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Interactions of carbon monoxide and hemoglobin at high altitude
Armosphmc
Ewrronm~nr
Vol.
17.
No
4. pp.
723-128.
0004-5981~83/040723& $03.00~0 C 1983 Pergamon Press Ltd.
1983
Prmted in Great Bnlam
INTERACTIONS OF CARBON MONOXIDE HEMOGLOBIN AT HIGH ALTITUDE
AND
CLARENCE R. COLLIER and JOHN R. GOLDSMITH University
of Southern
California Medical Center, North State Street, Los Angeles, CA 90033, U.S.A. Ben Gurion University of the Negev, Beer Sheva, Israel
Abstract-The health risks to U.S. populations who are exposed to ambient carbon monoxide and live at altitudes (such as Denver, Salt Lake City and Albuquerque) were evaluated using a set of mathematical models. The assumption that a given increase in carboxyhemoglobin would require a more stringent volumetric air quality standard was tested. The results using the model predict that the 8-h or l-h standards adopted for sea level conditions need not be altered to protect individuals against health risks at altitude, if the standards are in volumetric terms. They would need to be reduced if the standards are left in gravimetric terms. If the guideline is to be based on a given decrement of oxygen tension, many other variables must be specified, but expected differences in ambient carbon monoxide have a small impact compared to the effect of altitude itself.
NOMENCLATURE CO Symbols vco SC0 SC0 (f) SC0 (0) [COHb] D,CO
pica FICO M 0, Symbols v02 MET SO, DLO,
[O,Hbl PAO, PC02
absence of 0, and for the combination of variables in the Roughton-Darling
rate of endogenous production of CO, ml min- ’ (STPD) “/,COHb of total Hb On saturation of Hb with CO at any time, 9, saturation of Hb with CO at timk t = 0 concentration of COHb as CO in blood, ml ml ’ (STPD) diffusing capacity for CO, ml min _ 1torr _ ’ (STPD) partial pressure of CO in humidified inspired air, torr volumetric fractional concentration of CO in dry inspired air, ppm ratio of CO affinity to O2 affinity for Hb
STPD
1
O2 consumption, I@ min- ’ (STPD) ratio of actual V02 to resting V02 (250 ml min- I) 5” 0,Hb of total Hb diffusing capacity for 0,, ml min- ’ torr- I (STPD) concentration of 0,Hb as O2 in blood, ml ml-’ partial pressure of alveolar 02, torr mean partial pressure lary O,, torr
of pulmonary
capil-
Other VA
ALT PB
PACO, WO, I VB
Hb R ew Y(P)
6)
equation refers to the condition under which the volume of a gas is measured, i.e. WC, 760 torr and dry.
alveolar ventilation, ml min- ’ (STPD) altitude above sea level, lo3 m barometric pressure, torr partial pressure ofC0, in alveolar gas, torr partial pressure of CO, in arterial blood, torr time, min blood volume, ml hemoglobin concentration in blood, g dl_ 1 respiratory exchange ratio of CO* output to O2 consumption e, base of natural logarithms raised to power of x the empiric relation between ~0, and SO, for normal human blood. The same relationship holds for (M)pCO and SC0 in 723
INTRODUCTION Because carbon monoxide (CO) competes with oxygen in binding to hemoglobin (Hb), it has long been recognized that ambient carbon monoxide levels should be controlled to safe levels to protect the health of individuals. This has been done by estimating the concentration and duration of exposure that will keep the carboxyhemoglobin (COHb) level of non-smoking adults living at sea level below 1.552 ‘i,. For instance, the Federal maximum standard for CO has been set at 10 mg m- 3 (9 ppm) for 8 h. Ambient CO levels usually have wide diurnal fluctuations and steady-state equilibrium standards have not been set. At high altitudes, six additional factors need to be considered as follows: (1) Combustion tends to produce more CO at altitude. (2) Ambient partial pressure of 0; (PO,) is reduced at altitude producing more COHb at same ambient CO partial pressure @CO). (3) The ambient air quality standards defined by EPA uses gravimetric concentration units mg mm3, independent of altitude. The ambient pC0 is proportional to the gravimetricconcentration, independent of altitude. (4) Commonly the standard is also cited in terms of parts per million (volumetric). At altitude the same number of ppm has a smaller gravimetric concentration and pC0 than it would at sea level. (5) If volumetric standards were used for CO, the reduction of&O with altitude would be proportional to the reduction of ~0,. Therefore, altitude should
724
CLARENCE
R.
COLLIER
have minimal effect on ambient CO-COHb relations. (6) Besides, the reduction of O2 carrying capacity, CO also increases the afinity of Hb for O2 as manifested in a leftward shift of the oxygen dissociation curve (ODC) and a decrease in half saturation ~0, (psO)_ This might be detrimental at sea level but may be at least partly beneficial at altitude. Because volumetric standards appear to be more useful at different altitudes, this paper which reports theoretical calculations will primarily use ppm and secondarily calculate mg mm 3 for comparison. The interactions of 0,, CO and Hb will be considered. It is estimated that approximately 2.2 million people live in the U.S. at altitudes over 1524 m. It is likely that any risk of CO at altitudes will be greater in unacclimatized newcomers or tourists than in residents. Denver, Colorado at 1610m has ambient CO levels which are equal to or greater than sea level cities. Federal and State officials have unofficially used volumetric concentration standards for Denver and other high altitude cities such as Colorado Springs, Albuquerque and Salt Lake City and have designated them as nonattainment areas for CO. In 1976, the States of California and Nevada adopted CO standards for the Lake Tahoe air basin at 1900 m which are more stringent than Federal standards. The 8-h standard adopted was 6 ppm which would be 5.5 mg mW3 at P, = 6a4 torr, 20°C. The 8-h standard for Lake Tahoe was calculated from the equation of Coburn, Forster and Kane (CFK) (1965) as the concentration of ambient CO that would raise the COHb from 0.5 “/, to 1.5 “/,,in an 8-h period. It has recently been found that an error was made in these computations. This paper aims to rectify the error and to expand the computations to include the equilibrium state and also the arterial 0, saturation (SO,) with combinations of ambient CO and altitude.
and
JOHN
R.
