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Department of Anesthesia, The Hospital for Sick Children and the University of Toronto, Ontario, Canada
Address correspondence and reprint requests to Bruno Bissonnette, Department of Anesthesia, The Hospital for Sick Children, 555 University Ave., Toronto, Ontario, M5G 1X8, Canada. Address e-mail to bruno{at}anaes.sickkids.on.ca
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Abstract |
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IMPLICATIONS: Nitrous oxide, which increases cerebral blood flow, does not affect cerebrovascular reactivity to carbon dioxide (CCO2R) in children anesthetized with propofol. When preservation of CCO2R is required, the combination of nitrous oxide with propofol anesthesia in children may be suitable.
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Introduction |
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N2O is a cerebral vasodilator that increases the CMRO2 and CBFV in adults (6,7) and children (8). Increases in CBFV are seen with the addition of N2O to both volatile (9) and propofol (6,10) anesthesia. Despite this, CCO2R seems to be maintained when N2O is used alone (7). The aim of this study was to determine the effect of N2O on CCO2R in children during propofol anesthesia, as measured by transcranial Doppler (TCD) ultrasonography.
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Methods |
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Using computer-generated random number tables, each patient was randomized to receive either air followed by N2O or N2O followed by air, each in 35% fraction of inspired oxygen (FIO2). Further randomization determined the sequence order of 4 end-tidal (ET)CO2 levels (25, 35, 45, and 55 mm Hg) during each N2O and air phase.
Anesthesia was induced with 2% sevoflurane in N2O/O2. After establishing IV access, sevoflurane was discontinued, and propofol 2.5 mg/kg was administered. Tracheal intubation was facilitated with rocuronium 1 mg/kg, and intermittent positive-pressure ventilation with peak airway pressure of 15 cm H2O with zero end-expiratory pressure was instituted. The respiratory rate was adjusted to achieve an initial ETCO2 of 25 mm Hg. Thereafter, ventilatory variables, fresh gas flow, and the inspired oxygen concentration remained unchanged. ETCO2 was adjusted between 25, 35, 45, and 55 mm Hg in accordance with the randomization by the addition of CO2 to the ventilatory circuit from an exogenous source. Anesthesia was maintained with a propofol infusion based on a pediatric pharmacokinetic model aimed at producing a steady-state plasma propofol concentration of 3 µg/mL (11). This was achieved with a propofol infusion rate of 15 mg · kg-1 · h-1 for the first 15 min, 13 mg · kg-1 · h-1 for the next 15 min, 11 mg · kg-1 · h-1 from 30 to 60 min, and 10 mg · kg-1 · h-1 thereafter. A caudal epidural block was established using 1 mL/kg of 0.25% plain bupivacaine to eliminate the cerebrovascular response to surgical stimulation. Surgery was allowed to commence 20 min after the caudal block had been performed, and the block was assumed to be successful if on skin incision the heart rate (HR) and mean arterial blood pressure (MAP) did not increase more than 5% from preincision baseline. The study was performed while surgery proceeded. Body temperature was measured with a nasopharyngeal temperature probe, and normothermia was maintained with a conductive warming mattress and convective air warmer. Ringer’s-lactate solution at 10 mL · kg-1 · h-1 was administered and additional fluids given as required to replace surgical losses. All subjects remained horizontal and supine for the duration of the study period.
CBFV at the M1 segment of the middle cerebral artery (MCA) was measured by TCD ultrasonography (Neuroguard, Medasonics, Newark, CA). The MCA was insonated via the temporal window with a range-gated 2 MHz Doppler probe set at a power of 70%, a gain of 8 dB, and sample volume of 0.7 mm. The probe was fixed in position with a custom designed frame to ensure a constant angle of insonation throughout the study period (12). After each change in N2O concentration, 15 min were allowed for equilibration. After each change in ETCO2, 5 min were allowed. At each ETCO2 level, 3 sets of measurements of mean CBFV were recorded at 30-s intervals, with noninvasive MAP, HR, ET sevoflurane concentration, inspired oxygen concentration, SpO2, airway pressure, respiratory rate, and nasopharyngeal temperature being recorded simultaneously. The TCD data were recorded for later analysis by an investigator who was unaware of the sequence order changes in ETCO2 and N2O. CO2 was sampled from the distal end of the endotracheal tube via a 19-gauge catheter (Intracath, Becton Dickinson, Palo Alto, CA) to prevent contamination with the fresh gas flow. The CO2 analyzer (Capnomac Ultima, Datex, Helsinki, Finland) was calibrated with a reference gas mixture before each study.
