ORIGINAL ARTICLE

Fumihiko Sugino · Tokuo Ogawa · Satoshi UmemuraSatoru Suzuki · Yasuhiro Kawamura

Effect of acetazolamide on cerebral blood flow and tympanic temperaturein healthy subjects and patients with subacute subarachnoidhaemorrhage

Accepted: 3 September 1996

Abstract The influence of the increased cerebral bloodflow (CBF) induced by acetazolamide on tympanictemperature (Tty) was examined in three healthy malevolunteers and in five patients with subacute sub-arachnoid haemorrhage (SAH). The CBF was estimatedby means of stable xenon-enhanced computed tomo-graphy before and after the administration of acet-azolamide. The Tty was recorded continuously in bothears using thermistor thermometers. In all subjects, CBFincreased ranging from 11% to 108% after acetazolamideadministration. In all the healthy subjects and in twopatients with mild SAH, Tty was higher than the oeso-phageal temperature (Toes) and Tty decreased bilaterally,ranging from 0.07 to 0.35°C as CBF increased. Threepatients with severe SAH were febrile, their Toes ex-ceeding Tty, and their Tty rose by 0.30 to 0.53°C withincreased CBF. These observations suggest that Ttyfollows brain temperature which changes with an in-crease in CBF in euthermic subjects as well as in febrilesubjects.

Key words Subarachnoid haemorrhage · Tympanictemperature · Cerebral blood flow · Acetazolamide

Introduction

The brain is an organ with a high metabolic rate and itstemperature is generally higher than that of arterialblood. Therefore, the brain is cooled by circulatoryconvection, and an increase in cerebral blood flow(CBF) with no change in cerebral metabolic rate isconsidered to cause a decrease in brain temperature.

Acetazolamide has been known to induce an increase inCBF (Vorstrup et al. 1984), and consequently is con-sidered to cause a decrease in brain temperature, as longas arterial blood is cooler than the brain.

Tympanic membrane temperature (Tty) has beenshown in many reports to reflect brain temperature withhigh accuracy in animals (Tanabe et al. 1964; Baker et al.1972) as well as in humans (Benzinger 1959; Hirata et al.1988; Brinnel and Cabanac 1989; Cabanac 1993; Mariaket al. 1994; Ogawa 1994), if measured appropriately.There have also been studies demonstrating a close re-lationship between CBF and Tty (Nishita 1993; Ogawaet al. 1993; Umeyama et al. 1995).

The present study examined the Tty change associatedwith CBF modifications due to administration of acet-azolamide in healthy volunteers and in patients withcerebrovascular disorder. The CBF was estimated bymeans of stable xenon-enhanced computed tomography(XeCT). The cerebrovascular disorder examined wassubacute subarachnoid haemorrhage (SAH) in the acutephase because XeCT is carried out routinely in suchcases for the detection of vasospasmic foci in theGamagori City Hospital where the experiments werecarried out.

Methods

Subjects

The subjects were three healthy male volunteers, aged 28, 37 and 40years, and five patients with SAH (one man and four women), aged21–70 years, 5 or 6 days after onset. The volunteers and the pa-tients’ families provided written consent after being informed of thepurpose, procedure and risks of the experiment. Hunt and Kosnikgrading (Hunt and Kosnik 1974) was applied to classify the clinicalseverity of the SAH cases. They included two moderate cases withHunt and Kosnik grade 2 (SAH 2), and three severe cases withHunt and Kosnik grade 3 (SAH 3). The symptoms of grade 2 aredescribed as moderate to severe headache, nuchal rigidity, noneurological deficiencies other than cranial nerve palsy, and thoseof grade 3 as drowsiness, confusion, or mild focal deficiencies. Theexperimental procedure was approved by the Ethics Committee ofGamagori City Hospital.