GOLDSMITH
ous CO production, barometric pressure, diffusing capacity for CO, alveolar ventilation, blood volume, mean capillary pOz and OzHb concentration. The equation is: v d[COHb] B
= VCOS
dt
Definitions and units of all symbols are given in the Nomenclature. The mathematical model used was constructed from seven interrelated quantitative relationships: (1) the CFK equation; (2) an equation linking PO,, pC0, 02Hb and COHb from Roughton and Darling (1944); (3) the empiric 0, dissociation curve (ODC) giving 0,Hb as a function of pOz; (4) the alveolar air equation linking arterial pCO,, PO,, alveolar ventilation and 0, consumption (VO,); (5) an empiric equation linking diffusing capacity to i/O,: (6) an empiric equation of barometric pressure as a function of altitude and (7) an equation relating the pC0, as a function of altitude and acclimatization. Actually, as explained below, the equation was simplified to a single constant for unacclimatized individuals at altitudes less than 3660 m. (1) The CFK equation (Coburn et al., 1965) is a differential equation of mass balance for CO. The parameters are ambient CO concentration, endogen-
[COHb]pcOz [O,Hb]M 1
$+--
1
P -47
L
-’
"A
(1)
If all the parameters are constant, this equation is an ordinary linear first order differential equation that has been solved by Coburn et al. The solution has been rearranged and scaled to give FICO in ppm. Also the [O,Hb] and [COHb] have been transformed in 7, saturation by multiplying by 104/(1.34*Hb) giving: lo6 FICO = __ P,-47
K(SCO(t) - ESCO(O)) _ Z PC0 1-E
(2) where
K = Z = W= E =
pcO,/(M * SO,) l/D,CO+(P,-47)/v, 104*K/1.34*Hb exp[-(W*t/(Z*
V,))].
(2) The Roughton-Darling derived from Haldane’s first:
[COHbl _ [OJbl
(1944) equation
M
was
PC0 ___
PO,
and second laws: [COHb]
=f(pO,
+ [O,Hb]
+ M pCO),
wherefis the empiric function of the ODC. These 2 laws are implicit from the empiric finding that in the absence of 02, the following relationship holds: [COHb]
METHODS
PICO -
=.f(MpCO).
The Roughton-Darling equation eliminates M and holds for all relations of CO and O2 with Hb. Here it is expressed in terms of “/ saturation:
sco+so,
=f[pO*(l
+%)I
(3)
(3) The empiric function used for the ODC was that of Severinghaus (1979): SOz = [234OO/(pO; + 150~0~) + l] -’ x 100. (4) (4) The alveolar air equation was used in two forms, one to calculate the alveolar PO,: pA0, and the other (STPD): t,=
= 0.2094 (P,-47)-pACO,/R to calculate
the alveolar
i/02R(PB-47)/pAC02.
(5) ventilation
(6)
Equation (5) is only an approximate equation, but it is considered sufficiently precise for the purpose of this model.
125
Interactions of carbon monoxide and hemoglobin at high altitude (5) The D,O,Pi/O, relation was approximated from a summary diagram of Forster (1964). The D,CO was obtained by division of D,O, by 1.23: D,CO
= 24.4+0.0578
VO,.
(7)
(6) The Ps-ALT relation was obtained by polynomial regression of data from Rahn and Fenn (1955): P, = 3.817 ALT’ - 89.60ALT + 760.
(8)
It is good from 0 to 3.66 km. (7) Rahn and Otis (1949) have shown that the unacclimatized subject does not change his pC0, when exposed to artificial altitudes in the laboratory. Therefore, the alveolar and arterial pC0, is defined as: pAC0,
= paC0,
= 38.
(9)
They also give figures for acclimatized subjects at a range ofaltitudes and for unacclimatized individuals at altitudes greater than 3660 m, but these were not used in this study. Assumptions
(1) pc0, = pA0, - 5. This relation for mean capillary pOz is strictly arbitrary. The value given is certainly too high at rest at sea level but is probably much closer to reality during work at altitude. A relationship based on D,O, was sought but could not be found. (2) paC0, = 38. This relation does probably not hold for unacclimatized subjects except in the laboratory. However, in reality, the pC0, will probably be lower. This would increase the ~0, and lower the COHb from that calculated. (3) R = 0.8. This relation will not hold for many exercise states. The usual increase in R with exercise would increase the ~0, and lower the COHb similar to hyperventilation. (4) Neither pH nor pC0, is changed at altitude, rest and exercise. This is probably not strictly true but most of the variation would be due to hyperventilation (see Assumption 2). (5) pc0, and SO, do not change during the dynamic step function calculations. This is a gross simplification. However, since the SC0 steps of interest are only l-1.5 yO, the drop in SOz will be roughly only the same magnitude. The SO2 used is that calculated for the end of the step which is the lowest it will be. The rate of entry of CO in the body will be greater than it actually would be if the correct SO, were used at all times. Therefore, this assumption and also Assumptions 2, 3 and 4 will cause any standards developed from them to be more stringent. A variable SO, was tested in two forward problems (0.551.5”/, and 0.5-3 ‘,(, X0) and found to produce an 8-h SC0 that was within 0.1 “/ of that found assuming a constant SO,. (6) M is constant. A value of 220 was used for these
computations. A value greater than this would produce more stringent standards and vice versa. Methods
for
calculation
of dynamic
8-h
and
l-h
standards
The rearranged CFK equation (2) formed the basis for these calculations. SC0 (0) was set to 0.5”,, and various values were used for SC0 (t). The value of FICO calculated is that of a step function constant from t = 0 to 8 h (or 1 h) that would produce the given SC0 at the end of the step. Using the SC0 at end of step and the alveolar ~0, which is a function only of altitude and pCOz (which is assumed constant). the SO2 for this point was calculated using Equations (3) and (4). This was done by an iterative algorithm which assumed an SO, and calculated a new one from the equations. The procedure was reiterated until convergence was obtained. As stated earlier, this value of SO2 was assumed to exist during the whole time period. The following parameter values were used in all cases examined: V, = 5500 ml, Hb = 15 g dl ‘, R = 0.8, M = 220, VCO = 0.007 ml min- ‘, pC0, = 38 torr. Various combinations *of the following assigned parameters were used: ALT = 0 to 3.6 km, i/O, ‘, SC0 at end of period = l-3 “<,, = 25tX1250mlmint = 60 or 480min. The equations were used in the following order: 8, 5, 6, 7, (3 and 4 iterated), 2.
