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From the Department of Anesthesia, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
Dr. B. Bissonnette, Department of Anesthesia, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada. Phone: 416-813-7445; Fax: 416-813-7543; E-mail: bruno{at}anaes.sickkids.on.ca
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Abstract |
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Methods: Twelve ASA I or II children, aged one to six years undergoing elective urological surgery were randomized to receive one of two propofol dosing regimens. Half of the patients received propofol in an escalating fashion, initially targeting an estimated steady-state serum concentration of 3 µg•mL-1, which was then doubled. The other half received propofol designed initially to target the high concentration followed by the lower one. In each child anesthesia was induced and maintained with propofol according to the protocol, rocuronium was given to facilitate tracheal intubation, and a caudal epidural block was performed. A TCD probe was placed appropriately to measure Vmca. Cerebral blood flow velocity (CBFV), mean arterial pressure (MAP) and heart rate (HR) were recorded simultaneously at both levels of propofol administration.
Results: Twelve patients were studied. At the higher estimated target serum propofol concentration there were significant decreases in Vmca (17%, P < 0.001), MAP (6%, P < 0.002) and HR (8%, P < 0.05) when compared to the lower targeted concentration.
Conclusion: This study shows that a higher rate of propofol infusion is associated with lower CBFV and MAP values in children. Propofol’s cerebral vasoconstrictive properties may be responsible for this finding.
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Introduction |
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TOPAbstractIntroductionMethodsResultsDiscussionReferences |
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Studies in adults using 133Xenon (Xe) inhalation scintillography have demonstrated that propofol causes a significant decrease in cerebral blood flow and increases cerebral vascular resistance.6 Transcranial Doppler (TCD) studies have reported that cerebral blood flow velocity (CBFV) is decreased in adult patients receiving a propofol infusion, when compared to awake controls.7 The effect of propofol on CBFV in children remains unclear. The aim of this study was to test the hypothesis that a higher rate of propofol administration is associated with lower CBFV values in children, as measured by TCD sonography.
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Methods |
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In the other half of the patients anesthesia was induced with propofol 5 mg•kg-1, followed by an infusion of 30 mg•kg-1•hr-1 for the first 15 min, 26 mg•kg-1•hr-1 for the next 15 min, and 22 mg•kg-1•hr-1 from then on. Thirty minutes were allowed for steady state to be reached, at which point the same variables were recorded at one-minute intervals. In order to lower the estimated serum propofol concentration to 3 µg•mL-1, the infusion was stopped for five minutes, and restarted at 11 mg•kg-1•hr-1. Another 30 min were allowed for the new steady state to be reached, and Vmca, HR and MAP were again recorded three times at one-minute intervals. In all patients body temperature was monitored rectally and maintained constant with a conductive water mattress and convective air warmer under the surgical drapes. The subjects were supine and horizontal throughout the study period.
The number of patients needed to demonstrate a direct effect on CBFV during changes in propofol dosing 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, a total of seven patients was suggested. Twelve 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. Within group analysis of Vmca, HR and MAP data was achieved using the student unpaired t test, and between groups analysis was performed using ANOVA and the student Newman Keuls test for multiple comparisons. Analysis of TCD measurements was carried out by an investigator unaware of the sequence of propofol administration. A P < 0.05 was accepted for statistical significance.
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Results |
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TOPAbstractIntroductionMethodsResultsDiscussionReferences |
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At the higher estimated target serum propofol concentration there were significant decreases in Vmca (17%, P < 0.001), MAP (6%, P < 0.002) and HR (8%, P < 0.05) when compared to the lower targeted concentration (3 µg•mL-1; Figure 1
). Typical CBFV tracings for both the low and high propofol concentrations are shown in Figure 2. There were no complications that resulted from this study.
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Discussion |
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Propofol seems to demonstrate many of the properties of an ideal anesthetic agent for adults undergoing neurosurgical procedures, as it has been shown to decrease both cerebral metabolism and blood flow.6 In addition, its rapid metabolic clearance provides for an early, predictable and complete recovery, making propofol suitable for maintenance of anesthesia by continuous infusion.11 The propofol dosing regimen used in the present study was adapted from published pharmacokinetic studies of propofol infusion data in children.12–15 For the "low" propofol concentration arm of the study, a manual infusion regimen capable of maintaining an estimated steady state blood concentration of 3 µg•mL-1 in children was used.8 This same target concentration has been chosen in several adult studies.16–18 The blood propofol concentration required to achieve sedation or anesthesia is very similar in both children and adults.19 Due to significant pharmacokinetic and pharmacodynamic differences between children and adults however, propofol doses and infusion rates required to achieve a certain target blood concentration are higher for pediatric patients.13,16 In addition, the context-sensitive half-life of propofol is longer in children than in adults, presumably due to altered compartment volumes of distribution.8 This implies that recovery from a propofol infusion will be slower in children than in adults, which may limit its usefulness in prolonged neurosurgical procedures. Further evaluation aimed at validating this propofol infusion regimen might be beneficial. Pediatric propofol pharmacokinetic studies carried out by Kataria et al.15 and Short et al.14 have shown that upon discontinuation of a 30-min infusion, serum propofol levels decrease by 50% in well under ten minutes. The propofol dosing adjustment strategy used in the present study was derived in part from findings reported in these pharmacokinetic studies.
