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PEDIATRIC ANESTHESIA

The Effect of Sevoflurane on Cerebral Autoregulation in Young Children as Assessed by the Transient Hyperemic Response

Department of Anesthesia, Hospital for Sick Children, Toronto, Ontario, Canada

Address correspondence and reprint requests to Gordon Wong, FANZCA, Hospital for Sick Children, Department of Anesthesia, 555 University Avenue, Toronto, ON M5G 1X8, Canada. Address email to gordontcwong{at}hotmail.com.

	Abstract

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The transient hyperemic response (THR) test is a simple, noninvasive technique to evaluate cerebral autoregulation using transcranial Doppler. It has not yet been used in studies involving children. In this study we evaluated this response in children undergoing general anesthesia using sevoflurane. Twenty ASA physical status I children undergoing elective urological surgery sequentially received sevoflurane at 0.5, 1.0, and 1.5 MAC in a randomized order. Analgesia was solely provided by caudal anesthesia. The right middle cerebral artery flow velocities before (F1), during (F2), and after (F3) a 10-s ipsilateral carotid artery compression were recorded. The THR ratios (THRR) (± sd) for 0.5 MAC, 1.0 MAC, and 1.5 MAC were 1.24 ± 0.11, 1.16 ± 0.09, and 1.13 ± 0.07, respectively. The THRR was significantly different between 0.5 MAC versus 1.0 and 1.5 MAC, respectively (P < 0.05). However, no difference was detected between 1.0 and 1.5 MAC. A THRR of more than 1.09 has previously been accepted as the lower limit of a positive response. The results in this study suggest that THR is affected by sevoflurane in a dose-dependent fashion but is maintained at up to 1.5 MAC. This suggests cerebral autoregulation is preserved in children anesthetized with up to 1.5 MAC sevoflurane.

	Introduction

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Limited information is available about cerebral autoregulation in young children. There seem to be no age-related differences in autoregulatory capacity or lower limit of cerebral autoregulation in children when compared with adults (1,2). Out of practical necessity, acquisition of such data must be from either deeply sedated or anesthetized patients. In the aforementioned studies, data were acquired from patients anesthetized with sevoflurane. It has been demonstrated in adults that sevoflurane has a less intrinsic dose-dependent cerebral vasodilatory effect when compared with isoflurane (3). In addition, dynamic cerebral autoregulation (4), cerebral pressure autoregulation (5), and the transient hyperemic response (THR) are preserved with sevoflurane (6).

The effects of sevoflurane on the cerebral vasculature and autoregulation in children, as important as they may be, are only poorly defined when compared with adults. In healthy children receiving sevoflurane at up to 1.5 MAC, cerebral blood flow velocity is unaffected (7). Cerebrovascular reactivity to carbon dioxide is preserved with 1.0 MAC of sevoflurane, but the effect seems maximal above an end-tidal CO₂ (ETco₂) of 45 mm Hg (8). No such effect has been reported with any volatile anesthetic in adults. This may suggest a possible difference in the characteristics of the cerebral vasculature in this age group.

The THR test (THRT) uses transcranial Doppler ultrasound (TCD) to evaluate the cerebral autoregulatory potential in adults. The THR ratio (THRR) provides an index of cerebral autoregulation in healthy and head-injured adults (9,10). The test is noninvasive and requires no pharmacological manipulation, which makes it desirable for use in pediatric studies. However, it has not been used in previous scientific investigations involving pediatric subjects. The purpose of this study was to investigate the practicality of this test and the nature of the THR in normal children and to measure the effects of sevoflurane on cerebral autoregulation.

	Methods

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After obtaining Research Ethics Committee approval and informed consent from the parents, 20 ASA physical status I patients aged between 1 and 5 yr undergoing elective urological surgery were recruited. Patients were excluded if they had a history of prematurity, neurological, cardiac or pulmonary disease, or a contraindication to regional anesthesia.