Methodsfor
calculation
of equilibrium
standards
Coburn et al. (1965), have given an equation for the equilibrium state. This was transformed into a solution for FICO that will produce a given SC0 at each altitude: FICO = &[KSCO-ZI;CO].
(10)
B
This equation can be rearranged to give SC0 in terms of the endogenous and exogenous contribution: sco
=
FICo(PB47)+.: &o,
(11)
-- K
106K
The first term is the exogenous contribution and the second is the endogenous contribution. It was also found possible in the equilibrium state to obtain simultaneous explicit solutions for SC0 and SOz, given ALT, FICO and k’0,. Equation (11) can be solved for SC0 in terms of SO,: SC0
= G SO,
(12)
where G==
M
(FICO
(PB-47)10--6+Z
I’CO).
PC02
Since G also = SCO/SO,, written: SCO+SO,
Equation
=f[pO,(l
(4) can also be
+G)].
(13)
CLARENCE R. COLLIER and JOHN R. GOLDSMITH
726
The following explicit solutions can be obtained from (12) and (13):
sco=-
G ST
(14)
l+G
so, = ST-
SC0
where ST = SC0 f SO, from (13).
RESULTS
Table 1 gives sample results of calculations of the ambient CO volumetric concentrations that would be expected to produce given COHb saturations in 8 h and 1 h beginning at 0.5 ‘x COHb. The table gives only one level of activity VO, = 500 ml min- ’ or 2 METS. It can be seen that altitude has little effect on the loading of CO into the body under these conditions. The gravimetric standard was calculated for each case and would require a decrease of concentration of 60-707; in going from sea level to 3050 m. Figure 1 shows the effect of exercise on 8-h loading at various altitudes. Exercise obviously increases the CO load under these conditions, requiring a lower ambient CO, but altitude has little additional effect. Figure 2 shows the results of some of the computationsof the dynamic equilibrium state. It shows that under these conditions, altitude requires a modest decrease of ambient CO to produce the stated COkb concentration but exercise in this case decreases the stringency of ambient requirements. Exercise thus has the opposite effect of that seen in Fig. 1. It was postulated that this effect must be due to greater binding of endogenously produced CO as altitude increases. This was tested by use of Equation (11) and the results are shown in Fig. 3. The endogenous fraction is increased about 1.7 x by going from sea level to 3050m. This same fractional increase also holds if the subject has an elevated PC0 due to hemolytic anemia. The simultaneous equations (12)(14) for equilibrium were solved for ‘x COHb and ix OzHb for various combinations of ambient CO and altitude. The
Altitude,
km
Fig. 1. The ambient CO calculated according to Equation (2) at various altitudes that would raise the COHb from 0.5 to 1.5 % in 8 h in an unacclimatized subject. Each isopleth represents a given exercise level in METS. One MET represents a resting YOz of 0.25 I min. ‘. Other assumptions are given in the text. The ambient CO requirements are more stringent with exercise because of the larger ventilation. There is little change of ambient CO requirements at various altitudes. Ambient cot0 produce 15% COHb
I
I
I
I 0
i
I
05
I /
I
1
4
2
0
I5 Altftude.
I
8
6 Kft
E
/
10
I
25
I
3
km
Fig. 2. The ambient CO calculated by Equation (10) at various altitudes that would produce an equilibrium COHb of 1.5%. There is a substantial change with altitude especially at rest, and exercise decreases the stringency
Table 1. Volumetric ambient standards: estimated ambient CO for stated time period to produce stated COHb saturation from an original COHb of 0.5 % Unacclimatized. sedentary ( V02 = 500 ml mine ’ ) 8-h exposure 3050 m COHb at 8 h Sea level 1525 m 5.7 ppm 6.0 ppm 10.0 IO.I 14.3 14.2 18.6 18.4 1-h exposure
5.5 ppm 10.2 14.9 19.7
COHb at I h 1” 1,;
20.2 ppm 38.5
23.1 ppm 44.9
53.5 ppm 27.1
, 5.5
75.1 56.S
88.4 66.7
1/0 (” 1.5 2 2.5
--.-
106.2 79.8
Fig. 3. The fraction of COHb that was due to endogenous CO production was calculated by means of Equation ( t 11 and plotted for COHb = I ‘%,
Interactions Table 2. Calculated
of carbon
monoxide
Sea level
CO
0 wm 4 8 12 16
sedentary
% 0,Hb
Xl COHb
% 0,Hb
% COHb
0.20 0.8 1.4 2.1 2.7
97.3 96.8 96.2 95.6 95.1
0.26 0.9 1.6 2.3 2.9
93.6 93.0 92.5 91.9 91.4
0.35 1.1 1.8 2.5 3.2
3660 m
O$b
C&b
sedentary
orterlol
0,
(VOz-
500
I
I
5
10 Ambmt
Dynomvz equllibrlum
Amp
VO=05L/mln Y
I” 8
73.3 73.1 72.9 72.7 72.5
saturation ml/mm)
Altltuds Kft Km
700
IL
O&b
0.37 1.1 1.8 2.5 3.2
82.4 82.1 81.7 81.3 80.9
Eaulllbrium loo-
exposed to
( PO, = 500 ml min- t)
% COHb
results are given for fi0, = 500 ml min - ’ in Table 2 and in Figs 46. There is an increased % COHb with altitude even in the absence of ambient CO. The altitude effect is even greater in the presence of ambient CO as seen in Fig. 5. The effect of altitude on 9; OzHb is much greater than the decrement due to CO. This is particularly well seen in Fig. 6 where SAOz is plotted against FICO.
in humans
3050 m
1530m
727
at high altitude
equilibrium values of 7; COHb and % 0,Hb ambient CO at various altitudes Unacclimatized
Ambient
and hemoglobin
FICO,
I 15
12 3 6 20
rz~rn
Fig. 6. game as Fig. 5 using a different display. It can be seen that ambient CO has only a small effect of 0,Hb compared with a large effect of altitude.
I2 ppm_
DISCUSSION --6 4
I 2 1 05
I ,
I 4
I 6 IKft
15
Altitude,
1 2
I 8 I 25
0
IO I 3
km
Fig. 4. Similar to Fig. 2 except that metabolic rate is kept constant and COHb is calculated for a variety of altitudes and ambient CO concentrations. Calculation was done by Equations (12t(14)
Fig. 5. “/, 0,Hb and % COHb were calculated simultaneously using Equations (12t(14) for various altitudes and ambient CO concentration.
