It has been shown on many occasions that methylxanthines cause marked increases in both cerebrovascular tone and cerebrovascular resistance and accompanying decreases in both cerebral blood flow (CBF) and cerebral blood flow velocity [1-7]. One of the main mechanisms underlying these effects may be the blockade of adenosine receptors. Animal studies have shown that methylxanthines block adenosine induced cerebral vasodilation and have proved that adenosine has a prominent role in maintaining resting cerebrovascular tone and regulating cerebral blood flow [8-15]. The pronounced acute reduction in cerebral blood flow after a single bolus administration of theophylline is clinically very important. In studies with conscious adult asthmatics, patients with chronic obstructive pulmonary disease, and preterm infants, therapeutic doses of theophylline caused an immediate marked 20-30% reduction in CBF. Transcranial Doppler examination of conscious non-premedicated patients revealed similar results. The decrease in blood flow velocity after theophylline administration amounted to between 19 and 26% [2,7,16-22]. Volatile anaesthetics such as halothane, isoflurane, or even nitrous oxide can also influence cerebrovascular resistance and vascular tone. Comparative studies have shown that these anaesthetics can induce totally different substance-specific and dose-dependent changes in cerebral circulation during general anaesthesia [23-28]. Human clinical investigations on the potential interactive effects of theophylline and volatile anaesthetics on cerebral perfusion during general anaesthesia have not yet been published. Knowledge concerning such perfusion changes is, however, especially important for the maintenance of patients with pathological intracranial readings or for operations where there is a risk of inducing temporary cerebral ischaemia [21,29].
For these reasons, continuous monitoring of the CBF in patients is often of major interest, and the choice of an appropriate procedure for a comprehensive analysis is certainly difficult. For clinical purposes, the estimation of theophylline effects on CBF has to rely on non-invasive methods. Transcranial Doppler sonography, which is the most readily available technique, is extensively used during surgery and in intensive care units for the estimation of cerebral blood flow because measurement of CBF cannot be performed routinely at the patients bedside or in critically acute situations which require an immediate therapeutic treatment away from the apparatus. For this reason, the effects of theophylline administration during general anaesthesia with volatile anaesthetics on cerebral blood flow velocity should be known.
The aim of this study was therefore to investigate the acute effects of therapeutic doses of theophylline on cerebral blood flow velocity during general anaesthesia induced either by halothane or isoflurane.
Local Human Ethics Committee approval was obtained and all the patients gave their informed, written consent at least 1 day before the study. Thirty-four healthy, non-premedicated, patients (ASA I and II), scheduled for an arthroscopy of the knee in the supine position, were divided into two equal groups [the patients' biometric data are shown in Table 1] for a prospective randomized investigation. The patients with pre-existing diabetes mellitus, cardiovascular-, pulmonary-, cerebral-, neurological-, or allergic disorders were excluded from this study. Additionally, no patients received cardioactive drugs during the whole study period. All measurements were performed before surgery. Anaesthesia was started in both groups by giving 6 mg kg−1 thiopentone, 1.5 mg kg−1 suxamethonium and 25 μg kg−1 vecuronium bromide. Anaesthesia was then maintained using either 1 MAC (minimum alveolar concentration) halothane (HAL) 0.75 vol% end-tidal in 40% O2 (40% FiO2), or 1 MAC isoflurane (ISO) 1.15 vol% end-tidal in 40% FiO2. Endtidal concentrations of halothane and isoflurane were continuously monitored with a multigas (Sirecust®, Siemens) monitor. The gas monitor was calibrated twice before each examination. Muscle relaxation was continued using 75 μg kg−1 vecuronium bromide (there was no monitoring of muscle relaxation). The ventilator was adjusted to maintain normocapnia with the help of continuous recordings of end-expiratory-end-tidal-CO2 concentrations (Capnolog®, Dräger).
After an equilibration period of 20 min, after which steady-state anaesthesia had been achieved, theophylline administration was performed by infusing 6 mg kg−1 over a period of 7.5 min using an automatic infusion pump. Measurements were made prior to theophylline infusion (T0), immediately after 2 mg kg−1 theophylline (2.5 min, T1), immediately after 4 mg kg−1 theophylline (5 min, T2), immediately after completion of theophylline infusion (6 mg kg−1, 7.5 min, T3), as well as 5 min (T4), 10 min (T5), 15 min (T6), 20 min (T7), 30 min (T8) and 45 min (T9) after theophylline infusion.
