Effect of stable xenon inhalation on intracranial pressure during measurement of cerebral blood flow in head injury

J Neurosurg 81:822 828, 1994 Effect of stable xenon inhalation on intracranial pressure during measurement of cerebral blood flow in head injury JAN PLOUGMANN, M.D., JENS ASTRUP, M.D., JENS PEDERSEN, M.D., AND CARSTEN GYLDENSTED, M.D. Departments of Neurosurgery, Neuroanesthesia, and Neuroradiology, Aarhus Kommunehospital, Aarhus, Denmark Xenon-enhanced computerized tomography (CT) is well suited for measurements of cerebral blood flow (CBF) in head-injured patients. Previous studies indicated divergent results on whether inhalation of xenon may cause a clinically relevant increase in intracranial pressure (ICP). The authors employed Xe-enhanced CT/CBF measurements to study the effect of 20 minutes of inhalation of 33% xenon in oxygen on ICP, cerebral perfusion pressure (CPP), and arteriovenous oxygen difference (AVDO 2 ) in 13 patients 3 days (mean 1 to 5 days) after severe head injury (Glasgow Coma Scale score 7). The patients were moderately hyperventilated (mean PaCO 2 4.3 kpa or 32.3 mm Hg). Six patients were studied before and during additional hyperventilation. All 13 patients reacted with an increase in ICP and 11 with a decrease in CPP. The mean ICP increment was 6.9 7.7 (range 2 to 17 mm Hg). The mean CPP decrement was 9.7 14.6 (range 17 to 47 mm Hg). The time course of the ICP changes indicated that ICP increased rapidly during the first 5 to 6 minutes, then declined to a plateau (peak-plateau type in four of 13 patients), remained at a plateau (plateau type in six of 13), or continued to increase in three of 13, indicating individual variance in xenon reactivity. Additional hyperventilation had no effect on the xenon-induced increments in ICP but these occurred at lower ICP and higher CPP baseline levels. The AVDO 2 values, an index of flow in relation to metabolism, indicated a complex effect of xenon on CBF as well as on metabolism. This study indicates that xenon inhalation for Xe-CT CBF measurements in head-injured patients according to our protocol causes clinically significant increments in ICP and decrements in CPP. It is suggested that the effect of xenon is analogous to anesthesia induction. Individual variations were observed indicating possible individual tolerance, possible influence of type and extent of the cerebral injury, disturbances in cerebrovascular reactivity, and possible influence of medication. These effects of xenon suggest that hyperventilation should be ensured in patients with evidence of reduced compliance or high ICP. On the other hand, inhalation of stable xenon is not believed to pose a risk because no signs of cerebral oligemia or ischemia were indicated in the AVDO 2 values. KEY WORDS cerebral blood flow cerebral metabolism intracranial pressure hyperventilation head injury stable xenon-enhanced computerized tomography X ENON (Xe) is a lipophilic inert gas that provides surgical anesthesia at a concentration of approximately 50%. Its clinical effect at approximately 30% is similar to the clinical effect of nitrous oxide. The Xe-enhanced computerized tomography (CT) cerebral blood flow (CBF) measurement method provides valuable information about CBF and its regional distribution in patients with severe head injury. 1,8,12 Such studies imply inhalation of approximately 30% xenon during the wash-in period of 4 minutes or more, depending on the procedure. Experimental studies in animals and in humans have indicated that xenon in this concentration has an effect on cerebral hemodynamics, causing arterial vasodilatation and enhancement of CBF. 4,6,7,9,11,15 Studies of flow velocity, as measured by transcranial Doppler sonography, have varied, but an increase has been found in most cases. 2,5,14 At the same concentration level, xenon suppresses alpha activity on electroencephalogram. 2,9 The vasodilatory effect of xenon inhalation may cause an increase in intracranial pressure (ICP), particularly in conditions of reduced pressure-volume compliance as in acute head injury; however, the results published so far are not in agreement. The study by Harrington, et al., 8 clearly indicated an increase in ICP within a wide range; only two of their 27 patients had no rise in ICP. In contrast, Darby, et al., 3 and Marion and Crosby 13 indicated no significant effect of xenon inhalation on ICP when concomi- 822 J. Neurosurg. / Volume 81 / December, 1994

