Journal of Cerebral Blood Flow and Metabolism 11:1031-1035 © 1991 The International Society of Cerebral Blood Flow and Metabolism Published by Raven Press, Ltd., New York

Cerebral Blood Flow Reactivity to Changes in Carbon Dioxide Calculated Using End-Tidal Versus Arterial Tensions

William L. Young, *Isak Prohovnik, Eugene Ornstein, Noeleen Ostapkovich, and Richard S. Matteo Departments of Anesthesiology and *Psychiatry, Neurology, and Radiology, Columbia University College of Physicians and Surgeons, New York, New York, U.S.A.

Summary: We retrospectively examined arterial and end­ tidal estimations of CO2 tension used to calculate cere­ brovascular reactivity in 68 anesthetized patients. CBP was measured using the intravenous 133Xe technique at

+ 0.79; r = 0.73, p = 0.0001). Cerebrovascular reactivity to changes in CO2 (ml 100 g-l min-1 mm Hg-1) was similar (p = 0.358) when calculated by using either Paco2 ( 1.9 ± 0.8) or Pe,co2 ( 1.8 ± 0.8) and highly correlated (y = 0.86x + 0.23; r = 0.9 1, p = 0.0001). The CBP re­ sponse to changes in CO2 tension can be reliably esti­ mated from noninvasive measurement of Pe,co2• Key Words: Carbon dioxide reactivity-Carbon dioxide ten­ sion-Cerebral blood flow.

mean ± SD P aco2 values of 28.2 ± 5.2 and 38.8 ± 4.8 mm Hg. The correlation between all Paco2 and end-tidal Pco2 (Pe,co2) values was y = 0.85x - 0.49 (r = 0.93, p = 0.0001). There was a moderate correlation between age and the difference between Paco2 and Pc,co2 (y = O.llx

Estimation of

P aco2

during CBF determination is

tively examined the correlation between arterial and end-tidal estimations of CO2 tension and the

a critical requirement for quantitative interpretation of results. Owing to the potency of

Paco2

in regu­

relationship between the two methods to calculate

lation of vascular tone, neither comparative con­

cerebrovascular reactivity to changes in

CO2,

trasts nor inferences regarding metabolic rates can be made with confidence unless this powerful co­ variate is taken into account.

METHODS

CO2 responsiveness is

Data were collected from 68 anesthetized patients en­ rolled in CBP research protocols (Young et a!., 1989, 1990) undergoing elective carotid endarterectomy (n = 16), resection of cerebral arteriovenous malformation (n = 45), or cervical or thoracic laminectomies (n = 7). No patient had clinically significant pulmonary disease. An­ esthesia was induced with thiopental 4 mg/kg and endo­ tracheal intubation was facilitated with a nondepolarizing muscle relaxant. Anesthesia was maintained with 0.751.0% isoflurane in nitrous oxide and oxygen. Standard capnography (Hewlett Packard Capnometer 472IO-A) and arterial blood gas analysis were employed using daily rou­ tine clinical calibration procedures. CBP was measured with a Cerebrograph lOa (Novo Diagnostic Systems, Bagsvaerd, Denmark) using the intravenous 133Xe tech­ nique as previously reported (Young et a!., 1988-90). During stable levels of anesthesia, a baseline CBP mea­ surement was obtained. The Pe,co2 was then increased 10 mm Hg by addition of carbon dioxide to the inspired gas mixture. After a period of � 10 min of a stable P e,co2 level, CBP was again measured. Pe,c02 levels were ver-

particularly important in the assessment of cerebro­ vascular reserve in ischemic vascular disease (Bul­ lock et aI., 1985). However, direct measurement of

Paco2

requires arterial puncture and is most often

avoided in favor of monitoring noninvasive end­ tidal

CO2

tensions

(Petco2).