Eur J Appl Physiol (1997) 75: 252 – 255 Springer-Verlag 1997

F. Sugino (&) · S. Umemura · S. Suzuki · Y. KawamuraDepartment of Neurosurgery, Gamagori City Hospital,7-34 Yaotomi-cho Gamagori-shi Aichi-ken Japan 433

T. OgawaDepartment of Physiology, Aichi Medical University, Japan

The subjects were put on a bed in a supine position ready forcomputed tomography (CT) scanning in light casual clothes, in anair conditioned room (not strictly controlled to any particulartemperature). After 30 min of rest, acetazolamide in a 1.0-g dosewas administered i.v., the CBF was estimated first in the restingstate just before, and again at 20 min after administration ofacetazolamide. The XeCT was employed to estimate CBF, using aCT scanner (GE 9800, General Electric Corporation, Milwaukee).Xenon gas (35% concentration) was administered for 4 min, andafter 3 min of wash-out, a CT image was obtained. The expiratoryCO2 concentration and the end-tidal xenon concentration weremonitored continuously using Xetron 3 apparatus (Anzai Cor-poration, Tokyo), and these data were used as the input functionfor computing flow values using the Kety equation (Kety andSchmidt 1945). Each of the whole right and left hemispheres wasconsidered a region of interest (ROI).

The Tty were recorded continuously on both sides, because ithas been shown that the right and the left Tty are not always equaland may change differently in various experimental conditions(Ogawa 1994) and in cerebrovascular diseases (Nishita 1993). Forthe measurement, a spring-type thermistor element devised byMasuda and Uchino (1978) was used. Its placement on the tym-panic membrane is easy and painless. The external auditory canalwas plugged with a piece of absorbent cotton. In the three SAH 3patients, all of whom were febrile, the measurement of oesophagealtemperature (Toes) was proposed and it was monitored successfullyin two of them. The Toes were measured by a thin thermistor probewhich was flexible and coated with silicon rubber.

Since acetazolamide has a slight anaesthetic effect, the subjectswere kept awake to maintain a stable respiratory rate by frequentlyaddressing them and touching them during the experiment. Thediuretic effect of acetazolamide did not influence the subjects’ vitalsigns significantly.

Results

Overall, CBF of the ROI increased by 43% (SD 28%) onaverage, ranging from 11% to 108% after acetazolamideadministration (Fig. 1), with no significant difference inblood flow between the right and left hemispheres. TheCBF of the healthy volunteers increased by 11% to 39%,averaging 22.5% (SD 11.8%) after acetazolamide ad-ministration. On the other hand, the CBF increase in thetwo SAH 2 ranged from 16% to 60%, averaging 40.0%(SD 19.3%), and that in the three SAH 3 from 43% to108%, averaging 65.7% (SD 28.8%). The increase inSAH 3 was significantly higher than that in the healthyvolunteers, but there was no significant difference in theincrease either between the healthy volunteers and theSAH 2 or between SAH 2 and 3 (Fig. 1).

Figure 2 shows representative records of Tty on theright and left sides of one from each of the normal

subjects, SAH 2 and SAH 3. The Tty began to decreaseimmediately after acetazolamide administration in thenormal subjects (A) and in SAH 2 (B), whereas it in-creased in SAH 3 (C). The Tty levelled off within 20 minthereafter. In all the healthy subjects and in two SAH 2,Tty decreased by 0.14°C (SD 0.08°C) and 0.21°C (SD0.12°C) on average, ranging from 0.07 to 0.35°C, whileCBF increased (Fig. 3).

The three remaining SAH 3 were febrile, and their Ttyrose by 0.30 to 0.53°C, averaging 0.40°C (SD 0.09°C;Fig. 3); meanwhile, CBF increased. Figure 2C shows arepresentative record from one of those cases. In two ofthe three SAH 3, whose Toes was monitored successfully,Toes was always higher than the Tty, and increased afterthe acetazolamide administration (Fig. 2C).

During the experiment, both Xenon gas inhalationand acetazolamide administration caused only minimalchanges in the respiratory rate (–0.94% to 2.8%) and inthe end-tidal CO2 concentration (0%–0.5%) in all thesubjects.