Stable xenon and intracranial pressure tant changes in PaCO 2 were considered. This study reports the results of the effect of xenon inhalation in patients in the acute phase of severe head injury. Clinical Material and Methods Patient Population and Management From March, 1989, to June, 1990, we studied 13 patients admitted to our department suffering from severe head injury. The age of these patients varied between 15 and 65 years (median 23 years). There were two women and 11 men. On admission and on the day of study, they were all unconscious with Glasgow Coma Scale scores of 7 or less. They were intubated, moderate hyperventilation was induced, and they were sedated with barbiturates and morphine. As part of the clinical regimen intravenous and intra-arterial catheters were placed with a line in the internal jugular vein and the tip inserted in the bulb at the skull-base level. The ICP was measured by a subarachnoid bolt through an anterocoronal burr hole. This bolt allowed measurements of ICP, blood pressure, and hence cerebral perfusion pressure (CPP) as well as oxygen saturation, po 2, and pco 2 in the arterial and jugular blood using a Radiometer OSM2 and ABL 300.* The arteriovenous oxygen difference (AVDO 2 ) was calculated as the sum of the arterial and venous difference in oxygen saturation and of the dissolved oxygen content between arterial and jugular blood. Determination of CBF A CT scanner equipped with software for CBF and lambda calculations was used for the Xe-CT CBF studies. At the time of these studies, a protocol was chosen of 20-minute inhalation of 33% xenon in 67% oxygen to obtain optimum images of low-flow areas and lambda and to obtain a temporal profile of the xenon-induced changes in ICP and other variables. Peak-end expiratory xenon concentrations of 28% to 40% were achieved within 2 minutes and maintained during the inhalation time. End-tidal pco 2 was monitored using capnography, and the percentage of the xenon concentration was monitored by thermoconductivity. The patients were ventilated with 100% oxygen during transport from the intensive care unit and prior to and after xenon inhalation. On arrival at the CT room, the patients were connected to a volume-cycled ventilator, and this was used both prior to and during the Xe-CT CBF studies. Care was taken not to introduce any changes in inspiratory and expiratory ventilator pressures during the procedure and to maintain PaCO 2 in a stable manner. This way, the only variable was the xenon (and the oxygen) concentration. Blood * Radiometer A/S, Copenhagen, Denmark. Somatom RRH CT scanner with Siemens software obtained from Siemens Analytical X-Ray Instruments, Madison, Wisconsin. samples were obtained in the intensive care unit prior to transport to the CT scanning room; at 10, 2, and 1 minutes before; at 1, 2, 3, 5, 7, 5, 10, 15, and 20 minutes during xenon inhalation; and 1, 3, 5, and 10 minutes during the washout period. The study protocol was approved by the Ethics Committee of the County of Aarhus. All patients completed one Xe-CT CBF study while they were maintained on moderate hyperventilation equal to the clinical treatment regimen. The last six patients had a second Xe-CT CBF study with a 1-hour interval during additional hyperventilation. The time period of the Xe-CT CBF study after injury ranged from 1 to 5 days (median 3 days). Median outcome according to the Glasgow Outcome Scale score was 4 (range 1 to 4). Patient Medication All patients were sedated with pentobarbital. Three individuals received a combination of pentobarbital and phenobarbital, three a combination of pentobarbital and thiopental, and three a combination of all three barbiturates. The median dose was 400 mg with a range of 0 to 2525 mg per day. All patients received morphine: median dose of 45 mg, range 0 to 90 mg per day. All patients were also treated with paracetamol: range 0 to 4 gm per day (median dose 4 gm). Benzodiazepines and muscle relaxant medications were not used. Three individuals received dopamine for support of blood pressure. Results Baseline Value Findings In the 13 moderately hyperventilated patients, four had a baseline ICP above 20, six between 10 and 20 and three below 10 mm Hg. Two