Several physiological factors have been shown to alter CBFV, including PETCO2, cardiac output, surgical stimulation, body temperature and intra-thoracic pressure.20 End-tidal CO2 and body temperature remained unchanged throughout the study period, and any cerebrovascular effects of surgical stimulation seemed to have been successfully eliminated by the caudal epidural block, although this cannot be excluded with certainty.
There are some methodological considerations that need to be addressed. Although TCD sonography is a simple non-invasive method of measuring CBFV, it is not a direct measure of cerebral blood flow. However, studies measuring 133Xe clearance and radioactive microspheres have shown that relative changes in CBFV correlate well with changes in cerebral blood flow.21,22 TCD sonography is now widely used as a surrogate measure of cerebral blood flow.23 Interpatient variability in CBFV measurements can be due to variations in Doppler probe positioning, resulting in different angles of insonation (i.e., the angle at which the Doppler beam impacts on the artery). Intrapatient variability may result if the probe position changes during the course of a study. Thus in order to minimize these errors an experienced user fixed the Doppler probe to the subject’s head using a custom designed frame.6
In conclusion, the present study shows that increasing the rate of propofol infusion in children results in a 17% decrease in CBFV that outweighs the reduction (6%) in MAP. Propofol’s cerebral vasoconstrictive properties may be primarily responsible for this decrease in CBFV, however further evaluation will be necessary to confirm this hypothesis. Although propofol demonstrates, in theory, the properties of an ideal neuroanesthetic agent, additional dosing validation studies and direct clinical comparison to volatile agents are needed before this claim can be made for pediatric neurosurgical patients.
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Acknowledgments |
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Footnotes |
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Revision received June 10, 2002. Accepted for publication March 28, 2002.
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References |
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2 Weir PM, Munro HM, Reynolds PI, Lewis IH, Wilton NC. Propofol infusion and the incidence of emesis in pediatric outpatient strabismus surgery. Anesth Analg 1993; 76: 760–4.
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4 Doyle E, McFadzean W, Morton NS. I.V. anaesthesia with propofol using a target-controlled infusion system: comparison with inhalation anaesthesia for general surgical procedures in children. Br J Anaesth 1993; 70: 542–5.
5 Matta BF, Heath KJ, Tipping K, Summors AC. Direct cerebral vasodilatory effects of sevoflurane and isoflurane. Anesthesiology 1999; 91: 677–80.[Medline]
6 Vandesteene A, Trempont V, Engelman E, et al. Effect of propofol on cerebral blood flow and metabolism in man. Anaesthesia 1988; 43(Suppl): 42–3.
7 Eng C, Lam AM, Mayberg TS, Lee C, Mathisen T. The influence of propofol with and without nitrous oxide on cerebral blood flow velocity and CO2 reactivity in humans. Anesthesiology 1992; 77: 872–9.[Medline]
8 McFarlan CS, Anderson BJ, Short TG. The use of propofol infusions in paediatric anaesthesia: a practical guide. Paediatr Anaesth 1999; 9: 209–16.[Medline]
9 Karsli C, Luginbuehl I, Farrar MW, Bissonnette B. Cerebrovascular carbon dioxide reactivity in children anaesthetised with propofol. Paediatr Anaesth 2002 (in press).
10 McAuliffe G, Bissonnette B, Cavalle-Garrido T, Boutin C. Heart rate and cardiac output after atropine in anaesthetised infants and children. Can J Anaesth 1997; 44: 154–9.
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15 Kataria BK, Ved SA, Nicodemus HF, et al. The pharmacokinetics of propofol in children using three different data analysis approaches. Anesthesiology 1994; 80: 104–22.[Medline]
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19 Reed MD, Yamashita TS, Marx CM, Myers CM, Blumer JL. A pharmacokinetically based propofol dosing strategy for sedation of the critically ill, mechanically ventilated pediatric patient. Crit Care Med 1996; 24: 1473–81.[Medline]
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23 Sudikoff S, Banasiak K. Techniques for measuring cerebral blood flow in children. Curr Opin Pediatr 1998; 10: 291–8.[Medline]
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P <0.002; 
P <0.05. Vmca = middle cerebral artery blood flow velocity = Vmca = middle cerebral artery blood flow velocity; MAP = mean arterial pressure; HR = heart rate.