The number of patients required to demonstrate a direct effect on CBFV during changes in ETCO2 or N2O concentration was calculated with the assumption that a 20% change would be clinically relevant. Based on a statistical power of 0.8, 
2 of 0.05, and ß of 0.2, 7 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. The relationship between ETCO2 and CBFV was obtained by nonlinear regression analysis, and the correlation coefficient (r) was calculated. Within group analysis of middle cerebral artery blood flow velocity, HR and MAP data were achieved using repeated-measures analysis of variance and the Student-Newman-Keuls test for multiple comparisons. A P value of <0.05 was accepted for statistical significance.
Results
Ten patients were studied with a mean age and weight of 3.7 ± 1.5 yr and 16.3 ± 4.5 kg, respectively. The caudal block was successful in all patients, and TCD measurements were collected at all stages of the study in all patients. There were no complications from the study.
There were no significant changes in MAP or HR on the addition or removal of N2O, regardless of the ETCO2 level (Table 1). MAP remained within the accepted cerebral autoregulatory values for that age group. Body temperature and FIO2 were maintained constant throughout. There was no significant blood loss from any of the surgical procedures, and IV fluids were standardized to account for preoperative deficit and maintenance requirements.
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Discussion |
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Fox et al. (13) demonstrated that CCO2R was preserved in adults with propofol/N2O in the 30–50 mm Hg ETCO2 range. However, in that study, changes in ETCO2 were achieved by altering ventilation. As changes in intrathoracic pressure affect central venous pressure and hence cerebral perfusion pressure, a resultant alteration in CBFV cannot be excluded. In the current study, ventilatory variables were kept constant, with alterations in ETCO2 being achieved by the addition of exogenous CO2 to the circuit.
The plateau in CCO2R between 25 and 35 mm Hg of ETCO2 observed in children in the current study has not been demonstrated. In adult studies, the ETCO2-CBFV relationship is linear over a wide range of ETCO2 values. This has been reported in awake patients (14) as well as during propofol (5) and propfol/N2O anesthesia (13). However, in these studies, changes in CBF were measured at only three ETCO2 levels (hypo-, normo-, and hypercapnia). With only three data points over the same ETCO2 range as that of the present study, any plateau in CCO2R, if it exists, may be more difficult to detect. A plateau in CCO2R during propofol anesthesia has only been described in rabbit models (15).
A plateau in CCO2R at the hypercapnic ETCO2 range (more than 45 mm Hg) has been demonstrated with volatile anesthetics in children (16,17). This has not been demonstrated in adults with any of the volatile anesthetics within the same ETCO2 range.
N2O causes cerebral vasodilatation when used alone (8) and in combination with volatile anesthetics (9). In adults, a small but significant increase in CBFV is seen when N2O is added to propofol anesthesia (6), implying that some intrinsic vasodilatory activity of N2O is maintained. In a recent pediatric study, a 13% increase in CBFV was demonstrated with the addition of N2O to propofol anesthesia (10). This increase in CBFV has been reported to be reversible by hyperventilation (18). In the current study, it would seem that N2O had no effect on CBFV; however, it must be emphasized that this study was designed to investigate the steady-state effect of N2O on CCO2R rather than the effect of N2O on CBFV.