The unpremedicated patients underwent an inhaled induction with 8% sevoflurane in 100% oxygen. Standard monitors including electrocardiogram, noninvasive arterial blood pressure, pulse oximetry, end-tidal gas monitoring, and body temperature were instituted. After securing IV access, 0.6 mg/kg of rocuronium was administered to facilitate tracheal intubation. Up to 10 mL/kg of lactated Ringer’s solution was given to replace fasting deficits and thereafter administered at a rate sufficient to provide maintenance requirements and to replace intraoperative fluid losses. A caudal epidural block using 1 mL/kg of plain bupivacaine 0.25% was performed and the patient was then placed in the supine position for surgery. Twenty minutes were allowed for the caudal block to become effective, which was assumed to be successful if, on skin incision, the heart rate and mean arterial blood pressure (MAP) did not increase by more than 5% from the baseline obtained immediately before skin incision. No supplemental analgesics were given until the end of data acquisition. The lungs of the patients were ventilated with a fraction of inspired oxygen concentration (Fio₂) of 0.35 in air with a fresh gas flow of 3 L/min using intermittent positive pressure ventilation. Peak airway pressures of up to 15 cm H₂O were used with the respiratory rate adjusted to yield an ETco₂ of 35 mm Hg. Each patient received 0.5, 1.0, and 1.5 age-adjusted MAC of sevoflurane (11) in a randomized sequence, allowing 15 min to achieve steady-state after each change in the anesthetic concentration. End-tidal sevoflurane concentrations, Fio₂, and ETco₂ were continuously analyzed with a Datex monitor (Datex Capnomac Ultima, Datex Instruments Corporation®, Helsinki, Finland).

The M1 segment of the right middle cerebral artery (MCA) was insonated through the temporal bony window using a range-gated TCD (Neuroguard; Medasonics®, Fremont, CA) with 2 MHz emitted ultrasonic frequency. The transducer was secured in place using a custom-made frame (12) to maintain the angle of insonation constant. After obtaining the desired steady-state end-tidal concentration of sevoflurane, vital signs were recorded immediately before each compression. The patients were subjected to up to 3 consecutive right common carotid artery compressions for 10 s to produce a maximal decrease in cerebral blood flow velocity, allowing a minimum of 1 min between compressions. The TCD signals were digitally stored and made available for offline analysis. The outer spectral envelope corresponding to the maximum velocity throughout the cardiac cycle was used for analysis purposes. Peak flow velocities immediately before compression (F1), after compression (F2), and on release of compression (F3) were measured. The magnitude of the decrease in flow velocity in MCA is reflected in the compression ratio (CR) (9) and is calculated from the formula (F1 – F2) x 100/F1. A compression time of 10 s and a CR of 40% or more allowed for maximum expression of the hyperemic response in healthy adult volunteers (13).

Two indices of cerebral autoregulation have been derived from the THRT: the THRR (9) and strength of autoregulation (SA) (14). The THRR is defined as the ratio of F3/F1 and SA is calculated by the following formula:

where P2 denotes the estimated MCA pressure at the onset of compression. P2 is derived from the formula P2 = MAP · F2/F1 or the value of 60 mm Hg, whichever is greater.

As there are no THRR data for awake children, we referred to a similarly designed study in adults (15). From their pooled data, they found 8 patients were required for < 0.05 and ß > 0.95 to detect a change of 2 standard deviations for the SA. In the present study, it was decided to perform an interim analysis after 20 patients to account for any methodological difficulties and inherent differences between children and adults. A post-priori power analysis using the values obtained at 0.5 MAC as baseline indicated that this sample size had at least a power of 80% to detect a difference in THR between the groups and therefore no more patients were recruited. All parametric data are expressed as mean ± sd. Data were analyzed using repeated-measures analysis of variance and the Student-Newman-Keuls test for multiple comparisons, where appropriate.