The convenience and

safety of noninvasive monitoring should, however, be weighed against its precision as an estimate of arterial

CO2

tension. In this study, we retrospec-

Received January 30, 1991; revised May 3, 1991; accepted May 7, 1991. Address correspondence and reprint requests to Dr. W. L. Young at Department of Anesthesiology, Columbia-Presbyterian Medical Center, Neuroanesthesia-AP 901, 161 Fort Washington Ave., New York, NY 10032, U.S. A.

Abbreviations used: ANOVA, analysis of variance; Pa_eco2, difference between arterial and end-tidal Pco2; Pe,co2, end-tidal

Pco2·

1031

1032

W. L. YOUNG ET AL.

ified by arterial blood gas determination for P aco2' The two measurements at different levels of Paco2 were used to calculate CBF reactivity. The CBF data are expressed as the Initial Slope Index (ml 100 g -1 min -1 ) , assuming a Xe blood-brain partition coefficient of unity for the per­ fused tissue (Risberg et aI., 1975; Prohovnik et aI., 1983, 1985). The mean of up to 10 CBF detectors covering both middle cerebral artery supply territories was taken as an index of global CBF. The global CBF reactivity to carbon dioxide was calculated as the absolute increase in CBF in per millimeter mercury change in PaCoZ (ml 100 g -, min-' mm Hg-'). Decreasing temperature results in increased CO2 solu­ bility in blood; therefore, use of non-temperature­ corrected values will tend to overestimate the true Paco2 (Severinghaus et aI., 1957). Since the Paco2 values were measured and reported at 37°C, the influence of patient temperature was examined using the formula shown in Eq. 1 (Bergman, 1968) where T, is patient temperature and T2 is the temperature at which the blood gas machine measures COz tension; Pcoz (T,) is therefore the cor­ rected value and Pco2 (Tz) is the measured (uncorrected) value at 37°C:

(1)

(>65 years). Data were compared by linear regres­ sion or by analysis of variance (ANOYA); if an ANOY A was significant, differences between groups were isolated by Fisher's progressive least significant differences test. The threshold for signif­ icance was taken as p < 0. 05. All values are ex­ pressed as means ± SD.

RESULTS For the complete group of 68 patients, the base­ line

Paco2

was 28.2 ± 5. 2 mm Hg versus a temper­

ature-corrected value of 25. 9 ± 4.9 mm Hg (p

=

0.001). However, the correlation between the two = 0.93x - 0.46; r = 0.98, p 0. 0001) and use of the corrected versus uncor­

values was excellent (y =

rected values had no influence on the various sta­ tistical analyses. We have therefore presented the uncorrected values below, unless otherwise indi­ cated. Physiologic data for the three surgical subsam­ pIes, representing the baseline and CO2 challenge CBF measurement periods, are presented in Table

1. There were differences between the three groups The difference between simultaneous measure­

ment of Paco2 and P etC02 (Pa_eC02) was calculated at each CBF measurement. For the purpose of analy­

of surgical patients. Primarily, the carotid endar­ terectomy patients were older, were managed at a significantly higher level of Paco2' and had a higher

sis, patients were divided into three groups: young

MABP than the younger craniotomy and laminec­

(20-44 years), midage (45-65 years), and elderly

tomy patients.

± SD) from three groups of surgical patients: carotid endarterectomy (CEA), craniotomy for arteriovenous malformation resection (A VM), and cervical or thoracic laminectomy

TABLE 1. Physiologic data (mean

CEA (n Age (yrs) pH

PetCOZ (mm Hg)

Baseline C02c Baseline C02e Baseline

PaOZ (mm Hg)

COz" Baseline

Hemoglobin (mg/dl)

COz Baseline

MABP (mm Hg)

COz Baseline

Temperature eC)

COz Baseline

CBF (ml lOO g-l min-I)

COz Baseline

Pa--ecoz (mm Hg)

CO2' Baseline

PaCOZ (mm Hg)

COz

PaCOZ slope of CBF response (ml 100 g-l min -, mm Hg-') PetCOZ slope of CBF response (ml 100 g-' min-, mm Hg-')

