Department of Anesthesia, The Hospital for Sick Children and the University of Toronto, 555 University Avenue, Toronto, ON M5G 1X8, Canada
Corresponding author. E-mail: bruno@anaes.sickkids.on.ca Presented in part at the Annual meeting of the American Society of Anesthesiologists in Orlando, October 2002.
Accepted for publication: April 10, 2003
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Abstract |
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Methods. Ten children aged 1.56 yr were anaesthetized with sevoflurane and received a caudal block. Patients were allocated randomly to receive either airnitrous oxide or nitrous oxideair. Further randomization determined the sequence of E'CO2 (25, 35, 45, and 55 mm Hg) and sevoflurane (1.0 then 1.5 MAC or 1.5 then 1.0 MAC) concentrations. Once steady state had been reached, three measurements of Vmca, mean arterial pressure (MAP), and heart rate (HR) were recorded.
Results. Cerebrovascular carbon dioxide reactivity was reduced in the 2535 mm Hg E'CO2 range on the addition of nitrous oxide to 1.5 MAC, but not 1.0 MAC sevoflurane. A plateau in CCO2R of 0.40.6% per mm Hg was seen in all groups between E'CO2 values of 45 and 55 mm Hg. Mean HR and MAP remained constant throughout the study period.
Conclusions. Cerebrovascular carbon dioxide reactivity is reduced at and above an E'CO2 of 45 mm Hg during 1.0 and 1.5 MAC sevoflurane anaesthesia. The addition of nitrous oxide to 1.5 MAC sevoflurane diminishes CCO2R in the hypocapnic range. This should be taken into consideration when hyperventilation techniques for reduction of brain bulk are being contemplated in children with raised intracranial pressure.
Br J Anaesth 2003; 91: 1905
Keywords: anaesthesia, paediatric; anaesthetics gases, nitrous oxide; anaesthetics volatile, sevoflurane; brain, blood flow velocity; carbon dioxide; measurement techniques, Doppler ultrasonography
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Introduction |
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Sevoflurane and nitrous oxide are commonly used for the induction and maintenance of anaesthesia in children. As a neuroanaesthetic agent, sevoflurane may have advantages over other volatile agents.1 It has the least intrinsic cerebral vasodilatory activity of the volatile agents2 3 and maintains cerebral blood flow velocity (CBFV) constant with increasing MAC in both children and adults.4 5 The reduction in CBFV from awake levels is coupled with a reduction in cerebral metabolic rate for oxygen (CMRO2).6 7 Dynamic cerebral blood pressure autoregulation,8 ICP,9 and cerebrovascular reactivity to carbon dioxide (CCO2R) are maintained.6 1012
Nitrous oxide is known to cause cerebral vasodilatation, increase CMRO2 and CBFV in children and adults.1315 It has also been shown to increase CBFV when added to propofol16 17 and volatile anaesthetic agents,18 19 including sevoflurane.5 11 The CCO2R is maintained in adults with nitrous oxide alone,15 but is impaired when nitrous oxide is added to isoflurane anaesthesia.20
The aim of this study was to test the hypothesis that the addition of nitrous oxide affects CCO2R during 1.0 and 1.5 MAC sevoflurane in children.
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Methods |
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In each child anaesthesia was induced with sevoflurane in nitrous oxide/oxygen. I.V. access was secured and rocuronium 1 mg kg1 was administered to facilitate tracheal intubation. Anaesthesia was maintained with 1.0 and 1.5 MAC age-adjusted sevoflurane in the order determined by the randomization. Intermittent positive pressure ventilation was instituted with a peak airway pressure of 15 cm H2O and zero positive end-expiratory pressure. The respiratory rate was adjusted to achieve an initial E'CO2 of 25 mm Hg. Thereafter, ventilatory settings and fresh gas flow remained unchanged. The E'CO2 was adjusted between 25, 35, 45, and 55 mm Hg in accordance with the randomization, by the addition of carbon dioxide to the circuit from an exogenous source. The inspired concentration of oxygen was maintained constant at 35% after induction of anaesthesia for the duration of the study. All subjects received continuous caudal epidural anaes thesia with 1.0 ml kg1 of bupivacaine 0.25% without epinephrine in order to block the cerebrovascular response to surgical stimulation during the study period. Surgery was allowed to commence 20 min after the caudal block had been performed and the block was assumed to be successful if upon skin incision the HR and MAP did not increase more than 5% from the pre-incision baseline. The study was carried out while surgery proceeded. Body temperature was measured with a nasopharyngeal temperature probe and normothermia maintained with a conductive water mattress and convective air warmer. Ringers lactate solution 10 ml kg1 h1 was administered and additional fluids given as needed to replace surgical losses. All subjects remained horizontal and supine for the duration of the study period.
