Study 1: The Time Course of Vmca After Ketamine Administration During Propofol Anesthesia
Vmca after saline (Group A, n = 6) or ketamine (Group B, n = 10) administration during propofol anesthesia administration was measured in a randomized, double-blinded manner. All measurements were made before surgery to avoid the influence of surgical stimulation. Anesthesia was induced with 2.5 mg/kg IV propofol, and tracheal intubation was facilitated with 0.15 mg/kg IV vecuronium bromide. During the anesthetic induction, approximately 500 mL of lactated Ringer’s solution was infused IV to avoid hypotension. After the induction, lactated Ringer’s solution was infused at a rate of 3 mL · kg−1 · hr−1 until the end of the measurements. Additional doses of vecuronium were administered to achieve approximately 90%–95% motor blockade as indicated by a blockade monitor. After tracheal intubation, the lungs were mechanically ventilated with air in 40% oxygen. Anesthesia was maintained with continuous infusion of propofol at 6 mg · kg−1 · hr−1. After hemodynamics became stable for at least 20 min, ketamine was administered in Group B at a dose of 2 mg/kg IV followed by continuous infusion at mg · kg−1 · hr−1. In Group A, the same volume of saline was administered instead of ketamine. The Vmca, mean arterial pressure (MAP), heart rate (HR), and PETCO2 were measured and recorded at 1-min intervals for 10 min with a final data set collected after 15 min, because previous studies showed that Vmca, MAP, and HR were increased within 5 min after ketamine administration and returned to baseline values after 10–15 min (4,6). Arterial blood samples were obtained 0 and 15 min after starting ketamine or saline administration.
Study 2: Vmca and CO2 Response During Propofol With and Without Ketamine
Twenty-two patients were randomly allocated to one of three groups. Vmca in response to changes in PaCO2 was determined under the following conditions: awake (Group C, n = 7), propofol anesthesia (Group D, n = 7), and propofol-ketamine anesthesia (Group E, n = 8). Measurements in Group C were made before the induction of anesthesia. Measurements in Groups D and E were performed after tracheal intubation but before surgery to avoid the influence of surgical stimulation.
In Group C, patients wore a nose clip and breathed through a mouthpiece using a Mapleson D breathing system. PETCO2 was monitored in the expiratory limb of the breathing circuit close to the patient’s mouth. All patients breathed 100% O2 during normocapnic and hypocapnic states. After the patients were acclimated to the breathing system for 10–15 min, normocapnic Vmca was measured. Then, the fresh gas flow was increased, and intentional hyperventilation (PETCO2, 30–35 mm Hg) was maintained for 5 min to measure at least three hypocapnic Vmca values. Five minutes after recovery of normocapnia under spontaneous ventilation, hypercapnia was induced by a mixture of 95% O2-5% CO2 and was maintained for 5 min to measure at least three hypercapnic Vmca values. Anesthesia was induced 5 min after recovery of normocapnia under spontaneous ventilation.
In Group D, anesthesia was induced in the same way as in Study 1. In Group E, anesthesia was induced with propofol, 2.5 mg/kg, and ketamine, 2 mg/kg IV, and maintained with continuous infusion of propofol, 6 mg · kg−1 · hr−1, and ketamine, 2 mg · kg−1 · hr−1. After tracheal intubation, patients’ lungs were ventilated with air in oxygen at 40% for at least 15 min during normocapnia. Hypocapnia was induced after completion of the measurements under normocapnia. After the measurements under hypocapnia, normocapnia was maintained for 5 min before the induction of hypercapnia. A minimum of three paired Vmca-PaCO2 determinations were obtained for each CO2 response under anesthetic conditions. Hypocapnia and hypercapnia were induced by changing the respiratory rate under a constant tidal volume (10 mL/kg).
All determinations of Vmca were made after a steady PETCO2 was obtained for at least five respiratory cycles. Arterial blood samples were obtained for paired PaCO2-Vmca determinations.
After the operation, all patients were observed in the postanesthetic care unit for evidence of anxiety, confusion, hallucinations, or other psychomimetic side-effects at emergence from general anesthesia. All patients were visited 1 day after their anesthetic administration and were asked about hallucinations, nightmares, and other problems.
The paired PaCO2-Vmca and PaCO2-PI determinations were fit to both exponential and linear regression analyses to determine the best fit for the relationship. Linear regression analysis demonstrated a close relationship between PaCO2 and Vmca or PI with correlation coefficients of more than 0.93 or 0.89 and was used for subsequent comparisons. As the PaCO2 values at the time of Vmca and PI determinations varied among patients as well as between experimental conditions, it was difficult to make direct comparisons at any specific PaCO2 level. Therefore, to allow comparative analysis among the study conditions during normocapnia, hypocapnia, and hypercapnia, normalization of data was achieved by calculating the Vmca and PI for PaCO2 at 30, 40, and 50 mm Hg from each individual linear regression equation.
We also calculated a relative CO2 response slope, as expressed as a percent change of Vmca, for each group. Normalization of data was achieved by calculating the Vmca for PaCO2 at 40 mm Hg from each individual linear regression equation, and the paired PaCO2-%Vmca, percent change of Vmca at a PaCO2 of 40 mm Hg, determinations were fitted to both exponential and linear regression analysis to determine the best fit for the relationship.