67 7.42 7,35 35,7 45.4 27 38 192 189 13.2 \3,3 99 95 35,5 35,6 22 40 9 8

=

± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±

16) 10 0,05 0,05 4.2 4.4 4 6 36 28 2.0 1.9 12 10 0.6 0.6 8 12 2 3

AVM (n

36 7,50 7,38 25.5 36.6 21 32 224 181 12,3 12.5 79 82 35.2 35.3 22 43 5 5

=

± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±

45) 1O",b 0,04a,b 0,04a 2.5",b 2.5" 2",b 2" 27 36 2.0 1.9 8",b 9" 0.7 0.7 4 II 2a 2a

Laminectomy (n = 7)

45 7.46 7.37 28,5 37.9 24 34 197 192 13.2 \3.3 87 85 35.7 35,8 23 41 4 4

± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±

10" 0,03" 0,02 2,2" 2.6" 2" I" 37 28 2.0 2.0 9" 3" 0.5 0.5 6 5 2a 2a

1.9 ± 0,9

1.8 ± 0,9

2.1 ± 0.8

1.7 ± 0,8

1.8 ± 0.9

1.9 ± 0.6

Differences between groups were tested by analysis of variance and, if significant, by Fisher's progressive least significant differences test. PetCOZ' end-tidal Pcoz; Pa--ecoz, difference between arterial and end-tidal Pcoz' a Significantly different from the CEA group, p < 0.05, b Significantly different from the laminectomy group, p < 0.05, e All groups significantly different from baseline, p < 0.05,

J Cereb Blood Flow Metab, Vol,

11,

No, 6,

1991

ARTERIAL/END-TIDAL CO2 RELATIONSHIP

Paco2

The correlation between all measured

Petco2 values is shown in Fig. 1 (y

and

y

0.85x - 0.49; 0.0001). As shown in Fig. 2, there

14

was a moderate correlation between advancing age

12

r

=

0.93, p

=

and an increase in

0.73, p

Pa_eco2 (y

=

0.1 1x

=

0.79;

+

r

=

0.0001). Cerebrovascular reactivity to I I 1 changes in CO2 (ml 100 g- min- mm Hg- ) was similar (p = 0.358) when calculated by using either Paco2 ( 1.9 ± 0.8) or Petco2 (1.8 ± 0.8) and highly correlated (y = 0.86x + 0.23; r = 0.91, p = 0.0001) and is shown in Fig. 3. There was no influence of =

Q)I I �E E a..�

0.002x - 0.06;

r

0.104, p

=

age groups had significantly different =

(p

Pa_eco2 levels

0.0001). However, there was no difference

0.73

6 • o

2 o

c

10

20

T

c

30

40

60

50

70

SO

CEA AVM Laminectomy

90

Age

Pa_eco2 at baseline and during CO2

challenge as the within-group repeated measure, all

=

..

two-way ANOV A with age group as the between­ group factor and

r

0.79,

S

0.659). By

=

+

4

activity calculated with arterial or end-tidal values =

0.11x

10

C\I

o OOi

age on the difference between cerebrovascular re­

(y

=

1033

(yrs) Paco2 and

end-tidal Pco2 difference as a function of age. CEA, carotid endarterectomy; AVM, arteriovenous malformation.

FIG. 2. Scattergram of

(Pa.eC02)

between baseline and CO2 challenge values within each age group. The mean

Pa_eco2

values for the

nia. Use of temperature correction to adjust for the

young, midaged, and elderly groups for the baseline

difference in patient temperature and the tempera­

measurement were 4 ± 2, 6 ± 2, and 9 ± 3 mm Hg.

ture at which the

Paco2

was actually measured re­

vealed that, in the temperature range studied, abso­

Paco2

lute

DISCUSSION

levels were overestimated by �9%.