The results would indicate that unacclimatized individuals at moderate altitudes will probably be protected from excessive elevation of blood CO in the same manner as they would be at sea level without an altitude adjustment of the ambient 8-h and l-h standards, provided that the standards are volumetric standards (ppm). This finding was expected from inspection of Haldane’s first equation because altitude would decrease the inspired pC0 and p0, to the same extent. Of some surprise was the finding that a modest increase in stringency of ambient CO equilibrium standard would be required at higher altitudes. This finding is due largely to the effect of endogenous CO production. No standards have yet been set for equilibrium conditions probably because ambient levels fluctuate widely during each day. Endogenous CO is most important under resting conditions. Endogenous CO is produced by the breakdown of hemoglobin. The rate ofendogenous CO production is markedly increased in patients with hemolytic anemia. These calculations have dealt almost entirely with blood CO levels whereas CO is toxic mostly through its interference with O2 transport. However in the past, the values for ambient CO standards have been calculated for blood CO levels. The target CO levels were based on clinical response to CO levels but not to blood 0, levels. The only previous calculations for altitude and CO calculated the 8-h CO standard to produce an increase from 0.5 to 1.5 “/ COHb. On the
728
CLARENCER.
COLLIER and JOHN R. GOLDSMITH
basis of those calculations (which were in error), the standards for the Lake Tahoe Air Basin were set at 6 ppm CO without reference to the blood O2 levels that would be produced. This paper is written in part to correct the previous work. These calculations point out that if standards are to be based on increments in carboxyhemoglobin and expressed in volumetric terms, the more stringent standards are not supportable. If standards are expressed in gravimetr~c terms, the magnitude of change might be reasonable, but this was not the basis on which they were proposed. A smaller reduction from the sea level volumetric standard might be used for equilibrium conditions. There is no question that 0, transport is far more Important than blood CO levels but blood O2 levels may be very difficult to use as a means of setting standards even in a mathematical model. In the first place, it is obvious from Figs 5 and 6 and Table 2 that arterial saturation is much more dependent on altitude than upon blood CO levels. The person at risk from a low blood 0, would be much better protected if he sought a lower altitude than to have a lower CO level. inspection of Fig. 6 shows that if ambient FICO = 9 ppm at 1830 m under equilibrium conditions, the calculated arterial SO, would be 91.0%. Decrease of altitude to 1520 m at 9 ppm CO will increase the SO1 to 92.3 I’, which is slighly better than the calculated SO, for 1830 m at ambient CO = 0. The model predicts that the arterial SOZ is only slightly ~n~uenced by the ambient CO in comparison to the effect of altitude alone. As Goldsmith and Aronow (1975) have pointed out oxygen delivery to such critical organs as the myocardium or brain might be better criteria for regulations, and this is particularly the case for the substantial number of persons with impaired coronary and cerebral circulation. In such persons, the leftward shift of the oxyhemoglobin dissociation curve in the presence of carbon monoxide has a particularly strong impact on tissue oxygen delivery rates. It seems clear that subjects at obvious risk from generalized or localized hypoxia should remain at lower altitudes. If they go to altitude, it would be wise to sleep at a lower altitude. Special care should be taken to avoid CO exposure from tobacco smoking or from indoor fires. Patients with hemolytic anemia may also be at increased risk because of high endogenous CO production. At all altitudes, there is a lesser decrement in arterial 0,Hb saturation due to any CO level than the decrement at sea level. Thus CO, while it is not protective against altitude, does aid in oxygenation of arterial blood by decreasing the pso. One could properly question whether CO would help oxygenation of mixed venous blood or any tissue. This matter is being studied in a mathematical model and will be the subject of another paper. If a decision were made to use blood oxygen as a criterion for standard setting, an enormous number of questions would need to be answered. Where would
the 0, be measured? Arterial, mixed venous, coronary sinus, cerebral vein? What decrement would be acceptable and what decrement would be unacceptable? What type of people with what diseases would we be protecting? People have enormous ranges of arterial PO,, 0, saturation or O2 content and too often have little correlation between these values and their exact clinical state or prognosis. These calculations have made it clear that the volumetric standard is preferable to the gravimetric standard because little change of standards is required at various altitudes. In practice the volumetric standards have been used unofficially, probably for various reasons. These results will probably be useful to assist in setting air quality standards at altitude but the model should be tested in living healthy persons. Since the changes predicted by the model are small, an accurate analytical method for blood CO and O2 needs to be used both at sea level and at altitude. Since expected altitude effects are small, the experimental altitudes chosen should differ widely, preferably sea level and 3000-3660 m. Testing should be done soon after arrival at altitude because the model predicates no change in pC02. The testing of 8-h standards is probably too demanding on any subject unless a large chamber is available. Since this is unlikely at altitude, a l-h exposure could readily be tested using an inspired FICO ofabout 60 ppm. This test could be done resting or with steady-state low level exercise. Equilibrium testing really requires a chamber and so may not be amenable to testing the model. However, the effect of hemolytic anemia on blood CO levels at sea level and altitude could be evaluated while breathing low ambient CO levels of moderate stability. Blood samples could be tested in the morning on awakening to provide a fair test of the model.
REFERENCES
R. F., Forster R. E. and Kane P. B. (1965) Considerations of the physiological variables that de-
Coburn
termine the blood carboxyhemoglobin concentration in man. J. c/in. Invest. 44, 189991910. Forster R. E. (1964) Diffusion of gases. In Handbook oj Physiology, (Edited by Fenn W. D. and Rahn H.) chapter 33, pp. 839-872. Am. Physiol. Sot., Washington, D.C. Goldsmith J. R. and Aronow W. S. (1975) Carbon monoxide and coronary heart disease: a review. Enr;ir. Res. 10, 236248. Rahn H. and Fenn W. D. (1955) A Gruphiml Analysis oj I& Respiratory Gas Exchange, pp. I-41. Am. Physiol. Sot., Washington, D.C. Rahn H. and Otis A. B. (1949) Man’s respiratory response during and after acclimatimtion to high altitude. Am. J. Physiol. 157. 445. Roughton F. J. W. and Darling R. C. (1944) The effect of carbon monoxide on the oxyhemoglobin dissociation curve. Am. J. Ph:siol. 141, 17-31. Severinghaus J. W. (1979) Simple, accurate equations for
human blood 0, Physiol. 46, 599-602.
dissociation computations. J. uppi.