The M1 segment of the middle cerebral artery was insonated by transcranial Doppler ultrasonography (TCD, Neuroguard, Medasonics, CA, USA) via the temporal window with a range-gated 2 MHz Doppler probe. The probe was fixed in position with a custom designed frame to ensure a constant angle of insonation throughout the study period.21
Fifteen minutes were allowed to reach steady state at each nitrous oxide and sevoflurane concentration and 5 min at each E'CO2 concentration, at which time three measurements of the middle cerebral artery blood flow velocity (Vmca) were recorded 30 s apart. Mean arterial pressure (MAP), heart rate (HR), E'CO2, and Vmca were recorded simultaneously. The TCD data were recorded onto computer for later analysis by an investigator unaware of the sequence order. Carbon dioxide was sampled from the distal end of the tracheal tube via a 19G catheter (Intracath, Becton Dickson, CA), to prevent contamination with the fresh gas flow. The carbon dioxide analyser (Capnomac Ultima, Datex, USA) was calibrated with a reference gas mixture prior to each study patient.
Statistical analysis
The number of patients needed to demonstrate a direct effect on CBFV during changes in nitrous oxide, E'CO2, or sevoflurane concentration was calculated with the assumption that a 20% change would be clinically relevant. Based on a statistical power of 0.8, an 2=0.05 and a ß=0.2, seven patients were suggested. Ten patients were studied to account for methodological difficulties that could have led to exclusion from the study. Demographic and parametric data are expressed as mean (SD). A repeated three-way multi-factorial ANOVA was used to analyse the effect of E'CO2, nitrous oxide, and sevoflurane concentrations on the magnitude of change in CBFV. This technique was also used to determine whether the combined interaction of either two or all three of the above variables significantly affected CBFV. The Students NewmanKeuls test was used for multiple comparison analysis and a Bartletts test was computed to confirm homogeneity of variances. A value of P<0.05 was accepted for statistical significance.
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Results |
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There were no significant changes in MAP or HR on the addition or removal of nitrous oxide at 1.0 and 1.5 MAC sevoflurane, regardless of the E'CO2 level (Table 1). Although there was a trend for MAP to be lower at 1.5 MAC sevoflurane across E'CO2 levels, this did not reach statistical significance. MAP remained within the accepted cerebral autoregulatory values for that age group. During the study there were no significant changes in body temperature or FIO2. There was no significant blood loss for any of the surgical procedures and i.v. fluids were standardized to account for pre-operative deficit.
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Discussion |
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The observed CCO2R of 1.6% during hypocapnia in the 1.5 MAC sevoflurane in nitrous oxide group is similar in magnitude to that seen with 1.0 MAC isoflurane (2.6%) and 1.0 MAC halothane (1.4%) in a comparable group of children.23 In the current study, CCO2R at hypocapnia in the other groups (1.0 MAC sevoflurane with air and nitrous oxide and 1.5 MAC sevoflurane with air) shows reactivity to be well preserved and superior to that reported in an adult study with 0.7 MAC.22 In that study, CCO2R was said to be maintained between 20 and 50 mm Hg E'CO2; however, the degree of reactivity was reported less with sevoflurane in nitrous oxide than with isoflurane in nitrous oxide.22 No comparison of CCO2R was made without nitrous oxide in that study, nor between MAC values. As changes in E'CO2 were achieved by altering the ventilatory rate, changes in intrathoracic pressure affecting cerebral venous return and cerebral perfusion pressure cannot be excluded.
