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*Department of Radiology and Lawson Research Institute, St. Joseph’s Health Centre, Imaging Research Laboratories, Robart’s Research Institute and Department of Medical Biophysics, The University of Western Ontario; and
Department of Anesthesia, London Health Sciences Centre and The University of Western Ontario, London, Canada
Address correspondence and reprint requests to R. A. Craen, MD, Department of Anesthesia, University Campus, London Health Sciences Centre, London, Canada N6A 5A5. Address e-mail to rcraen{at}julian.uwo.ca
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Abstract |
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 Top Abstract IntroductionMethodsResultsDiscussionAppendix 1.References |
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Implications: During propofol anesthesia in rabbits with normal brains, a reduction in the arterial carbon dioxide level may not always be accompanied by a reduction in brain blood flow and blood volume.
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1.References |
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We have developed a dynamic contrast-enhanced computed tomography (CT) method based on a two-compartment model of the brain that provides repeated, absolute CBV measurements in the same subject (5–7). By using our dynamic CT-CBV method and the well established radiolabeled microsphere CBF measurement technique, the aim of this study was to simultaneously investigate the changes in CBV and CBF to varying PaCO2 levels in rabbits anesthetized with propofol alone. In addition, the stability over time of CBV and CBF during propofol anesthesia and normocapnia was also examined.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1.References |
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Rectal temperature was maintained at 38.5°C with a water-heating blanket, heat lamp, or ice packs. Hematocrit was measured every 30 min and arterial blood gases were determined before and after each CBV and CBF measurement. Phenylephrine was administered IV as required to maintain mean arterial pressure (MAP) between 75 and 85 mm Hg.
Each rabbit was anesthetized with halothane via a mask, and one ear vein was cannulated for the administration of muscle relaxant (vecuronium bromide) and radiographic contrast material during the experiment. After a tracheotomy was performed, the rabbits were mechanically ventilated to normocapnia with an air/O2 mixture (FIO2) 0.4). Halothane was then gradually withdrawn as 2% propofol (Diprivan; Zeneca Pharmaceuticals, Missausauga, Canada) was infused IV at a rate of 1.6 mg · kg-1 · min-1 for the initial 30 min followed by 1.2 mg · kg-1 · min-1, thereafter (see Appendix 1 for determination of infusion rates). After thoracotomy, a catheter was placed in the left atrial appendage. The chest wall was closed with surgical clips and the atrial catheter exteriorized. Both femoral arteries were catheterized with 18-gauge catheters to allow continuous measurement of MAP, as well as arterial blood sampling. Both femoral veins were also catheterized with 18-gauge catheters for fluid replacement, drug administration and return of blood previously withdrawn by the absorptiometry apparatus (see below). All surgical wounds were infiltrated with lidocaine 1%.
CT Scanning Protocol
The CBV measurements were acquired by using a slip-ring CT scanner (GE High Speed Advantage CT; Milwaukee, WI). With the rabbit positioned prone in the CT scanner, we selected a 3 mm coronal section through the brain at the level of the optic chiasm. All subsequent scans were taken at this same location.
After baseline CT scans and injection of radiographic contrast material, 1.5 mL/kg iopamidol (Isovue 300; Squibb Diagnostics, Stanford, CT), the first of two sets of 60 continuous dynamic scans were performed (80 kVp, 80 mA, 1 s scan time and no interscan delay). For technical reasons, a 5 s intergroup delay was required before the start of the second set of 60 dynamic scans. Lastly, there was an 11 s intergroup delay preceding the final 60 axial scans (80 kVp, 120 mA, 1 s scan time, and 9 s interscan delay). The first 120 dynamic scans were then retrospectively reconstructed at 0.5 s intervals to yield a total of 298 scans for each dynamic CT-CBV study.
During the 12-min CT scanning period, blood was continuously aspirated at a rate of 1.75 mL/min from a femoral artery catheter by a peristaltic pump. This sampled blood was passed through an absorptiometry unit which measured the concentration of contrast in arterial blood, before being returned to the rabbit via a femoral vein (8).
CT-CBV Measurements
The CT images and absorptiometry data were transferred to a SPARC-2 workstation (SUN Microsystems, Mountain View, CA) for analyses. Measurements of tissue contrast enhancement, Cb(t), were determined for a region of interest (ROI) encompassing the entire brain region of the CT image excluding regions which corresponded to large arteries or veins. These measurements were determined by subtracting the mean baseline CT number in the ROI (before radiographic contrast injection) from the mean CT number of each sequential contrast-enhanced image. The mean change in CT number is proportional to the contrast concentration within each ROI (9). This constant of proportionality (52.81 mean CT number per mgI/mL) was determined by imaging known concentrations of iopamidol within a phantom with radiographic attenuation characteristics similar to that of a rabbit’s head. The arterial plasma contrast concentration, Cp(t), was obtained from the in-line photon absorptiometry apparatus in units of mgI/mL (8). This blood curve (obtained with the absorptiometry unit) was dispersion corrected by deconvolution with a previously determined dispersion function (8).