However, since patient management was based on In this study we have demonstrated that there is a good correlation between arterial and end-tidal

the uncorrected values and the whole sample was studied in the same temperature range, use of the

estimates of Paco2 and, most importantly, that there

correction factor adding nothing to the interpreta­

is a close correlation between the calculated slope

tion of the results, and we have therefore presented

of the CBF response to changes in either

only the measured

PetCo2'

Paco2

or

Further, as demonstrated in Fig. 1, the cor­

relation between

PetC02

and

Paco2

appears to be

similar during both hypocapnia and mild hypercap-

50

=

0.S5x - 0.49,

r

=

v

,

v

v,'



,/

"

.s; .;:::;

;I

(J � Q) a:

v

-: ., """,, ' " ;""..J: c �w.,,� v ,

OI +-'E E 30 Q) ._ 0...

C\I

0 0

c

.,wyt v vv v 'v ,/ ov D c'" COCCDV ,"0 00

� '0

C

cifCan c

QID:IJ 20 cc,'P:'� � C

C

..�[][]c

o

Baseline

V

C02 challenge

PaC02 (mm Hg) PaC02 for

all patients.

0.86x

+

0.23.

r

0.91

=

C 4

c

3

v

c c

2

05'c



c

c

CC

o 0 •

I

---�

FIG. 1. Scattergram of end-tidal

=

.;:::;

15 �20 25 30 35 40 45 50 55

of

it does not appear to affect the compa-

+-'

v v�'

OOl 35

25

Pa_eco2,

>-

v

40

data.

5

0.93

45 C\J

of

y y

Paco2

Although advancing age affects the absolute level

Pco2 (PetC02)

o

'0 C ill

T

CEA AVM Laminectomy

0 0

2

3

4

Arterial C02 reactivity FIG. 3. Scattergram of CBF reactivity to changes in carbon

as a function

dioxide calculated using either end-tidal Pco2 values (y-axis) or P cO2 values (x-axis). Units are ml 100 g-1 min-1 mm Hg-�. CEA, carotid endarterectomy; AVM, arteriovenous malformation.

J Cereb Blood Flow Metab, Vol. 11, No.6, 1991

W. L. YOUNG ET AL.

1034

rability of CBF response slopes calculated using

ported mean P a_eco2 values of 4. 5 mm Hg during

measured, regardless of the degree of age-related

4. 7 mm Hg during mechanical ventilation (Paco2 = 32. 9 mm Hg), similar to the Pa_eco2 found in the

pulmonary dysfunction. The correlation between

present study.

Paco2 or PetC02' This is presumably attributable to a stable Pa_eco2 gradient in the range of CO2 values

spontaneous ventilation (Paco2 = 5 1. 7 mm Hg) and

advancing age and decreased pulmonary function is

The results of this study may not be directly ap­

well described (Kohn, 1963). Pulmonary function

plied to the awake state. However, if one assumes

becomes progressively compromised with increas­

that anesthesia is a "worst case," then the changes

ing age, involving respiratory mechanics, lung vol­

in both Paco2 and PetC02 relative to one another

ume, and gas exchange. Despite the widening

appear to be similar and it is reasonable to conclude

appear to be any influence of age on the agreement

in CO2 tension can be reliably estimated from non­

between arterial and end-tidal calculations of cere­

invasive measurement of

Pa_eco2 gradient with advancing age, there did not

that the true slope of the CBF response to changes

Petco2.

brovascular reactivity, because both normocapnic and hypercapnic levels were equally affected. An issue that this study did not address is the 133 errors inherent in using the intravenous Xe method where end-tidal gas is sampled to estimate the arterial input function to deconvolute the head curves. As most recently described by Hansen et ai.