Previous related paediatric studies have found a plateau in CCO2R at and above an E'CO2 of 45 mm Hg during sevoflurane,12 isoflurane and halothane23 anaesthesia, presumably due to a more potent inherent vasodilatory effect of these volatile anaesthetic agents in this age group. In the current study, a similar plateau effect was seen, which was unaffected by nitrous oxide. The reduction in CCO2R at 45 mm Hg E'CO2 demonstrated in children would suggest that maximal cerebral vasodilatation was achieved, suggesting that a further increase in E'CO2 could not elicit any further increase in CBFV. A plateau in CCO2R has not been demonstrated in adults with any of the volatile anaesthetic agents within the same E'CO2 range. A recent paediatric study has demonstrated a plateau effect in CCO2R during propofol anaesthesia, although at the hypocapnic range (below 35 mm Hg).24 Under the cerebral vasodilatory effects of sevoflurane, a plateau in CCO2R has been demonstrated in the hypercapnic E'CO2 range (above 45 mm Hg).12
Sevoflurane has been reported to maintain CBFV over a range of MAC values in both children and adults.4 5 This is in keeping with results of the current study, as no MAC-related differences in CBFV were seen at any E'CO2 level. Like all volatile anaesthetic agents however, sevoflurane does possess some dose related intrinsic vasodilatory activity. In adults an increase in CBFV during 0.5 and 1.5 MAC sevoflurane anaesthesia has been demonstrated,3 although this increase was of smaller magnitude than that seen with isoflurane, halothane, or desflurane.2 3 Positron emission tomography and magnetic resonance imaging studies have confirmed these findings.25 26
Nitrous oxide is a known cerebral vasodilator and has been shown to increase CBFV in children and adults when used alone,13 2731 and in combination with volatile anaesthetic agents 5 11 18 19 32 and propofol 16 33 at normocapnia. Despite this, nitrous oxide does not seem to affect dynamic CCO2R, as demonstrated in an adult TCD study.15 Reistrup and colleagues have confirmed this finding with SPECT scanning, demonstrating that in adults the addition of nitrous oxide 50% had no effect on overall CBV or flow during hypo- and hypercapnia.34 Cerebral autoregulation, which has been shown to be preserved during sevoflurane anaesthesia alone,8 is impaired with the addition of nitrous oxide.32
In the present study, the observed stability of HR and MAP would suggest that the changes in CBFV were not a result of systemic haemodynamic alteration. Nor were they likely to have been caused by the cerebrovascular response to surgical stimulation, which seemed to have been successfully eliminated by the caudal block. In children caudal anaesthesia does not affect haemodynamic variables35 and cerebral pressure autoregulation during sevoflurane anaesthesia has been reported to be intact within the carbon dioxide36 and MAC37 ranges studied. Other determinants of CBFV, including temperature, FIO2 and ventilatory parameters were kept constant. Changes in E'CO2 were achieved by the addition of exogenous carbon dioxide to the circuit, thus avoiding changes in airway pressure, intrathoracic pressure, or cerebral venous return. E'CO2 was sampled from the distal end of the tracheal tube, preventing mixing of expired gas with the fresh gas flow.38 In healthy children E'CO2 measurements have been shown to reliably reflect arterial carbon dioxide.39 As hyperoxia causes cerebral vasoconstriction and reduces CBFV,40 a constant FIO2 of 35% was maintained after anaesthetic induction and for the duration of the study period.
The age range of our study patients was chosen to minimize age-related effects on CBFV. From birth to 18 months CBFV increases rapidly, followed by a small further increase to peak values at around 7 yr of age, thereafter declining with increasing age.41 In our study population, 18 months to 6 yr old, CBFV should therefore be relatively unaffected by age.
Measurement of CBFV was made using TCD ultrasonography, which is a non-invasive, reproducible technique that has been validated in children as a surrogate measure of cerebral blood flow (CBF).42 Relative changes in CBFV have been shown to correlate well with changes in CBF measured with other techniques including i.v. xenon clearance and radioactive microspheres.43 44 Variability in CBFV measurements of up to 15% can result from changes in the angle of insonation of the Doppler beam with the MCA.45 To avoid this source of error, the Doppler probe was fixed in position using a custom designed frame.21 Having accounted for confounding factors that can affect CBFV and possible experimental errors, the observed changes in CBFV recorded are therefore likely to represent the effect of changes in E'CO2 and anaesthesia during the study period.
In conclusion, the combined effect of 1.5 MAC sevoflurane with nitrous oxide in children is sufficient to significantly reduce the cerebral vasoconstrictive effects of hypocapnia. During paediatric neuroanaesthesia, the apparent reduction in cerebrovascular carbon dioxide reactivity during 1.5 MAC sevoflurane anaesthesia with the addition of 70% nitrous oxide should be considered when hyperventilation techniques for reduction of brain bulk are being contemplated.
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