European Journal of Clinical Investigation (2000) 30, 501±504 Paper 663

Gastrotonometry represents dramatic increase in PcO2

after acetazolamide administration

K. Taki, K. Oogushi and K. Tozuka

Saga Medical College, Saga, Japan

See Commentary on page 467.

Abstract Background We sought to evaluate the parameters of CO2 transport during the adminis-

tration of acetazolamide in order to assess the role of carbonic anhydrase in CO2 transport.

Materials and methods The partial pressure of carbon dioxide in tissue (PtCO2), arterial

blood (PaCO2) and end-tidal gas (PETCO2) were monitored to study the correlation between

PaCO2, PtCO2 and PETCO2 in spontaneously breathing healthy volunteers after the intrave-

nous administration of acetazolamide 6 mg kgÿ1.

Results At 60 min after the administration of acetazolamide, the PtCO2 peaked at more than

60 mmHg, and although it decreased by 90 min, it then remained stable above the baseline

value. The PaCO2 did not change and the PETCO2 decreased signi®cantly. The changes in

PtCO2 were greater than those of either PaCO2 or PETCO2. The minute ventilation increased

progressively throughout the study.

Conclusions We concluded that gastrotonometry represents a new method for monitoring

the dramatic increase in PtCO2 induced by drugs such as acetazolamide clinically, and that it

could be a warning against acetazolamide administration in severe patients without keeping a

ventilation and circulation reserve.

Keywords Acetazolamide, carbon dioxide, CO2 gap, carbonic anhydrase, gastrotonometry,

respiration.

Eur J Clin Invest 2000; 30 (6): 501±504

Introduction

The partial pressure of CO2 (PtCO2) in the stomach lumen,

measured by gastrointestinal tonometry, can be important

to help estimate the prognosis, the course of therapy and the

oxygen metabolism in tissues. Previous studies of acetazol-

amide (AZ) have shown that it can disturb CO2 transport

and respiration [1±5]. The majority of carbonic anhydrase-

mediated reactions occur in the red blood cell and lung

capillary endothelium. The reactions in plasma occur much

more slowly. The reaction in red blood cells and endothe-

lium is facilitated by activation of carbonic anhydrase and

the rapid exchange of bicarbonate for chloride while blood

passes through the pulmonary capillaries, thus increasing

the rate of conversion of H2CO3 into H2O and CO2, and

thereby, the excretion of large amounts of CO2 [3,4].

Clinically, AZ is used for conditions such as glaucoma

and metabolic alkalosis, particularly in overhydrated

patients [6±8]. It delays the conversion of H2CO3 to CO2

in the blood and pulmonary capillary endothelium, and the

hydration of CO2 at the tissue level [9]. It thus may cause

considerable disturbances of CO2 transport in the tissue

and elimination of CO2 from the lungs, and produces a

signi®cant difference between the CO2 partial pressures in

arterial blood (PaCO2) and in alveolar gas (PACO2) or end-

tidal gas [3±5]. The time±course of changes in PCO2 after

intravenous (i.v.) administration of AZ has been described

in dogs and cats [10±12]. However, the changes in PCO2 in

the stomach lumen, arterial blood and end-tidal gas, have

not been measured after the administration of AZ.

The purpose of this study was to analyse the PtCO2,

PaCO2, and PETCO2 in healthy volunteers after i.v. adminis-

tration of AZ during spontaneous breathing.

Materials and methods

The experiments were performed in nine healthy male

volunteers, weighing 56±69 kg and aged 24±35 years,

who lay on a bed from 09.00 to 11.30 in the morning

Q 2000 Blackwell Science Ltd

Department of Emergency Medicine, Saga Medical College,

Nabeshima, Saga, Japan (K. Taki, K. Oogushi, K. Tozuka).

Correspondence to: Kenji Taki, MD, Dr Med. Sci., Department

of Emergency Medicine, Saga Medical College, 1-1, 5-Chome,

Nabeshima, Saga, Saga 849-8501, Japan. Tel: 0952±34±3160;

fax: 0952±34±1061.