	Results

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The caudal block was successful in all patients and there were no complications from the use of TCD and carotid compressions throughout the study period. The mean age and weight of the 20 children were 1.9 ± 0.7 yr and 12.6 ±1.2 kg, respectively. There was a significant increase in heart rate with increasing concentrations of sevoflurane, but MAP remained stable (Table 1). The peak flow velocities before compression did not vary significantly among the 3 different MAC values. The CR at 0.5 MAC was less than in the other 2 groups (Table 2). The THRR under the different MACs are shown in Figure 1.

View larger version (15K): [in this window] [in a new window]   Figure 1. Mean transient hyperemic response ratios (THRR) versus minimal alveolar concentration (MAC) of sevoflurane. The error bars indicate the standard deviations. THRR at 1.0 and 1.5 MAC are significantly different from that at 0.5 MAC (P < 0.05).

	Discussion

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This study indicates that the THR is present in healthy young children undergoing sevoflurane anesthesia. The THRR obtained at 1.5 MAC sevoflurane in this study exceeds 1.09; values less than this suggest an absence or impairment of cerebral autoregulation. Therefore this suggests that cerebral pressure autoregulation is preserved up to 1.5 MAC of sevoflurane, a finding similar to those found in adult studies (5,16). Further, sevoflurane appears to have a dose-dependent effect on this response without involving changes in MAP.

The THRT was first evaluated as a clinical tool by Giller (17) on a number of patients with neurosurgical disorders and subsequently analyzed theoretically by Czosnyka et al. (18). The test is based on the premise that with intact autoregulation, vasodilatation occurs after a short period of reduced cerebral blood flow induced by carotid artery compression, resulting in a temporary overshoot upon release until normal blood flow is reestablished in the dilated vessels. Assessment of cerebral autoregulation using THRT has shown to be comparable to autoregulatory indices derived from dynamic (9) and static methods of testing cerebrovascular reactivity (19).

THRT dictates the use of peak flow rather than mean flow velocity. Mean flow velocity shows the least variations and is thus most commonly used. The pre-compression peak velocity did not change significantly with increasing concentrations of sevoflurane, similar to the mean flow velocities (7). There were also no significant concentration-dependent changes in MAP in the study patients. Therefore, the observed changes in THRR can be attributable to the direct effects of sevoflurane on the cerebral vasculature, rather than through any changes in systemic hemodynamics which may secondarily affect the cerebral blood vessels.

Although THRR and SA are sensitive in reflecting changes in the static rate of autoregulation (19), the THR cannot be graded easily because the MCA perfusion pressure is not precisely known. Therefore, THRT has been used in a dichotomized fashion to indicate the absence of presence of cerebral autoregulation (20). A THRR of more than 1.09 has been considered a positive response in adults indicating intact autoregulation in a 3-s carotid compression test. Using this threshold in a group of adult patients with subarachnoid hemorrhages, Smielewski et al. (20) were able to demonstrate a highly significant correlation between a negative THR with a higher World Federation of Neurological Surgery score. As well, using the THRT with this threshold seems to be predictive of delayed ischemic deficits in patients with subarachnoid hemorrhage (21) and unfavorable outcome in patients with closed-head injury (10). However, there are limited data on the range of normal values for THRR in adults, and no data are available for children. Therefore, interpretation of the data in the present study is confined to a positive/negative response, using the adult value of 1.09 as a cut-off for a positive response. Using these adult values, the results from this study indicate that THR remains positive in children undergoing sevoflurane anesthesia at up to 1.5 MAC, a result that parallels the finding in adults (6). Increasing the dose of sevoflurane did reduce the magnitude of the THRR, but the reduction was not statistically significant beyond 1.0 MAC of sevoflurane. However, it may be that the THR may be significantly reduced at larger concentrations of sevoflurane.