A two-compartment model of the brain, consisting of the cerebral plasma volume (CPV) and the extravascular extracellular space (EES), was used in modeling the kinetics of the injected radiographic contrast material. We used iopamidol, a nonionic and biologically inert hydrophilic radiographic contrast agent (molecular weight = 777). The details of this model have been previously described and applied in both human and animal studies (5–7). For the purpose of this paper, we will state the operating equation of the model as follows: 
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We estimated CPV, K, and k by solving the previous equation and by using the measured Cb(t) and Cp(t) and a constrained quasi-Newton optimization algorithm (10,11) from the FORTRAN Nag Library (Downers Grove, IL). The lower bounds of the model variables were set to zero because negative values have no physiological meaning.
Then, we converted CPV to CBV by using the conversion formula:
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Cerebral Blood Flow Measurements
Cerebral blood flow was determined by left atrial injection of radioactive microspheres (13). Microspheres (15-µm diameter) labeled with 46Sc, 85Sr, and 141Ce (New England Nuclear, Boston, MA) were suspended in normal saline. Before withdrawal into syringes, the microspheres in their vials were ultrasonically agitated in a water bath and immediately before injection, the syringes were thoroughly agitated by using a vortex mixer. For each level of PaCO2, a different microsphere was randomly selected and flushed into the left atrium. By using a Harvard syringe pump, 3.0 mL of blood was withdrawn from a femoral artery at a rate of 1 mL/min over a period of 3 min, starting 1 min before microsphere injection. At the completion of the experiment, 20 tissue samples and 3 arterial blood reference samples were obtained. A total of eight samples from each cerebral hemisphere at the level of the optic chiasm was matched to the CT slice for CBF measurement. A total of four samples from both kidneys was to verify that adequate mixing of microspheres had occurred. Gamma-ray spectroscopy was used to determine the amount of each radiolabeled microsphere in the tissue samples. Cerebral blood flow was calculated for each level of PaCO2 by using the following equation:
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Statistical analysis was performed by using the Jandel Scientific Software Package (Sigma Plot and Sigma Stat, Jandel Scientific, Chicago, IL). Analysis of variance for repeated measurements was used to determine whether monitored physiological data varied between sequential studies. When analysis of variance revealed statistically significant differences (P < 0.05), a Tukey’s multiple comparison test was used to isolate the group or groups that differed from the others. Paired sample t-tests (two-tailed) were used to compare CBF and CBV values between sequential studies. A Pearson product moment correlation test was used to determine the correlation between CBF and CBV values. All data were presented as mean ± SD. Statistical significance was declared at the P < 0.05 level.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1.References |
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In the control group, we found no significant differences (P > 0.10) between repeated measurements for both CBF and CBV during the 2 h experimental period. PaCO2 remained unchanged during this part of the experiment (P > 0.10). Analysis of variance for repeated measurements also yielded a precision estimate method of our two-compartment CT-CBV (or coefficient of variation) of 11.3%.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1.References |
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One possible explanation for the smaller change in CBV than CBF may be because of the lower responsiveness of the venous system relative to the arterial system on increasing PaCO2 (15). Cerebral blood volume reflects the total blood volume in the arterial, capillary, and venous systems, and because <20% of CBV is located within the arterial tree (16), hypercapnia-induced vasodilation of the small arteries and arterioles may not produce large CBV changes. Conversely, the fact that these principal resistance vessels control flow, and that flow is directly related to the fourth power of the radius, implies that relatively small changes in vessel diameter can have a major effect on CBF (17).