Received 30 July 1999; accepted 20 February 2000

502 K. Taki et al.

without having a breakfast. Spontaneous breathing on room

air was maintained throughout the experiment. A cannula

was placed in the radial artery for blood sampling. PETCO2

was measured by collecting end-tidal gas through a mouth-

piece with a nose clip in place, and PtCO2 was measured by

collecting gastrotonometry gas through a nasogastric tono-

metry catheter with a semipermeable Silastic balloon (TRIS,

NGS catheter; Tonometrics, Helsinki, Finland), in which

gas was equilibrated with PCO2 in the stomach lumen for

15 min. The sample was measured by an automated infra-

red gas analyser (Tonocap; Tonometrics), calibrated with a

standard mixed gas, 20´6% O2 and 5´0% CO2, and room

air. Arterial pressure was measured and arterial blood gases

were analysed by the blood gas analyser (Radiometer ABL

3, Radiometer Medical A/S, Copenhagen, Denmark).

After baseline measurements of systolic blood pressure,

heart rate, respiratory rate, blood gas, PtCO2, PETCO2 and

minute ventilation volume (VÇ E) (Ohmeda 5420 Volume

Monitor, Datex-Ohmeda, Louisville, CO, USA) were

obtained, they were repeated at 30, 60, 90 and 120 min

after i.v. injection of AZ, 6 mg kgÿ1.

The results were expressed as the mean 6 standard error

(SE) of each set of measurements. The signi®cance of the

measurements was assessed by an analysis of variance

(ANOVA) and multiple comparison test. A level of P <0´05

was regarded as statistically signi®cant.

Results

Systolic blood pressure, heart rate and respiration rate were

unchanged during the study. The pH remained slightly

reduced, and the PaO2 increased signi®cantly 90 min after

the administration of AZ.

Before administration of AZ, the baseline values of

PtCO2, PaCO2, and PETCO2 were comparable; the difference

between them was less than 1´0 mmHg. After the

intravenous administration of AZ, the PtCO2 increased

signi®cantly, to a peak of 62´4 mmHg at 60 min; the

PaCO2 remained stable for 120 min, and the PETCO2 was

signi®cantly lower at 60 and 120 min (Fig. 1a). After

60 min, the PtCO2 declined gradually, but was still signi®-

cantly higher at 120 min than at baseline. The VÇ E increased

progressively and signi®cantly throughout the study period.

The maximum VÇ E occurred at a PtCO2 of 46´1 mmHg at

120 min, although the maximum PtCO2 occurred at 60 min

(Fig. 1b).

The PaCO2ÿPETCO2 difference (a±ET)PCO2, was sig-

ni®cantly higher 60 min after the administration of AZ

and remained at least 2´0 mmHg higher for more than

60 min. The PtCO2ÿPaCO2 difference (t±a)PCO2, increased

in parallel with the changes in PtCO2. It reached a peak of

22´12 mmHg 60 min after the administration of AZ, and

remained more than 7´0 mmHg higher for more than

60 min (Table 1).

Discussion

Pulmonary carbon dioxide excretion is derived primarily

from bicarbonate. When carbonic anhydrase is inhibited,

only a fraction of CO2 is eliminated through the lung via

carbamino compounds and dissolved CO2: 45% of CO2

excretion is derived from dissolved CO2, 38% from carba-

mino compounds, and only 17% from bicarbonate [10,11].

After AZ administration, the PETCO2 decreases, and

PtCO2 at the subconjunctival cavity increases progressively

[9,10]. The elimination of CO2 is limited, resulting in a

signi®cant increase in PtCO2 and a decrease in PETCO2.

There is signi®cant tissue retention of CO2 induced by the

disequilibration of CO2 concentrations between tissue,

arterial blood and alveolar gas [4,7]. With constant ventila-

tion (a±ET)PCO2 increases. In the absence of carbonic

anhydrase activity, there is a build-up of CO2 stores in

Q 2000 Blackwell Science Ltd, European Journal of Clinical Investigation, 30, 501±504

Table 1 Sequential changes in oxygenation and ventilation parameters following acetazolamide administration