Blood flow velocity over the middle cerebral artery (MCA) was measured using transcranial Doppler sonography (pulsed 2-MHz system, TC2-64B®, manufactured by EME, Überlingen, Germany) via the transtemporal window at a depth of ≈45-55 mm employing the technique described by Aaslid et al.[30,31]. Before theophylline administration, the temporal window depth for each individual patient was optimized. All measurements were made by the same operator and during the whole study period the ultrasonic measurement depth remained unchanged. Parameters recorded included systolic, mean, and diastolic blood flow velocity (Vs-MCA, Vm-MCA and Vd-MCA, respectively). These parameters were recorded continuously (on-line) during the whole study period and were averaged exactly over a period of 15 s to exclude physiological variations in blood flow velocities. The pulsatility-index (PI) was calculated according to the following formulae: PI=(Vsys-MCA − Vd-MCA)/Vm-MCA. Peripheral oxygen saturation (Oxylog®, Dräger), arterial blood pressure (Dinamap®, Criticon), heart rate as well as rectal-(Tr) and oesophageal (To) temperatures were recorded continuously.
Statistical methods included one-factor analysis of variance without repeated measures (method: Student's t-test) [age, height, weight, theophylline dosages] and two-factor analysis of variance for repeated measures of one factor (ANOVA), [Vsys, Vd, Vm, PI, HR, MAP, end-tidal pCO2, O2 Sat, To, Tr] and the Scheffé-test (connecting test for checking of within-group differences) where appropriate. Differences were considered significant at a probability level of P<0.05.
Theophylline administration was well tolerated by all the study subjects; no adverse events were observed during the whole procedure for any patient. Heart rate, blood pressure, end-tidal pCO2, arterial oxygen saturation as well as rectal and oesophageal temperatures remained constant during the whole study period. There were no intergroup differences between the base-line values for any monitored parameters.
Theophylline significantly decreased Vm-MCA in both groups (Fig. 1). During 1 MAC halothane anaesthesia, Vm-MCA fell significantly from 62.8 cm s−1 (T0) to 53.6 cm s−1 (T1, a 14.6% fall relative to T0), 49.0 cm s−1 (T2; an 8.6% fall relative to T1) and 47.1 cm s−1 (T3; a 3.8% fall relative to T2). Vm-MCA during 1 MAC isoflurane anaesthesia decreased from 60.6 cm s−1 (T0) to 51.0 cm s−1 (T1; a 15.8% fall relative to T0), 45.1 cm s−1 (T2; an 11.6% fall relative to T1) and 42.0 cm s−1 (T3; a 6.8% fall relative to T2). Altogether, Vm-MCA fell by 25% in the halothane group and 30.6% in the isoflurane group (T3 vs. T0). In the monitoring period which followed there were no relevant changes. At the end of the examination, Vm-MCA had not returned to the initial values observed either in the halothane group or in the isoflurane group. For both groups, Vm-MCA values were ≈26% below initial values (T9 vs. T0). In the halothane group, pulsatility-index (PI) [Fig. 2] remained constant over the whole study period, but PI in the isoflurane group increased significantly from 0.74 (T0) to 0.89 (T3); a total PI increase of +20.2% (T3 vs. T0). In the period that followed, PI values remained high until the end of the examination (a rise of 12.2%; T9 vs. T0).
In the human clinical study presented here the effects of theophylline on blood flow velocity in the middle cerebral artery were investigated and compared during steady-state anaesthesia induced by halothane or by isoflurane. A therapeutic theophylline dose leads to an acute and dose-dependent reduction in cerebral blood flow velocity both under halothane and isoflurane anaesthesia given at doses of 1 MAC (FiO2: 40% and without the use of nitrous oxide).
No human studies have described the influence of therapeutic theophylline doses on cerebral haemodynamic responses during halothane or isoflurane anaesthesia. Acute changes in CBF and cerebral blood flow velocity, comparable in extent with the cerebral blood flow velocity induced changes that we observed following therapeutic theophylline administration, have until now only been seen in patients with bronchial asthma, chronic obstructive pulmonary diseases and in preterm infants [2,16-21,32]. Bowton et al.[2,16] showed that a theophylline dose of 6 mg kg−1, i.v., in conscious, spontaneously breathing patients with bronchial asthma and chronic obstructive pulmonary disease lead to a 26% reduction in regional cerebral blood flow which persisted at 23% below base-line values throughout the maintenance phase. In preterm and low birth weight infants, similar reductions in CBF and cerebral blood flow velocity were also described during a theophylline therapy with prolonged apnoea. Aminophylline administration was associated with parallel falls in CBF and cerebral blood flow velocity of up to 30% [19,20]. In further studies, the prolonged effects of theophylline on cerebral circulation could be described. In these studies, the CBF was still 13.8% , and the cerebral blood flow velocities were about 21% below base-line values, respectively, 1 h after theophylline administration [7,17].