In contrast, we found that decreasing PaCO2 from 41 to 27 mm Hg caused minimal changes in CBV and CBF. To the best of our knowledge, there has not been a controlled animal or human study investigating the simultaneous effects of varying PaCO2 levels on CBV and CBF, during propofol anesthesia. The response to changes in PaCO2 is usually less during hypocapnia versus hypercapnia (18), and further impairment of the cerebrovascular response to hyperventilation in our study may be explained by propofol producing near-maximal cerebral vasoconstriction at normocapnia. Hence, there was no significant change in CBV or CBF with further hyperventilation. This suggests that, in this model, during propofol anesthesia, instituting hyperventilation to produce hypocapnia may not be accompanied by a reduction in CBV, and hence ICP. However, Watts et al. (19) demonstrated, in a rabbit model of intracranial hypertension (ICP = 26 mm Hg), that the addition of hyperventilation during propofol anesthesia resulted in a decrease in raised ICP and by inference, a decrease in CBV. Our results differ and one factor may be the difference in the intracranial compliance of the animal model used. The animals in our study had no intracranial pathology and, presumably, normal intracranial compliance, whereas in Watts et al. (19), ICP was increased to a critical point on the intracranial compliance curve to the extent that a small increment in intracranial volume (0.02 mL water) resulted in an increase in ICP of greater than 3 mm Hg. The presence or absence of reduced intracranial compliance can affect the results of ICP studies as noted by Ravussin et al. (20) who examined the effects of mannitol in patients with and without increased ICP. It is also possible that we missed very small changes in CBV, and a change in intracranial volume of this magnitude is probably beyond the resolution of our measurement technique. We have previously measured the precision of CT-CBV measurement technique and found it to be 11% (7).
The absolute CBF response to hyperventilation during propofol anesthesia has previously been investigated (3,4). In healthy patients, Fox et al. (4) demonstrated that CBF decreased by 42% when PaCO2 was reduced from 42 to 31 mm Hg. Also, Stephan et al. (3) revealed a 25% reduction in CBF when premedicated patients undergoing coronary artery bypass surgery were hyperventilated to a PaCO2 of 30 mm Hg. However, in the study by Fox et al. (4), the CBF-CO2 reactivity was investigated in subjects anesthetized with propofol and nitrous oxide. It is well established that nitrous oxide is a potent cerebral vasodilator, and this confounding effect must be considered when comparing their results to our findings. With regard to Stephan et al. (3), the series of prescribed cardiac drugs (ß-adrenergic blockers, calcium channel antagonists, and benzodiazepines) may have significantly affected their findings. Moreover, the observed differences between our study and the previously mentioned patient studies may reflect either an interspecies difference in the response to propofol or a difference in the CBF measurement technique used. One study using transcranial doppler to measure CBF velocity found that cerebral carbon dioxide reactivity remained intact during propofol-induced isoelectric EEG (21). This study differs from ours in that it was performed in humans, cerebral blood volume and cerebral blood flow were not measured directly, and PaCO2 was varied between 4.0 and 7.0 kPa (i.e., 30–53 mm Hg). Their data reveal that the magnitude of the changes in mean middle cerebral artery blood flow velocity was also reduced at the lower ranges of PaCO2.
In this study, the absolute CBF-CO2 reactivity was found to be 2.46 mL · 100 g-1 · min-1 · mm Hg-1 during hypercapnia. This is similar to the value found by Forster et al. (22) of 2.5 mL · 100 g-1 · min-1 · mm Hg-1 in healthy patients during midazolam anesthesia and hypercapnia. Midazolam, like propofol, decreases CBF at normocapnia (23,24). When PaCO2 was increased from 40 to 60 mm Hg during thiopental anesthesia in dogs, Kassel et al. (25) demonstrated a slightly lower absolute CBF-CO2 reactivity (2.0 mL · min-1 · 100 g-1). The large doses of barbiturates used in this study may have contributed to this smaller value. Kassel et al. (25) also showed that CBF-CO2 reactivity during nitrous oxide alone was at least twice that with barbiturates alone. Our group previously showed that during hypercapnia, the CBF-CO2 reactivity in rabbits during 1 minimum alveolar anesthetic concentration (MAC) isoflurane is 3 times greater than with propofol (7). Overall, these studies suggest that, during hypercapnia, the absolute CBF-CO2 reactivity is increased significantly with inhaled anesthetics than with IV anesthetics, such as propofol, which are vasoconstrictors,.
In a previous study, our group investigated the CBV and CBF responses to PaCO2 changes during isoflurane anesthesia in rabbits under the same experimental conditions as the current study (7). However, in contrast to the current study, when PaCO2 was reduced from 40 to 25 mm Hg in the isoflurane animals, a significant decrease in CBF (27%) and CBV (13%) was seen (Figure 1 A and 1B). This differing response to hyperventilation between the two anesthetics may be explained as follows: at normocapnia, the mean CBF (110 mL · 100 g-1 · min-1) and CBV (3.22 mL/100 g) values with isoflurane were, respectively, 94% and 34% greater than the mean CBF and CBV values with normocapnia during propofol anesthesia. These findings are consistent with those of Todd et al. (26), who found that in normocapnic rats, CBF and CBV values were also significantly higher with isoflurane than with propofol anesthesia. Because CBF, and hence CBV, is directly related to the radius of cerebral vessels (17), this suggests that the diameter of the vessels is larger with isoflurane at normocapnia. Also, since isoflurane is a known cerebral vasodilator, the vessels have the capacity to further constrict with hyperventilation. In contrast, the null response implies that the combination of propofol and normocapnia caused vasoconstriction of cerebral vessels to the extent that they had a very limited capacity to constrict further with the introduction of hypocapnia.