This study has notably omitted the strength of autoregulation in its analysis. This index of autoregulation is defined as the ratio between the observed hyperemic response and the expected hyperemic response under ideal autoregulation. In effect, it is the THRR normalized for the change in MCA perfusion pressure, down to the lower limit of autoregulation (LLA) of 60 mm Hg. SA has been shown to be significantly less variable than, and equally sensitive as, THRR in detecting changes in cerebral autoregulation at graded levels of ETco₂ (14). Its calculation involves using the estimated MCA pressure at the onset of compression, P2. This pressure is in turn calculated by (F2/F1) multiplied by either MAP or an assigned value of 60 mm Hg, whichever is greater. Although other observations suggest that LLA in children may not differ from that in adults (2), the data were acquired on a small number of subjects anesthetized with sevoflurane. In addition, MAP is generally lower and closer to LLA in young children when compared with adults, resulting in the calculated P2 being far below the LLA in children, as was the case in our study population. Consequently, choosing 60 mm Hg, as P2 may be a gross over-estimation and may be invalid in this group. Given this problem, the SA was not calculated and compared in this study. Any calculations and interpretations of the SA index, if possible, would have to be made with great caution.

There are a number of inherent differences in performing THRT in children. The relative tachycardia in children compared with adults makes it more difficult to time the release of compression to end-diastole. Several attempts may be required to elicit a response that fulfills the specified criteria. It is very unlikely that this test could be performed in conscious children to obtain baseline values. The MAP of children lies closer to the LLA. Furthermore, the CR in this study is more than that reported from adult studies (15,19). Compression would almost universally place the MCA perfusion pressure far below the LLA. Because THR was present despite these conditions, it could be speculated that the LLA for young children may be less than that reported in adults.

All patients were unpremedicated and underwent similar surgical procedures, which was very well localized, associated with minimal fluid shift and no compression of major vessels and/or abdominal contents. The use of caudal epidural anesthesia in all patients in the present study enabled us to eliminate the effects of nociceptive stimulation without the use of systemic analgesics. As such, any possible confounding effects of premedication, systemic analgesics, mechanical interference to venous return, and large fluid shifts on cerebral perfusion, and hence the TCD readings were minimized.

There are a number of limitations to the design of this study. First, THR cannot differentiate changes in autoregulation from changes in the gradient or width of the autoregulatory plateau or a combination of both. As such, it should be used with the understanding that it is an indicator of vascular reactivity to pressure changes only. As mentioned previously, assessment of cerebral autoregulation using THRT has been shown to be comparable to autoregulatory indices derived from dynamic and static methods of testing in adults (9,19). However, studies directly comparing THRT to established methods of assessing cerebral autoregulation would have to be performed in children, preferably in the same subjects under the same conditions. Given ethical considerations and the impracticality of studying conscious young children, THR data may only be acquired from deeply sedated or anesthetized children. Consequently, baseline normal values may not be readily available for comparison in children, which constitutes the main limitation of this study. Further, the threshold of 1.09 for a positive response was derived from a group of head-injured adults, whose brains may behave differently than those of healthy children. As such, further investigations may be needed to characterize the response in children. Finally, the study did not use phenylephrine or other vasopressors to maintain MAP at baseline or above, which may have permitted calculation of SA. To do so may require invasive monitoring and longer data acquisition time than what this type of surgery would permit.

In conclusion, it is possible to perform the THRT in young children. A positive response can be elicited in children anesthetized with up to 1.5 MAC of sevoflurane. This suggests that sevoflurane may be a suitable anesthetic to use when studying cerebral autoregulation in children. Given its simplicity, the THRT seems to be a useful tool in anesthetic and neurosurgical research in children, but more studies are required to further characterize the THR in children.

	Footnotes

 
Accepted for publication November 4, 2005.

	References

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Wong, G. T. Articles by Bissonnette, B. Search for Related Content PubMed PubMed Citation Articles by Wong, G. T. Articles by Bissonnette, B. Related Collections Neuroanesthesia Pediatrics Pharmacology