In conscious, non-anaesthetized patients, it is hard to differentiate effects on CBF and cerebral blood flow velocity induced by theophylline alone. In spontaneously breathing patients, theophylline also causes a reduction in PaCO2 which occurs due to the increase in respiratory minute volume which is normally regulated positively by the alveolar pCO2. This effect is caused by a pharmacologically mediated increase in the sensitivity of medullary respiratory centres to the stimulatory actions of CO2. This therapeutic action is particularly desirable in pathophysiological states such as Cheyne-Stokes respiration or apnoea in preterm infants [17-20,32]. An often observed consequence of arterial pCO2 reduction is vasoconstriction of cerebral resistance vessels. As such, the CBF and cerebral blood flow velocity alterations observed in spontaneous breathing patients are often the combined effects of a direct theophylline action and an increase in the respiratory volume per minute. In our examination the patients were under controlled ventilation (the ventilator was adjusted to keep end-tidal pCO2 constant within normal limits) virtually excluding any significant changes in arterial pCO2. Our results are supported by some animal data [3,5,6]. Furthermore Govan et al., in a study on preterm neonates under normocapnia, observed significant reductions in CBF and cerebral blood flow velocity which were similar in extent to those observed in our study involving awake conscious patients . Because no changes were recorded among the other transcranial Doppler sonography influencing factors (particularly in the systemic circulation), the changes in blood flow velocities under both halothane and isoflurane were most likely to have been caused by the effects of theophylline on cerebral haemodynamic responses.
Additionally, in our study there were no differences in cerebral blood flow velocities between the two experimental groups following theophylline treatment. These results correspond well with earlier CBF and cerebral blood flow velocity measurements which showed that equipotent doses of different inhalation anaesthetics, ranging up to 1 MAC in oxygen/air, comparably affect cerebral perfusion. Distinct effects on cerebral perfusion were found when patients received different inhalational anaesthetics in higher doses (> 1 MAC) and especially when nitrous oxide is given simultaneously [23-27]. Thiel et al. first compared the effects of halothane, enflurane and isoflurane on cerebral blood flow velocity. Differences in cerebral blood flow velocity became evident especially with high halothane concentrations (> 1.6 vol% end-tidal given in nitrous oxide/oxygen 2:1) compared with enflurane and isoflurane even at high doses. However, in future investigations it could be a point of interest to determine possible different substance specific effects of the volatile anaesthetics on theophylline induced alterations in cerebral haemodynamic responses as possible causes.
Methodological reservations concerning the interpretation of the findings arose, however, because changes in the cross sectional areas of the middle cerebral arteries could not be assessed by transcranial Doppler sonography. Because the already mentioned substance-specific influences of both the halogenated anaesthetics and theophylline on cerebral haemodynamic responses, an influence on the cross-sectional areas of the basal brain arteries certainly seems credible, and this could lead to a misinterpretation of the actual CBF changes when using transcranial Doppler sonography. However, a direct comparison between the effects of theophylline administration on general anaesthesia induced by halothane and isoflurane using established CBF measurement techniques as well as transcranial Doppler sonography for the purpose of validating the results of Doppler sonography remains to be undertaken.
None of the factors which affect recording by transcranial Doppler sonography (e.g. constant Doppler probe position, ultrasonic measurement depth, arterial pCO2 and O2, blood pressure, heart rate, body temperature) showed any significant changes over the whole study. As such, ventilation influences or partial hypoxaemic or hypothermic phases could be excluded as causes underlying the recorded flow velocity changes [31,33,36]. All transcranial Doppler sonography recordings were made by the same operator, and the Doppler probe was fixed in position during the measurement period. Systematic changes in the insonation angle seems to us very unlikely and a change in cerebral blood flow velocity <2% would not be clinically relevant. A slight, non-significant increase in heart rate and a minor insignificant decrease in mean arterial pressure during theophylline administration could be seen in both groups; these changes returned almost to base-line at the end of the study period. Such modest effects are commonly seen after theophylline doses during isoflurane or halothane anaesthesia and could also be excluded as causes for the observed blood flow velocity changes [38-40].
Our results showed that application of a therapeutic dose of theophylline during halothane or isoflurane induced anaesthesia resulted in an acute and clinically significant reduction in cerebral blood flow velocity. Because the other experimental conditions remained constant, it is very possible that there was a simultaneous reduction in CBF. Previous studies have also showed, the effects of theophylline on the systemic circulation were not the primary cause of its effects on the cerebral circulation. In this respect, it would be interesting to perform further experiments which could determine whether theophylline application can lead to significant decreases in cerebral oxygen delivery and brain tissue oxygenation [21,29]. For patients either with borderline intracranial compliance (even pre-operatively), or those with reduced circulation, a therapeutic theophylline application during halothane or isoflurane induced anaesthesia could lead to an uncontrolled reduction in cerebral circulation with the accompanying danger of cerebral tissue hypoxia.
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