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A previous study in dogs (27) demonstrated that CBF significantly decreases over time during prolonged anesthesia. We performed control experiments to investigate whether maintenance with propofol induces any significant changes in CBF and CBV over time. We found that neither CBF nor CBV changed significantly during the two-hour experimental period. Hence, the order in which the PaCO2 level was changed (i.e., normocapnia, hypocapnia, and then, hypercapnia) for the PaCO2 study group is not critical, because the control data exclude the possibility that a time effect influenced the PaCO2 results. Furthermore, from the repeated measurements made in the steady-state control group, we estimated that the precision of CBV, measured with our dynamic CT two-compartment method, was 11%. This precision compares well with that obtained by others who reported variabilities of 14% in rabbits (28) and 20% in humans (29) using different dynamic CT methods.
It is possible that the use of phenylephrine altered CBV and CBF. Although there are some controversies about the effects of 
agonists on the cerebrovasculature, phenylephrine, unlike angiotensin, has not been shown to constrict cerebral vessels in the rabbit (30), or significantly change CBF in dogs (31). Watts et al. (32) also showed that, in rabbits with raised ICP, phenylephrine increases MAP, however, does not alter ICP or, presumably, CBV.
In conclusion, these results show that the cerebrovascular response to CO2 during propofol anesthesia is maintained during hypercapnia but is markedly diminished during hypocapnia. These results indicate that the combination of propofol and normocapnia caused vasoconstriction of cerebral vessels to the extent that they had a limited capacity to constrict further with hyperventilation. In addition, our results indicate that maintenance of anesthesia with propofol does not induce significant changes in CBF and CBV over time (two hours).
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Appendix 1. |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1.References |
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The concept of minimum alveolar concentration (MAC), the minimum alveolar concentration at which 50% of animals move in response to painful stimulus, has become the standard of reference in measuring the depth of inhalational anesthesia. The purpose of this study was to determine a 1 MAC-equivalent for 2% propofol in the New Zealand white rabbit, or the minimum infusion rate which prevents movement in 50% of animals in response to a painful stimulus.
A total of six male rabbits (2.6–3.5 kg) were used in this study which was approved by the Animal Ethics Committee at the University of Western Ontario (London, Canada). All animals were initially anesthetized with halothane via a nose cone. Once asleep, the animals were instrumented with femoral arterial and venous catheters, and a marginal ear vein was cannulated. All superficial wounds were infiltrated with 1% lidocaine. Animals were kept normothermic (39°C) on a circulating hot water blanket. Heart rate, mean arterial pressure, arterial blood gases, and rectal temperature were continuously monitored. Halothane was discontinued and 20 mg/mL IV 2% propofol was infused at a predetermined rate of 1.0 mg · kg-1 · min-1. At 60 min after the start of infusion, anesthetic depth was assessed by response to painful stimulus. The webbing between the two toes of the right hind leg was compressed with a hemostat. If there was movement, the concentration of propofol was increased by 10% and allowed to equilibrate for 15 min as recommended by Eger et al. (33). A positive response was only noted for purposeful movement (e.g., kicking, withdrawing or twisting of the torso) on stimulus. Stiffening, coughing, or hyperventilation was not considered a positive response. If no movement occurred (i.e., negative response), the concentration was decreased by 10% and allowed to reach a steady-state level for 15 min. The painful stimulus was then reapplied. This process of equilibration and stimulus response was repeated at least five times in each rabbit. For each rabbit, the 1 MAC-equivalent for propofol was calculated as the average of the highest infusion rate permitting movement and lowest infusion rate preventing movement (i.e., the bracketing values) (32).
Table 3 lists the mean concentrations of propofol for the sequential positive and negative responses observed in each rabbit, as well as the 1 MAC-equivalent for each rabbit. The infusion rates used ranged from 0.80 to 1.60 mg · kg-1 · min-1. From the six rabbits, the average 1 MAC-equivalent was 1.20 ± 0.08 mg · kg-1 · min-1. Thus, for our experiment, we chose 1.2 mg · kg-1 · min-1 as our maintenance infusion rate. To avoid a loading bolus dose, we used an initial infusion rate of 1.6 mg · kg-1 · min-1 for 30 min before the maintenance infusion rate of 1.2 mg · kg-1 · min-1.
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Acknowledgments |
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We gratefully acknowledge the animal care assistance provided by Sarah Henderson and Monique Labodie.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1.References |
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