Ewrronm~nr
Vol.
17.
No
4. pp.
723-128.
0004-5981~83/040723& $03.00~0 C 1983 Pergamon Press Ltd.
1983
Prmted in Great Bnlam
INTERACTIONS OF CARBON MONOXIDE HEMOGLOBIN AT HIGH ALTITUDE
AND
CLARENCE R. COLLIER and JOHN R. GOLDSMITH University
of Southern
California Medical Center, North State Street, Los Angeles, CA 90033, U.S.A. Ben Gurion University of the Negev, Beer Sheva, Israel
Abstract-The health risks to U.S. populations who are exposed to ambient carbon monoxide and live at altitudes (such as Denver, Salt Lake City and Albuquerque) were evaluated using a set of mathematical models. The assumption that a given increase in carboxyhemoglobin would require a more stringent volumetric air quality standard was tested. The results using the model predict that the 8-h or l-h standards adopted for sea level conditions need not be altered to protect individuals against health risks at altitude, if the standards are in volumetric terms. They would need to be reduced if the standards are left in gravimetric terms. If the guideline is to be based on a given decrement of oxygen tension, many other variables must be specified, but expected differences in ambient carbon monoxide have a small impact compared to the effect of altitude itself.
NOMENCLATURE CO Symbols vco SC0 SC0 (f) SC0 (0) [COHb] D,CO
pica FICO M 0, Symbols v02 MET SO, DLO,
[O,Hbl PAO, PC02
absence of 0, and for the combination of variables in the Roughton-Darling
rate of endogenous production of CO, ml min- ’ (STPD) “/,COHb of total Hb On saturation of Hb with CO at any time, 9, saturation of Hb with CO at timk t = 0 concentration of COHb as CO in blood, ml ml ’ (STPD) diffusing capacity for CO, ml min _ 1torr _ ’ (STPD) partial pressure of CO in humidified inspired air, torr volumetric fractional concentration of CO in dry inspired air, ppm ratio of CO affinity to O2 affinity for Hb
STPD
1
O2 consumption, I@ min- ’ (STPD) ratio of actual V02 to resting V02 (250 ml min- I) 5” 0,Hb of total Hb diffusing capacity for 0,, ml min- ’ torr- I (STPD) concentration of 0,Hb as O2 in blood, ml ml-’ partial pressure of alveolar 02, torr mean partial pressure lary O,, torr
of pulmonary
capil-
Other VA
ALT PB
PACO, WO, I VB
Hb R ew Y(P)
6)
equation refers to the condition under which the volume of a gas is measured, i.e. WC, 760 torr and dry.
alveolar ventilation, ml min- ’ (STPD) altitude above sea level, lo3 m barometric pressure, torr partial pressure ofC0, in alveolar gas, torr partial pressure of CO, in arterial blood, torr time, min blood volume, ml hemoglobin concentration in blood, g dl_ 1 respiratory exchange ratio of CO* output to O2 consumption e, base of natural logarithms raised to power of x the empiric relation between ~0, and SO, for normal human blood. The same relationship holds for (M)pCO and SC0 in 723
INTRODUCTION Because carbon monoxide (CO) competes with oxygen in binding to hemoglobin (Hb), it has long been recognized that ambient carbon monoxide levels should be controlled to safe levels to protect the health of individuals. This has been done by estimating the concentration and duration of exposure that will keep the carboxyhemoglobin (COHb) level of non-smoking adults living at sea level below 1.552 ‘i,. For instance, the Federal maximum standard for CO has been set at 10 mg m- 3 (9 ppm) for 8 h. Ambient CO levels usually have wide diurnal fluctuations and steady-state equilibrium standards have not been set. At high altitudes, six additional factors need to be considered as follows: (1) Combustion tends to produce more CO at altitude. (2) Ambient partial pressure of 0; (PO,) is reduced at altitude producing more COHb at same ambient CO partial pressure @CO). (3) The ambient air quality standards defined by EPA uses gravimetric concentration units mg mm3, independent of altitude. The ambient pC0 is proportional to the gravimetricconcentration, independent of altitude. (4) Commonly the standard is also cited in terms of parts per million (volumetric). At altitude the same number of ppm has a smaller gravimetric concentration and pC0 than it would at sea level. (5) If volumetric standards were used for CO, the reduction of&O with altitude would be proportional to the reduction of ~0,. Therefore, altitude should
724
CLARENCE
R.
COLLIER
have minimal effect on ambient CO-COHb relations. (6) Besides, the reduction of O2 carrying capacity, CO also increases the afinity of Hb for O2 as manifested in a leftward shift of the oxygen dissociation curve (ODC) and a decrease in half saturation ~0, (psO)_ This might be detrimental at sea level but may be at least partly beneficial at altitude. Because volumetric standards appear to be more useful at different altitudes, this paper which reports theoretical calculations will primarily use ppm and secondarily calculate mg mm 3 for comparison. The interactions of 0,, CO and Hb will be considered. It is estimated that approximately 2.2 million people live in the U.S. at altitudes over 1524 m. It is likely that any risk of CO at altitudes will be greater in unacclimatized newcomers or tourists than in residents. Denver, Colorado at 1610m has ambient CO levels which are equal to or greater than sea level cities. Federal and State officials have unofficially used volumetric concentration standards for Denver and other high altitude cities such as Colorado Springs, Albuquerque and Salt Lake City and have designated them as nonattainment areas for CO. In 1976, the States of California and Nevada adopted CO standards for the Lake Tahoe air basin at 1900 m which are more stringent than Federal standards. The 8-h standard adopted was 6 ppm which would be 5.5 mg mW3 at P, = 6a4 torr, 20°C. The 8-h standard for Lake Tahoe was calculated from the equation of Coburn, Forster and Kane (CFK) (1965) as the concentration of ambient CO that would raise the COHb from 0.5 “/, to 1.5 “/,,in an 8-h period. It has recently been found that an error was made in these computations. This paper aims to rectify the error and to expand the computations to include the equilibrium state and also the arterial 0, saturation (SO,) with combinations of ambient CO and altitude.
and
JOHN
R.