Discussion

There have been many reports describing the relation-ship between brain temperature and Tty, but their results

Fig. 1 Percentage changes of cerebral blood flow (%nCBF) in theright (R) and left (L) hemispheres after acetazolamide administrationin each subject. SAH Subarachnoid haemorrhage, H and K grades 2and 3 Hunt and Kosnik (1974) grades 2 and 3

Fig. 2 Continuous records showing the change in tympanic tempera-ture (Tty) on the right (R) and left (L) sides following acetazolamideadministration in three representative subjects: a healthy volunteer(37 years, male, A), a patient with SAH grade 2 (77 years, male, B)and a patient with SAH grade 3 (57 years, female, C). The change inoesophageal temperature (Toes) is also shown in C. For otherdefinitions see Fig. 1

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are controversial. Randall et al. (1963) have reportedthat the cat hypothalamus was cooled by arterial bloodflow while the tympanic membrane was warmed by thelatter. On the other hand, Tanabe and Takaori (1964) inthe rabbit and Baker et al. (1972) in cat and monkeyhave observed that Tty fluctuated in parallel with thehypothalamic temperature. Shiraki et al. (1988) havemaintained that there is a discrepancy between changesin lateral ventricular and white matter temperatures andthose in Tty from observations in a patient with a pinealtumor. However, there seems to be an erroneous inter-pretation of their observations as pointed out by Ca-banac (1993). Recently, close correlations betweenintracranial temperatures and Tty have been demon-strated in many postcraniotomy observations (Soutsu1991; Mariak et al. 1994; Ogawa 1994).

Relatively few studies have addressed the relationshipbetween CBF and Tty in humans (Nishita 1993; Ogawaet al. 1993; Umeyama et al. 1995). Ogawa et al. (1993)has shown that Tty is influenced by the head position,and demonstrated an asymmetry in CBF between theright and left hemispheres, by means of single photonemission computed tomography (SPECT) using[99mTc]hexamethylpropylene-amine oxime (HMPAO).From these results, they have concluded that increasedCBF was associated with decreased brain temperature,as reflected by Tty. Umeyama et al. (1995) have observedalso that stellate ganglion block caused an increase in theblood flow of the hemisphere and a decrease in the Ttymore on the block side than on the other side as esti-mated by SPECT using HMPAO. In the present study,we measured the dynamic changes of Tty and CBF si-multaneously by means of stable XeCT, and noted thatTty declined as CBF increased in the healthy volunteersas well as in the patients with mild SAH (SAH 2). Theseresults are well in accord with those in previous studies.

It has been well established that intense heat lossfrom the head is achieved in many species by thermalpanting, and in humans also the upper airway maycontribute to brain cooling (Rasch et al. 1991). During

the present experiments, neither the respiratory rate northe end-tidal CO2 concentration, which indicates arterialCO2, changed meaningfully after acetazolamide admin-istration. Therefore, it is unlikely that there was anychange in the rate of heat loss from the upper air-way toaccount for cooling of the intracranial structures or thetympanic membrane. Similarly, it has been suggestedthat cooling of the scalp may contribute to cooling thebrain, especially when it is hyperthermic (Cabanac andBrinnel 1985; Nagasaka et al. 1990; Rasch et al. 1991).However, out subjects’ heads were covered with a gauzeand air pad and therefore there was no significantchange in scalp temperature.

Some authors have suggested that heat is conducteddirectly from the carotid artery to the tympanic mem-brane (Uchino 1989). In our experiments it was unlikelythat acetazolamide changed the carotid artery tempera-ture.

It was intended to carry out experiments on eu-thermic patients with severe subarachnoid haemorrhage,but we failed to recruit any such cases and all three ofour SAH 3 were febrile. In all of them, Tty rose as CBFincreased. The metabolic rate might have been disturbedin these patients due to elevated intracranial pressure,resulting in the arterial temperature exceeding the braintemperature. The Toes measured in two of them wasalways higher than the Tty. In such cases, an increase inCBF may have warmed rather than cooled the brain.This is in accord with observations on patients withcerebral infarct by Nishita (1993) that Tty on the sidewith the infarcted hemisphere was significantly lowerthan Tty on the opposite side with the intact hemisphere.It is of interest, however, that not only Tty but also Toesincreased after acetazolamide injection. Since acet-azolamide did not cause hyperthermia in the euthermicsubjects, it may somehow have exerted a facilitative ef-fect on the pyrogenic mechanism, but we have no furtherevidence to confirm this suggestion at present.

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Fig. 3 Changes in tympanic temperature (nTty) on the right (R) andleft (L) sides after acetazolamide administration in each subject

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