individuals had CPP below 70 mm Hg (48 and 62 mm Hg). Four had surgery on the day of admission: two for subdural, one for epidural, and one for both subdural and epidural hematomas. Two of these patients had ICP above 20 mm Hg (23 and 33 mm Hg) when studied. Baseline values of ICP, CPP, whole slice CBF (ventricular system excluded), PaCO 2, and AVDO 2 are presented in Table 1. Correlations between baseline CBF and PaCO 2, CBF and AVDO 2, and PaCO 2 and AVDO 2 were present (Fig. 1). Hyperventilation Studies Six patients were studied during additional hyperventilation. As shown in Table 1, PaCO 2 decreased in six of six, AVDO 2 increased in six of six; however, CBF decreased in only four of six, ICP decreased in five of five and CPP increased in five of five (one baseline ICP value missing due to a technical error). The effect of hyperventilation was more pronounced in AVDO 2 than in CBF. Effect of Xenon on ICP and CPP As indicated in Table 1, all 13 patients had an J. Neurosurg. / Volume 81 / December, 1994 823

J. Plougmann, et al. FIG. 1. Scatterplots indicating corresponding baseline values of PaCO 2, arteriovenous oxygen difference (AVDO 2 ) and whole slice cerebral blood flow (CBS) and their interrelation. The correlation coefficient r was calculated by parametric correlation analysis. For conversion of PaCO 2 in kpa to mm Hg, use 7.5 as the proportionality constant. increase in ICP during xenon inhalation. Eleven patients experienced decreased CPP, one remained unchanged, and one increased. Three different types of ICP changes were recognized: 1) a peak-plateau type in four patients; 2) a plateau type in six patients; and 3) a steady-rise type was seen in three. Examples of these easily recognizable types are shown in Fig. 2. The pattern and magnitude of the increase in ICP was not significantly affected by additional hyperventilation although baseline ICP was lower, see also Fig. 2. The three types of changes in ICP in response to xenon inhalation were not related to level of PaCO 2, AVDO 2, ICP, CBF, medication, age or sex, or final outcome. There was a decrease in ICP and an increase in CPP during additional hyperventilation, although the changes in PaCO 2 were only moderate. The increase in CPP was proportionally higher than the decrease in ICP because of an increase in blood pressure concomitant with hyperventilation. Accordingly, CPP was better preserved during xenon inhalation with additional hyperventilation. There was a weak positive correlation (r = 0.76) between baseline ICP and the magnitude of increase in ICP either to the peak or to the plateau. This correlation was further weakened by additional hyperventilation (r = 0.30). Effect of Xenon on AVDO 2 No consistent effect of xenon inhalation on AVDO 2 was observed. The AVDO 2 could increase or decrease in relation to the increase in ICP, as indicated in Fig. 2. The effect of xenon on AVDO 2 fluctuated, particu- 824 J. Neurosurg. / Volume 81 / December, 1994

Stable xenon and intracranial pressure FIG. 2. Graphs demonstrating five patients typical changes in intracranial pressure (ICP), PaCO 2, arteriovenous oxygen difference (AVDO 2 ), and cerebral perfusion pressure (CPP) occurring during 20 min of 33% xenon-enhanced computerized tomography cerebral blood flow (CBF) studies in head-injured patients. Cases A and B show the peak-plateau type, Cases C and D the plateau type, and patient E the steady increase type of change in ICP. Cases A to D were studied before (filled circles) and after (open circles) additional hyperventilation. The hatched bar on the abscissa indicates the xenon inhalation time. For conversion of PaCO 2 in kpa to mm Hg, use 7.5 as the proportionality constant. J. Neurosurg. / Volume 81 / December, 1994 825