GOLDSMITH
ous CO production, barometric pressure, diffusing capacity for CO, alveolar ventilation, blood volume, mean capillary pOz and OzHb concentration. The equation is: v d[COHb] B
= VCOS
dt
Definitions and units of all symbols are given in the Nomenclature. The mathematical model used was constructed from seven interrelated quantitative relationships: (1) the CFK equation; (2) an equation linking PO,, pC0, 02Hb and COHb from Roughton and Darling (1944); (3) the empiric 0, dissociation curve (ODC) giving 0,Hb as a function of pOz; (4) the alveolar air equation linking arterial pCO,, PO,, alveolar ventilation and 0, consumption (VO,); (5) an empiric equation linking diffusing capacity to i/O,: (6) an empiric equation of barometric pressure as a function of altitude and (7) an equation relating the pC0, as a function of altitude and acclimatization. Actually, as explained below, the equation was simplified to a single constant for unacclimatized individuals at altitudes less than 3660 m. (1) The CFK equation (Coburn et al., 1965) is a differential equation of mass balance for CO. The parameters are ambient CO concentration, endogen-
[COHb]pcOz [O,Hb]M 1
$+--
1
P -47
L
-’
"A
(1)
If all the parameters are constant, this equation is an ordinary linear first order differential equation that has been solved by Coburn et al. The solution has been rearranged and scaled to give FICO in ppm. Also the [O,Hb] and [COHb] have been transformed in 7, saturation by multiplying by 104/(1.34*Hb) giving: lo6 FICO = __ P,-47
K(SCO(t) - ESCO(O)) _ Z PC0 1-E
(2) where
K = Z = W= E =
pcO,/(M * SO,) l/D,CO+(P,-47)/v, 104*K/1.34*Hb exp[-(W*t/(Z*
V,))].
(2) The Roughton-Darling derived from Haldane’s first:
[COHbl _ [OJbl
(1944) equation
M
was
PC0 ___
PO,
and second laws: [COHb]
=f(pO,
+ [O,Hb]
+ M pCO),
wherefis the empiric function of the ODC. These 2 laws are implicit from the empiric finding that in the absence of 02, the following relationship holds: [COHb]
METHODS
PICO -
=.f(MpCO).
The Roughton-Darling equation eliminates M and holds for all relations of CO and O2 with Hb. Here it is expressed in terms of “/ saturation:
sco+so,
=f[pO*(l
+%)I
(3)
(3) The empiric function used for the ODC was that of Severinghaus (1979): SOz = [234OO/(pO; + 150~0~) + l] -’ x 100. (4) (4) The alveolar air equation was used in two forms, one to calculate the alveolar PO,: pA0, and the other (STPD): t,=
= 0.2094 (P,-47)-pACO,/R to calculate
the alveolar
i/02R(PB-47)/pAC02.
(5) ventilation
(6)
Equation (5) is only an approximate equation, but it is considered sufficiently precise for the purpose of this model.
125
Interactions of carbon monoxide and hemoglobin at high altitude (5) The D,O,Pi/O, relation was approximated from a summary diagram of Forster (1964). The D,CO was obtained by division of D,O, by 1.23: D,CO
= 24.4+0.0578
VO,.
(7)
(6) The Ps-ALT relation was obtained by polynomial regression of data from Rahn and Fenn (1955): P, = 3.817 ALT’ - 89.60ALT + 760.
(8)
It is good from 0 to 3.66 km. (7) Rahn and Otis (1949) have shown that the unacclimatized subject does not change his pC0, when exposed to artificial altitudes in the laboratory. Therefore, the alveolar and arterial pC0, is defined as: pAC0,
= paC0,
= 38.
(9)
They also give figures for acclimatized subjects at a range ofaltitudes and for unacclimatized individuals at altitudes greater than 3660 m, but these were not used in this study. Assumptions
(1) pc0, = pA0, - 5. This relation for mean capillary pOz is strictly arbitrary. The value given is certainly too high at rest at sea level but is probably much closer to reality during work at altitude. A relationship based on D,O, was sought but could not be found. (2) paC0, = 38. This relation does probably not hold for unacclimatized subjects except in the laboratory. However, in reality, the pC0, will probably be lower. This would increase the ~0, and lower the COHb from that calculated. (3) R = 0.8. This relation will not hold for many exercise states. The usual increase in R with exercise would increase the ~0, and lower the COHb similar to hyperventilation. (4) Neither pH nor pC0, is changed at altitude, rest and exercise. This is probably not strictly true but most of the variation would be due to hyperventilation (see Assumption 2). (5) pc0, and SO, do not change during the dynamic step function calculations. This is a gross simplification. However, since the SC0 steps of interest are only l-1.5 yO, the drop in SOz will be roughly only the same magnitude. The SO2 used is that calculated for the end of the step which is the lowest it will be. The rate of entry of CO in the body will be greater than it actually would be if the correct SO, were used at all times. Therefore, this assumption and also Assumptions 2, 3 and 4 will cause any standards developed from them to be more stringent. A variable SO, was tested in two forward problems (0.551.5”/, and 0.5-3 ‘,(, X0) and found to produce an 8-h SC0 that was within 0.1 “/ of that found assuming a constant SO,. (6) M is constant. A value of 220 was used for these
computations. A value greater than this would produce more stringent standards and vice versa. Methods
for
calculation
of dynamic
8-h
and
l-h
standards
The rearranged CFK equation (2) formed the basis for these calculations. SC0 (0) was set to 0.5”,, and various values were used for SC0 (t). The value of FICO calculated is that of a step function constant from t = 0 to 8 h (or 1 h) that would produce the given SC0 at the end of the step. Using the SC0 at end of step and the alveolar ~0, which is a function only of altitude and pCOz (which is assumed constant). the SO2 for this point was calculated using Equations (3) and (4). This was done by an iterative algorithm which assumed an SO, and calculated a new one from the equations. The procedure was reiterated until convergence was obtained. As stated earlier, this value of SO2 was assumed to exist during the whole time period. The following parameter values were used in all cases examined: V, = 5500 ml, Hb = 15 g dl ‘, R = 0.8, M = 220, VCO = 0.007 ml min- ‘, pC0, = 38 torr. Various combinations *of the following assigned parameters were used: ALT = 0 to 3.6 km, i/O, ‘, SC0 at end of period = l-3 “<,, = 25tX1250mlmint = 60 or 480min. The equations were used in the following order: 8, 5, 6, 7, (3 and 4 iterated), 2.
Methodsfor
calculation
of equilibrium
standards
Coburn et al. (1965), have given an equation for the equilibrium state. This was transformed into a solution for FICO that will produce a given SC0 at each altitude: FICO = &[KSCO-ZI;CO].