In the present study, the observed stability of HR and MAP would suggest that the changes in CBFV were not a result of systemic hemodynamic alteration. Nor were they likely to have been caused by the cerebrovascular response to surgical stimulation, which seemed to have been successfully obtunded by the caudal block. In children seven years of age and younger, caudal and spinal anesthesia do not affect hemodynamic variables, (19) and cerebral blood pressure autoregulation during propofol anesthesia has been reported to be intact over the CO2 range studied (4). Other determinants of CBFV, including temperature, FIO2, and ventilatory variables were kept constant. Changes in ETCO2 were achieved by the addition of exogenous CO2 to the circuit, preventing changes in airway pressure, intrathoracic pressure, or cerebral venous return.
ETCO2 was sampled from the distal end of the endotracheal tube, preventing mixing of expired gas with the fresh gas flow (20). In healthy children, ETCO2 measurements reliably reflect arterial CO2 (21). Because hyperoxia causes cerebral vasoconstriction and reduced CBFV (22), a constant FIO2 of 35% was maintained after anesthetic induction and for the duration of the study period. Depth of anesthesia was maintained at a constant level with a propofol infusion regime aimed at attaining an estimated steady-state plasma propofol concentration of 3 µg/mL. This was based on a pharmacokinetic model that is applicable to pediatric patients between 3 and 11 years of age (11). Although some of the patients in the current study were between 18 months and 3 years old, their exclusion would have meant that a clinically important and relevant subgroup of patients would be omitted. Furthermore, there are no published guidelines for propofol dosing to maintain the predicted steady-state levels of 3 µg/mL in children between 18 months and 3 years of age. CBF increases rapidly from birth to 18 months of age, followed by a much slower increase to a peak at age 7 (23). As such, CBFV should be relatively unaffected by age in the patient group currently studied.
TCD ultrasonography is a simple, reliable, and reproducible method of measuring CBFV and has been validated as a surrogate measure of CBF in children (24). Relative changes in CBFV correlate well with changes in CBF, as measured by other methods including IV xenon clearance and radioactive microspheres (25,26). Variability in CBFV measurements of up to 15% can result from changes in the angle of insonation of the Doppler beam with the MCA (27). To avoid this source of error, the Doppler probe was fixed in position using a custom designed frame (12).
Propofol seems to demonstrate the properties of an anesthetic suitable for neuroanesthesia. It has a favorable pharmacokinetic profile and reduces CBFV with a parallel reduction in CMRO2 in a dose-dependant manner, demonstrated in both children and adults (2,3). Propofol does not cause an epileptiform electroencephalogram and may have a cerebral protective effect during ischemia (28). Static and dynamic autoregulation to changes in blood pressure are maintained, and CCO2R is preserved (4,13).
In conclusion, the present study demonstrates that the addition of N2O to propofol anesthesia does not affect CCO2R in children. A plateau in CCO2R is seen in the hypocapnic range with propofol, suggesting that cerebral vasoconstriction at and less than 35 mm Hg of ETCO2 is near maximal, such that a further reduction in ETCO2 will have little further effect on CBFV. When preservation of CCO2R is required, the combination of N2O with propofol anesthesia in children would seem suitable.
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Footnotes |
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This article has been cited by other articles:
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  H. R. Munoz, L. I. Cortinez, M. E. Ibacache, and F. R. Altermatt Remifentanil Requirements During Propofol Administration to Block the Somatic Response to Skin Incision in Children and Adults Anesth. Analg., January 1, 2007; 104(1): 77 - 80. [Abstract] [Full Text] [PDF]
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 R. Barlow, C. Karsli, I. Luginbuehl, and B. Bissonnette Desflurane increases cerebral blood flow velocity when used for rapid emergence from propofol anesthesia in children: [Le desflurane augmente la vitesse circulatoire cerebrale quand il est utilise pour un reveil rapide apres l'anesthesie au propofol chez des enfants] Can J Anesth, October 1, 2004; 51(8): 824 - 828. [Abstract] [Full Text] [PDF]
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C. Karsli, I. Luginbuehl, and B. Bissonnette The Cerebrovascular Response to Hypocapnia in Children Receiving Propofol Anesth. Analg., October 1, 2004; 99(4): 1049 - 1052. [Abstract] [Full Text] [PDF]
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P < 0.001 with 45 mm Hg; #P < 0.001 with 45 mm Hg.