Baseline 30 min 60 min 90 min 120 min

SBP 124 6 2 126 6 2 124 6 2 125 6 2 125 6 2

HR 73 6 2 74 6 1 76 6 1 72 6 2 273 6 2

RR 15´0 6 1´0 12´91 6 0´9 11´40 6 0´7 12´5 6 1´1 13´6 6 0´6

VÇ E 5´68 6 0´26 5´76 6 0´31 5´97 6 0´27 6´58 6 0´26* 6´95 6 0´19*

pH 7´43 6 0´01 7´40 6 0´01 7´39 6 0´01 7´39 6 0´01 7´38 6 0´01

PaO2 94´5 6 3´5 94´6 6 2´7 93´1 6 3´3 103´1 6 3´4 105´6 6 3´2

BE 1´71 6 0´6 ÿ0´1 6 0´5 ÿ0´5 6 0´4 ÿ1´0 6 0´3 ÿ2´0 6 0´4

PaCO2 39´7 6 0´5 39´6 6 0´5 40´3 6 0´7 39´6 6 0´7 38´9 6 0´6

PtCO2 40´0 6 2´4 53´9 6 4´2* 62´4 6 3´9* 47´3 6 1´4* 46´1 6 1´3*

PETCO2 37´4 6 0´9 38´1 6 0´8 36´5 6 0´8 35´0 6 0´6* 34´5 6 0´7*

(a-ET)PCO2 2´3 6 0´6 1´5 6 1´0 3´8 6 0´7 4´7 6 0´8* 4´1 6 0´4*

(t-a)PCO2 2´3 6 2 16´2 6 4´2* 24´3 6 3´8** 9´7 6 1´0* 9´2 6 1´4*

*P< 0´05 compared with baseline, **P< 0´01 compared with baseline, (mean 6 SE).SBP, systolic blood pressure (mmHg); HR, heart rate (beat minÿ1); RR, respiratory rate (minÿ1); VÇ E, minute

ventilation volume (L minÿ1); BE, base excess (mEq/L); PtCO2, partial pressure of CO2 in tissue; PaCO2, partialpressure of CO2 in artery; PETCO2, partial pressure of CO2 in end-tidal gas.

Gastrotonometry PCO2 with acetazolamide 503

Q 2000 Blackwell Science Ltd, European Journal of Clinical Investigation, 30, 501±504

the tissues [12,13]. Because of the increase in the tissue

CO2 in the respiratory centre after AZ administration,

ventilation increased progressively. This may have been

partially responsible for the decrease in PETCO2 reported

previously [9,10], and the marked increase in PtCO2 in

this study. The transfer of dissolved CO2 in the lung is

increased by the increased CO2 gradient from mixed

venous blood to alveolar gas, and the increased VÇ E

[7,10]. However, it is not known why the response of the

respiratory centre to CO2 is delayed after AZ-related

carbonic anhydrase inhibition [14], despite our observation

that the respiratory centre is stimulated by the increase in

tissue PCO2.

The PtCO2 in the stomach lumen measured by naso-

gastric tonometry re¯ects only the gastric intramucosal

PCO2 [15]. An increase in PtCO2 has been reported to signify

problems with regional circulation and oxygenation, hyper-

carbia and low tissue metabolism [16±18]. A dramatic

AZ-induced increase in PtCO2 has not previously been

reported, nor has the dramatic increase in PtCO2 at 60 min,

as shown in this study. It is also possible in this study that

the release of CO2 from bicarbonate in the stomach lumen

is in¯uenced by inhibiting secretory carbonic anhydrase

(CA VI) which normally enters the gastric ¯uid from

parotid secretions. However, the prohibition of having

meals in the previous 10 h gave constant intragastric emp-

tying during this study to reduce the in¯uence of the CA VI

on the release of CO2 in the stomach lumen. Therefore, the

increase in intragastric CO2 is caused by an increase in

tissue PCO2 which occurs when carbonic anhydrase is inhib-

ited. In states of low carbonic anhydrase activity, such as

hyperthyroidism and severe conditions in intensive care

units, the high PtCO2 may be misunderstood to be due to

the imbalance between oxygen demand and supply during

gastrointestinal ischaemia [16±18], instead of the low

carbonic anhydrase activity.

The (t±a)PCO2 also increased dramatically during the

®rst 60 min following the administration of AZ, and by

120 min, the VÇ E had increased by approximately 20%.

Since the (a±ET)PCO2 re¯ects the degree of dead space

ventilation, an increase by 1´8 mmHg can be explained to

re¯ect a change in dead space ventilation induced by

Figure 1 Mean value with the standard

error (SE) for partial pressures of CO2

in tissue (PtCO2), artery (PaCO2) and

end-tidal gas (PETCO2) and minute ven-

tilation volume (VÇ E) after the intrave-

nous administration of acetazolamide

(AZ) 6 mg kgÿ1. (* P<0´05 compared

with baseline). Immediately after intra-

venous AZ, PETCO2 decreased and

PtCO2 increased dramatically (a). At

60 min, PtCO2 reached its highest value,

63 mmHg. PaCO2 was stable throughout

the study. The PtCO2ÿPaCO2 difference

increased rapidly, the increase in the

PaCO2ÿPETCO2 difference was delayed,

and both differences were maintained

until the end of the study. VÇ E increased

dramatically 60 min after the injection of

AZ (b).