(10)
B
This equation can be rearranged to give SC0 in terms of the endogenous and exogenous contribution: sco
=
FICo(PB47)+.: &o,
(11)
-- K
106K
The first term is the exogenous contribution and the second is the endogenous contribution. It was also found possible in the equilibrium state to obtain simultaneous explicit solutions for SC0 and SOz, given ALT, FICO and k’0,. Equation (11) can be solved for SC0 in terms of SO,: SC0
= G SO,
(12)
where G==
M
(FICO
(PB-47)10--6+Z
I’CO).
PC02
Since G also = SCO/SO,, written: SCO+SO,
Equation
=f[pO,(l
(4) can also be
+G)].
(13)
CLARENCE R. COLLIER and JOHN R. GOLDSMITH
726
The following explicit solutions can be obtained from (12) and (13):
sco=-
G ST
(14)
l+G
so, = ST-
SC0
where ST = SC0 f SO, from (13).
RESULTS
Table 1 gives sample results of calculations of the ambient CO volumetric concentrations that would be expected to produce given COHb saturations in 8 h and 1 h beginning at 0.5 ‘x COHb. The table gives only one level of activity VO, = 500 ml min- ’ or 2 METS. It can be seen that altitude has little effect on the loading of CO into the body under these conditions. The gravimetric standard was calculated for each case and would require a decrease of concentration of 60-707; in going from sea level to 3050 m. Figure 1 shows the effect of exercise on 8-h loading at various altitudes. Exercise obviously increases the CO load under these conditions, requiring a lower ambient CO, but altitude has little additional effect. Figure 2 shows the results of some of the computationsof the dynamic equilibrium state. It shows that under these conditions, altitude requires a modest decrease of ambient CO to produce the stated COkb concentration but exercise in this case decreases the stringency of ambient requirements. Exercise thus has the opposite effect of that seen in Fig. 1. It was postulated that this effect must be due to greater binding of endogenously produced CO as altitude increases. This was tested by use of Equation (11) and the results are shown in Fig. 3. The endogenous fraction is increased about 1.7 x by going from sea level to 3050m. This same fractional increase also holds if the subject has an elevated PC0 due to hemolytic anemia. The simultaneous equations (12)(14) for equilibrium were solved for ‘x COHb and ix OzHb for various combinations of ambient CO and altitude. The
Altitude,
km
Fig. 1. The ambient CO calculated according to Equation (2) at various altitudes that would raise the COHb from 0.5 to 1.5 % in 8 h in an unacclimatized subject. Each isopleth represents a given exercise level in METS. One MET represents a resting YOz of 0.25 I min. ‘. Other assumptions are given in the text. The ambient CO requirements are more stringent with exercise because of the larger ventilation. There is little change of ambient CO requirements at various altitudes. Ambient cot0 produce 15% COHb
I
I
I
I 0
i
I
05
I /
I
1
4
2
0
I5 Altftude.
I
8
6 Kft
E
/
10
I
25
I
3
km
Fig. 2. The ambient CO calculated by Equation (10) at various altitudes that would produce an equilibrium COHb of 1.5%. There is a substantial change with altitude especially at rest, and exercise decreases the stringency
Table 1. Volumetric ambient standards: estimated ambient CO for stated time period to produce stated COHb saturation from an original COHb of 0.5 % Unacclimatized. sedentary ( V02 = 500 ml mine ’ ) 8-h exposure 3050 m COHb at 8 h Sea level 1525 m 5.7 ppm 6.0 ppm 10.0 IO.I 14.3 14.2 18.6 18.4 1-h exposure
5.5 ppm 10.2 14.9 19.7
COHb at I h 1” 1,;
20.2 ppm 38.5
23.1 ppm 44.9
53.5 ppm 27.1
, 5.5
75.1 56.S
88.4 66.7
1/0 (” 1.5 2 2.5
--.-
106.2 79.8
Fig. 3. The fraction of COHb that was due to endogenous CO production was calculated by means of Equation ( t 11 and plotted for COHb = I ‘%,
Interactions Table 2. Calculated
of carbon
monoxide
Sea level
CO
0 wm 4 8 12 16
sedentary
% 0,Hb
Xl COHb
% 0,Hb
% COHb
0.20 0.8 1.4 2.1 2.7
97.3 96.8 96.2 95.6 95.1
0.26 0.9 1.6 2.3 2.9
93.6 93.0 92.5 91.9 91.4
0.35 1.1 1.8 2.5 3.2
3660 m
O$b
C&b
sedentary
orterlol
0,
(VOz-
500
I
I
5
10 Ambmt
Dynomvz equllibrlum
Amp
VO=05L/mln Y
I” 8
73.3 73.1 72.9 72.7 72.5
saturation ml/mm)
Altltuds Kft Km
700
IL
O&b
0.37 1.1 1.8 2.5 3.2
82.4 82.1 81.7 81.3 80.9
Eaulllbrium loo-
exposed to
( PO, = 500 ml min- t)
% COHb
results are given for fi0, = 500 ml min - ’ in Table 2 and in Figs 46. There is an increased % COHb with altitude even in the absence of ambient CO. The altitude effect is even greater in the presence of ambient CO as seen in Fig. 5. The effect of altitude on 9; OzHb is much greater than the decrement due to CO. This is particularly well seen in Fig. 6 where SAOz is plotted against FICO.
in humans
3050 m
1530m
727
at high altitude
equilibrium values of 7; COHb and % 0,Hb ambient CO at various altitudes Unacclimatized
Ambient
and hemoglobin
FICO,
I 15
12 3 6 20
rz~rn
Fig. 6. game as Fig. 5 using a different display. It can be seen that ambient CO has only a small effect of 0,Hb compared with a large effect of altitude.
I2 ppm_
DISCUSSION --6 4
I 2 1 05
I ,
I 4
I 6 IKft
15
Altitude,
1 2
I 8 I 25
0
IO I 3
km
Fig. 4. Similar to Fig. 2 except that metabolic rate is kept constant and COHb is calculated for a variety of altitudes and ambient CO concentrations. Calculation was done by Equations (12t(14)
Fig. 5. “/, 0,Hb and % COHb were calculated simultaneously using Equations (12t(14) for various altitudes and ambient CO concentration.