(1990), an increased pulmonary dead space will re­ sult in an underestimation of the arterial input func­

Acknowledgment: This work was supported in part by NIH ROI-NS277 13 to Dr. Young. The authors wish to thank Angela Wang for expert technical assistance, Joyce Ouchi for assistance in preparation of the manuscript, and Drs. J. W. Correll, D. O. Quest, B. M. Stein, and R. A. Solomon in the Department of Neurological Surgery and Dr. T. A. Wang and P. O. Alderson in the Department of Radiology for their cooperation in performing these stud­ ies.

tion and therefore of true CBF. However, this ef­

REFERENCES

fect presumably is constant at the two different lev­

els of Paco2 measured in this study and therefore does not impact on the conclusions regarding the comparability of cerebrovascular reactivity calcu­

lated by using either Paco2 or P etCo2' In fact, the findings of this study can be interpreted as support­ ing the validity of using end-tidal input functions, even in elderly patients, for repeated within-patient observations.

ing Paco2 and P etC02 in awake patients, as most have been carried out in anesthetized patients ow­ ing to the ease of obtaining simultaneous arterial and end-tidal samples for analysis. The influence of anesthetics on cerebrovascular CO2 reactivity is not altogether clear (Michenfelder, 1988). Inhalational anesthetics such as isoflurane probably increase re­ activity (Young et aI., 1990). General anesthesia

Pa_eco2 relationship. Although endo­

tracheal intubation decreases anatomic dead space, general anesthesia increases physiologic dead space (Askrog et aI., 1964) and may clearly decrease the correlation and increase the disparity between

Petco2

and

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228 Bullock R, Mendelow AD, Bone I, Patterson J, Macleod WN, Allardice G (1985) Cerebral blood flow and COz responsive­ ness as an indicator of collateral reserve capacity in patients with carotid arterial disease. Br J Surg 72:348-351

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may affect the

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Paco2.

Even so, most (Whitesell et aI.,

1981; Weinger and Brimm, 1987; Frei and Konrad, 1990) but not all (Raemer et aI., 1983) of the previ­ ous studies in anesthetized patients have demon­ strated good agreement between the relative con­ stancy of the arterial/end-tidal gradient. Mechanical ventilation per se does not seem to influence

Pa_eco2' In 12 healthy patients (mean age 35 years) during general anesthesia, Nunn and Hill ( 1960) re-

J Cereb Blood Flow Metab, Vol. 11, No.6, 1991

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Physiol 15:383-389 Prohovnik I, Knudsen E, Risberg J (1983) Accuracy of models and algorithms for determination of fast-compartment flow by noninvasive 133Xe clearance. In: Functional Radionu­ elide Imaging of the Brain (Magistretti PL, ed), New York, Raven Press, pp 87-115 Prohovnik I, Knudsen E, Risberg J (1985) Theoretical evaluation and simulation test of the Initial Slope Index for noninvasive rCBF. In: Cerebral Blood Flow and Metabolism Measure­ ment (Hartmann A, Hoyer S, eds), Berlin, Springer-Verlag, pp 56-60 Raemer DB, Francis D, Philip JH, Gabel RA (1983) Variation in Peoz between arterial blood and peak expired gas during anesthesia. Anesth Analg 62:1065-1069 Risberg J, Ali Z, Wilson EM, Wills EL, Halsey JH Jr (1975) Regional cerebral blood flow by 133Xenon inhalation. Stroke

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ARTERIAL/END-TIDAL CO2 RELATIONSHIP Severinghaus JW, Supfel MA, Bradley AF (1957) Alveolar dead space and arterial to end-tidal carbon dioxide differences during hypothermia in dog and man. J Appl Physiol 10:349-

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1035

Correll JW, Alderson PO (1988) Rapid monitoring of intra­ operative cerebral blood flow using 133Xe. J Cereb Blood

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J Cereb Blood Flow Metab, Vol. 11, No.6, 1991

Cerebral blood flow reactivity to changes in carbon dioxide calculated using end-tidal versus arterial tensions.

We retrospectively examined arerial and end-tidal estimations of CO2 tension used to calculate cerebrovascular reactivity in 68 anesthetized patients...
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