504 K. Taki et al.

increasing VÇ E rather than changes due to AZ administra-

tion. However, the slow increase in VÇ E may have been

secondary to an increased respiratory drive induced by the

elevated PtCO2. Eventually the PtCO2 declined, and a steady

state was reached at 120 min as the increased VÇ E lowered

the PtCO2, which in turn decreased the respiratory drive.

Gastrotonometry represents a new method for studying the

relationship between respiration and tissue metabolism,

and monitoring the dramatic increase in PtCO2 induced

by drugs such as AZ clinically. It could also be used as a

warning against the administration of acetazolamide in

severe patients without keeping ventilation and circulation

reserve.

References

1 Nagai I, Jitsukawa S, Kawashima Y, Manabe H, Fujimoto K.

Effect of carbonic anhydrase inhibition on CO2 elimination.

Med J Osaka Univ 1974;24:253±65.

2 Effros RM, Chang RSY, Silverman P. Acceleration of plasma

bicarbonate conversion to carbon dioxide by pulmonary

carbonic anhydrase. Science 1978;199:427±9.

3 Bidani A, Mathew SJ, Crandall ED. Pulmonary vascular

carbonic anhydrase activity. J Appl Physiol 1983;55:75±83.

4 Swenson ER. The respiratory aspects of carbonic anhydrase.

Ann NY Acad Sci 1984;429:547±60.

5 Taki K, Mizuno K, Takahashi N, Wakusawa R. Disturbance

of CO2 elimination in the lungs by carbonic anhydrase

inhibition. Jpn J Physiol 1986;36:523±32.

6 Petounis AD, Chondreli S, Vadalnka-Sekioti A. Effect of

hypercapnoea and hyperventilation on human intraocular

pressure during general anaesthesia following acetazolamide

administration. Br J Ophthalmol 1980;64:422±5.

7 Krintel JJ, Haxholdt OS, Berthelsen P, Brockner J. Carbon

dioxide elimination after acetazolamide in patients with

chronic obstructive pulmonary disease and metabolic

alkalosis. Acta Anaesthesiol Scand 1983;27:252±4.

8 Berthelsen P, Gothgen I, Husum B, Jacobsen E. Oxygen

uptake and carbon dioxide elimination after acetazolamide in

the critically ill. Intens Care Med 1985;11:26±9.

9 Taki K, Hirahara K, Totoki T, Takahashi N. Retention of

carbon dioxide in tissue following carbonic anhydrase

inhibition in dogs. Clin Therap 1993;15:884±6.

10 Cain SM, Otis AB. Carbon dioxide transport in anesthetized

dogs during inhibition of carbonic anhydrase. J Appl Physiol

1961;16:1023±8.

11 Carruthers B, Ponte J, Purves MJ. Changes in partial

pressure on carbon dioxide with time in carotid arterial blood

in cats. J Physiol (London) 1980;298:13±23.

12 Hatle L, Rokseth R. The arterial to end-expiratory carbon

dioxide tension gradient in acute pulmonary embolism and

other cardiopulmonary diseases. Chest 1974;66:353±5.

13 Lee T-S. End-tidal partial pressure of carbon dioxide does

not accurately re¯ect PaCO2 in rabbits treated with

acetazolamide during anaesthesia. Br J Anaesth

1994;73:225±6.

14 Tojima H, Kuriyama T, Fukuda Y. Arterial to end-tidal

PCO2 difference varies with different ventilatory conditions

during steady state hypercapnia in the rat. Jpn J Physiol

1988;38:445±57.

15 Fiddian-Green RG, Pittenger G, Whitehouse WM Jr.

Back-diffusion of CO2 and its in¯uence on the intramural

pH in gastric mucosa. J Surg Res 1982;33:39±48.

16 Fiddian-Green RG, McGough E, Pittenger G, Rothman E.

Predictive value of intramural pH and other risk factors for

massive bleeding from stress ulceration. Gastroenterology

1983;85:613±20.

17 Grum CM, Fiddian-Green RG, Pittenger GL, Grant BJ,

Rothman ED, Dantzker DR. Adequacy of tissue oxygenation

in intact dog intestine. J Appl Physiol 1984;56:1065±9.

18 Fiddian-Green RG, Baker S. Predictive value of the stomach

wall pH for complications after cardiac operations.

Comparison with other monitoring. Crit Care Med

1987;15:153±6.

Q 2000 Blackwell Science Ltd, European Journal of Clinical Investigation, 30, 501±504