The results would indicate that unacclimatized individuals at moderate altitudes will probably be protected from excessive elevation of blood CO in the same manner as they would be at sea level without an altitude adjustment of the ambient 8-h and l-h standards, provided that the standards are volumetric standards (ppm). This finding was expected from inspection of Haldane’s first equation because altitude would decrease the inspired pC0 and p0, to the same extent. Of some surprise was the finding that a modest increase in stringency of ambient CO equilibrium standard would be required at higher altitudes. This finding is due largely to the effect of endogenous CO production. No standards have yet been set for equilibrium conditions probably because ambient levels fluctuate widely during each day. Endogenous CO is most important under resting conditions. Endogenous CO is produced by the breakdown of hemoglobin. The rate ofendogenous CO production is markedly increased in patients with hemolytic anemia. These calculations have dealt almost entirely with blood CO levels whereas CO is toxic mostly through its interference with O2 transport. However in the past, the values for ambient CO standards have been calculated for blood CO levels. The target CO levels were based on clinical response to CO levels but not to blood 0, levels. The only previous calculations for altitude and CO calculated the 8-h CO standard to produce an increase from 0.5 to 1.5 “/ COHb. On the
728
CLARENCER.
COLLIER and JOHN R. GOLDSMITH
basis of those calculations (which were in error), the standards for the Lake Tahoe Air Basin were set at 6 ppm CO without reference to the blood O2 levels that would be produced. This paper is written in part to correct the previous work. These calculations point out that if standards are to be based on increments in carboxyhemoglobin and expressed in volumetric terms, the more stringent standards are not supportable. If standards are expressed in gravimetr~c terms, the magnitude of change might be reasonable, but this was not the basis on which they were proposed. A smaller reduction from the sea level volumetric standard might be used for equilibrium conditions. There is no question that 0, transport is far more Important than blood CO levels but blood O2 levels may be very difficult to use as a means of setting standards even in a mathematical model. In the first place, it is obvious from Figs 5 and 6 and Table 2 that arterial saturation is much more dependent on altitude than upon blood CO levels. The person at risk from a low blood 0, would be much better protected if he sought a lower altitude than to have a lower CO level. inspection of Fig. 6 shows that if ambient FICO = 9 ppm at 1830 m under equilibrium conditions, the calculated arterial SO, would be 91.0%. Decrease of altitude to 1520 m at 9 ppm CO will increase the SO1 to 92.3 I’, which is slighly better than the calculated SO, for 1830 m at ambient CO = 0. The model predicts that the arterial SOZ is only slightly ~n~uenced by the ambient CO in comparison to the effect of altitude alone. As Goldsmith and Aronow (1975) have pointed out oxygen delivery to such critical organs as the myocardium or brain might be better criteria for regulations, and this is particularly the case for the substantial number of persons with impaired coronary and cerebral circulation. In such persons, the leftward shift of the oxyhemoglobin dissociation curve in the presence of carbon monoxide has a particularly strong impact on tissue oxygen delivery rates. It seems clear that subjects at obvious risk from generalized or localized hypoxia should remain at lower altitudes. If they go to altitude, it would be wise to sleep at a lower altitude. Special care should be taken to avoid CO exposure from tobacco smoking or from indoor fires. Patients with hemolytic anemia may also be at increased risk because of high endogenous CO production. At all altitudes, there is a lesser decrement in arterial 0,Hb saturation due to any CO level than the decrement at sea level. Thus CO, while it is not protective against altitude, does aid in oxygenation of arterial blood by decreasing the pso. One could properly question whether CO would help oxygenation of mixed venous blood or any tissue. This matter is being studied in a mathematical model and will be the subject of another paper. If a decision were made to use blood oxygen as a criterion for standard setting, an enormous number of questions would need to be answered. Where would
the 0, be measured? Arterial, mixed venous, coronary sinus, cerebral vein? What decrement would be acceptable and what decrement would be unacceptable? What type of people with what diseases would we be protecting? People have enormous ranges of arterial PO,, 0, saturation or O2 content and too often have little correlation between these values and their exact clinical state or prognosis. These calculations have made it clear that the volumetric standard is preferable to the gravimetric standard because little change of standards is required at various altitudes. In practice the volumetric standards have been used unofficially, probably for various reasons. These results will probably be useful to assist in setting air quality standards at altitude but the model should be tested in living healthy persons. Since the changes predicted by the model are small, an accurate analytical method for blood CO and O2 needs to be used both at sea level and at altitude. Since expected altitude effects are small, the experimental altitudes chosen should differ widely, preferably sea level and 3000-3660 m. Testing should be done soon after arrival at altitude because the model predicates no change in pC02. The testing of 8-h standards is probably too demanding on any subject unless a large chamber is available. Since this is unlikely at altitude, a l-h exposure could readily be tested using an inspired FICO ofabout 60 ppm. This test could be done resting or with steady-state low level exercise. Equilibrium testing really requires a chamber and so may not be amenable to testing the model. However, the effect of hemolytic anemia on blood CO levels at sea level and altitude could be evaluated while breathing low ambient CO levels of moderate stability. Blood samples could be tested in the morning on awakening to provide a fair test of the model.
REFERENCES
R. F., Forster R. E. and Kane P. B. (1965) Considerations of the physiological variables that de-
Coburn
termine the blood carboxyhemoglobin concentration in man. J. c/in. Invest. 44, 189991910. Forster R. E. (1964) Diffusion of gases. In Handbook oj Physiology, (Edited by Fenn W. D. and Rahn H.) chapter 33, pp. 839-872. Am. Physiol. Sot., Washington, D.C. Goldsmith J. R. and Aronow W. S. (1975) Carbon monoxide and coronary heart disease: a review. Enr;ir. Res. 10, 236248. Rahn H. and Fenn W. D. (1955) A Gruphiml Analysis oj I& Respiratory Gas Exchange, pp. I-41. Am. Physiol. Sot., Washington, D.C. Rahn H. and Otis A. B. (1949) Man’s respiratory response during and after acclimatimtion to high altitude. Am. J. Physiol. 157. 445. Roughton F. J. W. and Darling R. C. (1944) The effect of carbon monoxide on the oxyhemoglobin dissociation curve. Am. J. Ph:siol. 141, 17-31. Severinghaus J. W. (1979) Simple, accurate equations for
human blood 0, Physiol. 46, 599-602.
dissociation computations. J. uppi.