks to l) ambient altitude, 2) ambient alti- tude + 100 ppm CO, 3) 4676 m (15,000 ft) simulated high altitude and 4) 100 ppm CO at 4676 m.

Four thousand six hundred seventy-six meters had no effect on left ventricle plus septum (LV+S), adrenal, spleen, or kidney weights, it did decrease body weights, and increase hematocrit ratios, as well as right ventricle (RV), total heart (HT) and pituitary weights. One hundred ppm CO has no effect on body weights, RV, HT, adrenal, spleen or kidney weights, but it did increase hematocrit ratios and LV+S weights. There was no significant interaction between alti- tude and CO on any parameter except kidney weight. The author concluded that although there was a tendency for hematocrit ratios, spleen weights and total heart weights to be elevated by combined CO-altitude exposure, the results were not significant and, in general, the effects produced by 4676 m altitude are not intensified by exposure to 100 ppm CO.

McDonagh et al. (13) studied cardiac hypertrophy and ventricular capillarity in rats exposed to 5611 m (18,000 ft) and 50, 100 and 500 ppm CO (Table 2). Coronary capillarity increased after exposure to 5611 m for 6 weeks, but this re- sponse was blocked by CO. Right ventricular thickness was increased by altitude, but was not increased further by CO. At 500 ppm CO the right ventricular hypertrophy was at- tenuated, but the results are uncertain due to the high mor- tality in this group.

Left ventricular thickness was also increased at 5611 m (18,000 ft) and increased further by CO. Because capillarity is reduced while ventricular thickness is increased with alti- tude plus CO, it is possible that the myocardium may be underperfused.

Cooperet al. (5) evaluated the effects of CO at altitude on the ECG and cardiac weights. Rats were exposed to a) am- bient (amb), b) ambient + 500 ppm CO (amb+CO), c) 4676 m (15,000 ft) (alt), and d) 4676 m + 500 ppm CO (alt+CO) for 6 weeks. COHb values were 36.2 and 34.1% in the arab+CO and alt+CO groups, respectively. Hematocrits were 54- + l, 77-+1, 68-+1 and 82-+1%, in the amb, arab+CO, ait and alt+CO groups, respectively.

In the amb+CO, alt and alt+CO groups, respectively, the mean electrical axis shifted 33.2 ° left, 300 right, and ! 16.4 ° right. HW/BW ratios were 2.6, 3.2, 3.2 and 4.0× 10 -3 in the amb, amb+CO, air and alt+CO groups, respectively. Whereas CO increased left ventricular weight and alt in- creased right ventricular weight, alt+CO increased both. ECG changes were consistent with changes in cardiac weight.

These results indicate that whereas CO inhaled at ambient altitude causes a left electrical axis deviation, CO inhaled at 4676 m exacerbates the well-known phenomenon of right electrical axis deviation.

CONCLUSIONS

Thus, while there are many studies comparing and con- trasting inhaling CO with exposure to altitude, there are relatively few reports on the effects of inhaling CO at alti- tude. There are data to support the concept that the effects of these two hypoxia-inducing experiences are at least additive. The data presented by Luomanmaki and Coburn (12) suggest that the effects of breathing CO at altitude may be more than additive. There are data that indicate decrements in visual sensitivity and flicker fusion frequency in subjects exposed to CO (COHb=5-10%) at altitude. When the Eisenhower Tunnel was constructed at 3429 m (l !,000 ft), there was con- cern for the hypoxia that would potentially result from the decreased partial pressure of O~. caused by altitude combined with CO from smoking and automobile exhaust. Based on a study by Miranda et al. (17), it was recommended that CO concentrations in the tunnel be kept below 25 ppm.

There are even fewer studies of the long-term effects of CO at altitude. These studies generally indicate few changes at CO concentrations below 100 ppm and altitudes below 4676 m (15,000 ft). A provocative study by McDonagh et al. (13) suggests that the increase in ventricular capillarity seen with altitude exposure may be blocked by CO.

314 M c G R A T H

ACKNOWLEDGEMENTS I wish to thank Debbie Parker for reviewing and typing this

manuscript. "'Research described in this article is conducted under contract to the Health Effects Institute (HEI), an organization that supports the conduct of independent research and is jointly funded by the United States Environmental Protection Agency (EPA) and automotive manufacturers. Publication here implies nothing about the view of the contents of HEi or its research sponsors. HEI's

Health Review Committee may comment at any time and will eval- uate the final report of the project.Additionally, although the work described in this document has been funded in part by the U.S. Environmental Protection Agency under assistance agreement X808859 with HEI, the contents do not necessarily reflect the view and policies of the Agency; nor does mention of trade names or commercial products constitute endorsement or recommendatmn for use."

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