J Plougmann, et al. larly in the first minutes of xenon inhalation. This indicates that xenon is not a metabolic neutral vasodilator, but has a more complex effect on flow and metabolism. Discussion The results of this study show that under the present conditions xenon inhalation for Xe-CT CBF measurements caused an increase in ICP and a decrease in CPP. This is a matter of concern in some head-injured patients in whom ICP may increase considerably so that CPP falls below 70 mm Hg (Fig. 2A to C, and Table 1). Our patients were studied during conditions of moderate (mean PaCO 2 4.3 kpa or 32.3 mm Hg) and additional hyperventilation. This additional hyperventilation improved CPP by reducing baseline ICP and increasing blood pressure, while the increase in ICP during xenon inhalation was more or less unaffected (Table 2, see dicp-xe; Fig. 2). Accordingly, CPP was better preserved when Xe-CT CBF was performed during additional hyperventilation. Furthermore, we found a weak positive correlation between baseline ICP and the ICP increase during xenon inhalation. These results have led us to be cautious with Xe-CT CBF studies in patients with elevated ICP or in the early acute phase before ICP is monitored, if mass lesions or other CT signs of elevated ICP, such as brain swelling and reduced basal cisterns are present. Under such conditions, hyperventilation should be performed prior to the Xe-CT CBF study; however, we do not consider the effect of xenon to be a risk for the patient. It may be argued that the increase in ICP and decrease in CPP pose a risk of ischemia. If so, this would be indicated by an increase in AVDO 2, which was not the case in any of the patients, not even in the patient data illustrated in panel A of Fig. 2 with the largest decrease in CPP. In comparison, additional hyperventilation well within generally accepted therapeutic levels caused a clear increase in AVDO 2 (Table 1 and Fig. 2). Literature Review and Comparison of Technique The results of this study are in agreement with the results of Harrington, et al. 8 In a similar group of patients, they observed average increases in ICP of 81% (range 16% to 132%) in patients monitored by a ventriculostomy catheter and 50% (range 0% to 120%) in patients monitored by a subarachnoid bolt as in this study. They applied 35% xenon in oxygen for 7 minutes; no data on PaCO 2 were stated, but the patients were hyperventilated as part of the treatment regimen to maintain ICP below 15 to 20 mm Hg. Their PaCO 2 baseline and inspiratory pressure values probably did not change when switched to xenon because no ventilator parameters were adjusted. The results of our study are, however, at variance with the studies of Darby, et al., 3 and Marion and Crosby. 13 In two studies, they applied 32% xenon in oxygen for 4.5 minutes to groups of patients who were similar to our patients. The levels of baseline PaCO 2 prior to xenon inhalation were similar: 23.8 mm Hg (3.17 kpa) and 28.1 mm Hg (3.75 kpa) in the study by Darby, et al., and 34.5 mm Hg (4.6 kpa) in the study by Marion and Crosby. In the study by Darby and colleagues, the patients were divided into groups with baseline ICP greater than 20 or ICP less than 20. No significant ICP change was found in the high-icp group, whereas a small significant increase from 14.9 to 15.7 mm Hg at 3 minutes was observed in the low- ICP group. Three patients had increases to a maximum of 5 to 6 mm Hg, one of whom had unstable ICP requiring frequent CSF shunting and the other two coughed due to tracheobronchial secretion during the xenon inhalation. In the study by Marion and Crosby, no significant changes in ICP were observed either in the high-icp ( 20 mm Hg) or the low-icp ( 20 mm Hg) groups. Furthermore, it was observed that individual changes in ICP during xenon inhalation were closely correlated to concomitant unintended variations in PaCO 2. Our observed increases in ICP during xenon inhalation could not be explained as concomitant changes in PaCO 2 and were observed to the same degree during additional hyperventilation, although at lower baseline ICP and higher CPP levels. One apparent difference between these studies and this study is their much shorter inhalation time of 4.5 minutes, compared to our 20-minute time. Their endtidal xenon concentration reached peak values at 1 minute compared to our 20-minute period, thus exposing the brain to xenon a little faster. However, our ICP peak increases were already observed at maximum after 5.6 minutes and were up above 75% at 4.5 minutes (Fig. 2). Thus, the short inhalation time does not explain the difference in observations. If an increase in ventilatory pressure had occurred when switching to xenon inhalation, this could explain an increase in ICP simply as an increase in central venous pressure. However, care was taken in the planning of this study to avoid any such changes, and there was no variation in respirator settings when switching from 100% oxygen to the xenon/oxygen mixture. Accordingly, we conclude that the increase in ICP during xenon inhalation is caused by an increase in cerebral blood volume and probably also in blood flow due to a vasodilatory effect on the arterial side by xenon. The conclusion suggesting a vasodilatory effect of xenon makes the observation of AVDO 2 of interest as a parameter, indicating the match between global flow and global metabolism. If xenon acts as a metabolic neutral vasodilator to increase blood flow, this should be mirrored by a decrease in AVDO 2 ; however, as indicated in Fig. 2 no such changes in AVDO 2 were observed. On the contrary, the AVDO 2 values were unstable and fluctuating during the minutes of ICP increase. This indicates that xenon either causes dilatation of the large vessels to increase cerebral blood volume but not flow, or alternatively, if blood flow is increased then cerebral metabolism must also be increased. The latter possibility accords with many studies indicating an increase in CBF by 826 J. Neurosurg. / Volume 81 / December, 1994

Stable xenon and intracranial pressure xenon. 4,6,7,9,11,15 The lack of correlation between AVDO 2 and the effect of xenon on ICP points toward the ability of xenon to enhance blood flow as well as metabolism. The reliability of AVDO 2 values may be questioned as part of this argument. Because oxygen partial pressures were very high and changed from 100% to 70% when switching to xenon, the amount of dissolved oxygen in blood is significant and must be considered. By calculation, we added the amount of dissolved oxygen to the saturation on the jugular venous and arterial side. The baseline values of AVDO 2 were correlated to PaCO 2 and to CBF as seen in Fig. 1 B and C as a sign of reliability of this parameter. When discussing the effects of xenon on CBF and metabolism, it is reasonable to mention the studies on EEG and transcranial Doppler sonography. From their observations of EEG changes in human volunteers, Holl, et al., 10 found enhanced beta activity during 5 minutes of xenon inhalation. They suggest an effect of xenon similar to the state of induction in general anesthesia with enhanced cerebral activation and metabolism. Hartmann, et al., 9 studied EEG s and regional CBF in baboons during xenon inhalation. They found suppression of alpha and beta activity when compared to administration of 66% nitrous oxide. Regional blood flow measured by the intra-arterial 133 Xe method increased initially and then declined gradually, not unlike our peak-plateau type of ICP changes. Intracranial Doppler studies of flow velocities in the middle cerebral artery in human volunteers during 5 minutes of xenon inhalation have been published by Giller, et al. 5 They found increasing flow velocities during the 5 minutes of inhalation in spite of a tendency to hyperventilate. The time course of their flow velocity increases is strikingly similar to our first 5- minute observations of ICP increases in the peakplateau or plateau type. At the same time the pulsatile index decreased indicating a fall in peripheral resistance and vasodilatation. Observations in accordance with this in human volunteers have been published by Marks, et al., 14 and by Broich, et al. 2 These studies also underline the individual variations in reactivity. Most volunteers react by an increase in flow velocity but some (approximately 20% to 30%) react adversely by showing no change or even a fall in flow velocity. Considering the analogy between xenon inhalation and anesthesia induction, individual levels of reactivity are to be expected. This has indeed been our experience in clinical practice with the Xe-CT CBF method. 16 Another variable in patients with head injury may be the extent and type of brain lesion with varying degree of disturbances in cerebrovascular reactivity. It is possible that patient medication may influence and possibly block part of the effects of xenon on CBF and metabolism. Variations in patient medication may explain the fact that minimal or no effect of xenon inhalation on ICP was observed in some studies. 3,13 However, lack of detailed information about patient medication makes a comparison between the studies impossible. None of our patients received any kind of benzodiazepines or muscle relaxant drugs. Conclusions We conclude that xenon inhalation in acute headinjured patients causes an increase in ICP and a decrease in CPP, which in the majority of patients are most pronounced after 5 to 6 minutes, as indicated by peak plateau or just plateau types of changes. Hyperventilation did not change this individual reaction but the ICP changes during hyperventilation occurred at a lower baseline level of ICP and at a higher baseline level of CPP. It is suggested that xenon increases cerebral metabolism and blood flow in an analogous fashion to anesthesia induction. Individual variations were observed indicating possible individual tolerance, influence of type and extent of the cerebral injury, disturbances in cerebrovascular reactivity, and influence of medication. These effects of xenon have led us to ensure hyperventilation in patients with evidence of reduced compliance or high ICP. On the other hand, inhalation of stable xenon is not considered to pose a risk because no signs of cerebral oligemia or ischemia were indicated in the AVDO 2 values. References 1. Bouma GJ, Muizelaar JP, Stringer WA, et al: Ultra-early evaluation of regional cerebral blood flow in severely head-injured patients using xenon-enhanced computerized tomography. J Neurosurg 77:360 368, 1992 2. Broich H, Bülau P, Hartmann A, et al: The effect of stable xenon inhalation on cerebral blood flow velocities and topographic electroencephalography in normal volunteers, in Yonas H (ed): Cerebral Blood Flow Measurement with Stable Xenon Enhanced Computed Tomography. New York: Raven Press, 1992, pp 292 295 3. Darby JM, Yonas H, Pentheny S, et al: Intracranial pressure response to stable xenon inhalation in patients with head injury. Surg Neurol 32:343 345, 1989 4. Dewitt DS, Fatouros PP, Wist AO, et al: Stable xenon versus radiolabeled microsphere cerebral blood flow measurements in baboons. Stroke 20:1716 1723, 1989 5. Giller CA, Purdy P, Lindstrom WW: Effects of inhaled stable xenon on cerebral blood flow velocity. AJNR 11: 177 182, 1990 6. Gur D, Yonas H, Jackson DL, et al: Measurement of cerebral blood flow during xenon inhalation as measured by the microspheres method. Stroke 16:871 874, 1985 7. Gur D, Yonas H, Jackson DL, et al: Simultaneous measurements of cerebral blood flow by the xenon/ct method and the microsphere method. A comparison. Invest Radiol 20:672 677, 1985 8. Harrington TR, Manwaring K, Hodak J: Local basal ganglia and brain stem blood flow in the head-injured patient using stable xenon-enhanced CT scanning, in Miller JD, Teasdale GM, Rowan JO, et al (eds): Intracranial Pressure VI.Berlin: Springer-Verlag, 1986, pp 680 686 9. Hartmann A, Wassman H, Czernicki Z, et al: Effect of stable xenon in room air on regional cerebral blood flow and electroencephalogram in normal baboons. Stroke 18: 643 648, 1987 10. Holl K, Nemati N, Kohmura E, et al: Stable-xenon-CT: J. Neurosurg. / Volume 81 / December, 1994 827

J. Plougmann, et al. Effects of xenon inhalation on EEG and cardio-respiratory parameters in the human. Acta Neurochir 87:129 133, 1987 11. Junck L, Dhawan V, Thaler HT, et al: Effects of xenon and krypton on regional cerebral blood flow in the rat. J Cereb Blood Flow Metab:126 132, 1985 12. Marion DW, Bouma GH: The use of stable xenon-enhanced computed tomographic studies of cerebral blood flow to define changes in cerebral carbon dioxide vasoresponsivity caused by a severe head injury. Neurosurgery 29:869 873, 1991 13. Marion DW, Crosby K: The effect of stable xenon on ICP. J Cereb Blood Flow Metab 11:347 350, 1991 14. Marks EC, Yonas H, Sanders HM, et al: Effects of xenon and CO 2 inhalation on flow velocity measured with transcranial Doppler, in Yonas H (ed): Cerebral Blood Flow Measurements with Stable Xenon Enhanced Computed Tomography. New York: Raven Press, 1992, pp 286 291 15. Obrist WD, Jaggi J, Harel D, et al: Effect of stable xenon in human CBF. J Cereb Blood Flow Metab 5:557 558, 1985 16. Pentheny SL: Patient care considerations, in Yonas H (ed): Cerebral Blood Flow Measurement with Stable Xenon Enhanced Computed Tomography. New York: Raven Press, 1992, pp 16 21 Manuscript received October 29, 1993. Accepted in final form February 17, 1994. Address reprint requests to: Jens Astrup, M.D., Department of Neurosurgery, Aarhus Kommunehospital, 8000 Århus C, Denmark. 828 J. Neurosurg. / Volume 81 / December, 1994