Data were expressed as mean ± SE. The comparisons among groups were performed by Mann-Whitney U-test and Kruskal-Wallis test. Intragroup comparisons were evaluated by using a repeated measure analysis of variance. When significance was found, the Scheffé test was used for post hoc testing. A probability value of <0.05 was regarded as significant.
Table 1 shows the demographic data. There were no significant differences between Groups A and B. Body temperature remained constant between 36.0 and 37.0°C. Table 2 shows arterial blood gas values. There were no significant differences between Groups A and B for values at 0 or 15 min. Changes in Vmca, PI, MAP, HR, and PETCO2 for both groups are presented in Table 3. There were no significant changes in Vmca, PI, MAP, HR, or PETCO2 over the course of the studies. The MAP did not decrease to <60 mm Hg in any patient.
Table 1 shows the demographic data. There were no significant differences among Groups C, D, and E. Body temperature remained constant between 36.0 and 36.8°C. The mean hematocrit of arterial blood measured just before the measurements was 40% ± 1% in Group C, 43% ± 2% in Group D, and 41% ± 2% in Group E, with no significant differences among them. The MAP and HR recorded during the study are shown in Table 4. During hypercapnia, MAP was lower in Group D compared with that in Group C; otherwise, there was no significant difference among Groups C, D, and E. The MAP did not decrease to <60 mm Hg in any subject.
The calculated Vmca in Groups D and E was significantly lower than that in Group C at each level of PaCO2 (Table 5). The CO2 response slopes in Groups D and E were significantly lower than that of Group C (Table 6). Neither the calculated Vmca at each level of PaCO2 nor the CO2 response slopes were significantly different between Groups D and E. The relative CO2 response slopes showed no significant difference among Groups C, D, and E. The calculated PI in Groups D and E tended to be higher as compared with that in Group C (Table 5).
Postoperatively, no anxiety, confusion, hallucinations, or other psychomimetic side effects were observed in either the propofol- or propofol-ketamine-treated patients.
Our results show that ketamine did not produce any significant change in Vmca or CO2 response of Vmca in propofol-anesthetized patients with mechanically ventilated lungs, without neurological complications.
There are some explanations for the reported ketamine-induced increase in CBF. Ketamine is reported to increase CBF in part because of an increase in MAP or PaCO2. In this study, ketamine administration did not affect Vmca, MAP, or PaCO2 during propofol anesthesia administration. Thus, MAP and PaCO2 may help explain our results. However, Strebel et al. (4) reported that the ketamine-induced increase in CBF velocity was not blocked by maintaining arterial pressure with esmolol and suggested that ketamine increases CBF velocity via a direct effect rather than a secondary effect caused by a change in arterial pressure and/or PaCO2. Another explanation for the ketamine-induced increase in CBF is that ketamine-induced central nervous excitation stimulates cerebral metabolism. Kochs et al. (6) reported that the ketamine-induced increase in CBF velocity was closely correlated to the increase in neuronal activity in healthy volunteers. However, some studies showed that ketamine decreased electroencephalogram activity in patients during propofol sedation or isoflurane/nitrous oxide anesthesia (7,9). This discrepancy for the action of ketamine on neuronal activity may be caused in part by differences in the absence or presence of other medications. Although our study provides no data on neuronal activity or the metabolic state, there is a possibility that propofol blocks ketamine-induced increases in neuronal activity, resulting in inhibition of the increase in CBF.
Our results confirmed that propofol reduces Vmca compared with the awake state at varying levels of PaCO2 and that the CO2 response is slightly attenuated during propofol anesthesia (11). The present data also show that Vmca and the CO2 response during propofol-ketamine anesthesia administration are similar to those during propofol anesthesia administration. Analyzing the CO2 response slopes in terms of relative percent change showed a similar pattern in the three groups. This difference may be mediated by a decrease in Vmca during propofol with and without ketamine anesthesia. The PI values during propofol with and without ketamine anesthesia tended to be higher than in the awake state. With the assumption that the diameter of the MCA is nearly constant, the reduction in Vmca associated with an increase in PI during propofol or propofol-ketamine anesthesia is explainable as a decrease in CBF.
The MAP values during propofol and propofol-ketamine anesthesia administration were slightly lower than those during the awake state. However, it is unlikely that the lower MAP influenced the decreased Vmca during the anesthesia. Propofol does not affect autoregulation of CBF in rats (12) or humans (13,14). If autoregulation functions normally, CBF does not change when cerebral perfusion pressure increases or decreases within a certain range. In the present study, MAP did not decrease to <60 mm Hg in any patient and was maintained within the autoregulatory range. Thus, the differences in MAP would not account for the low Vmca during anesthesia.
Our results do not provide data on ICP or electroencephalographic activity, and patients with neurological complications or sympathetic nervous system disorders may have different responses. However, we show the possibility that propofol could eliminate the effect of ketamine on CBF in patients without neurological complications. These results should be confirmed in larger groups of patients with and without neurological complications.
In conclusion, propofol reduces Vmca at varying levels of PaCO2 compared with the awake state, and the CO2 response is slightly attenuated during propofol anesthesia administration. Ketamine does not influence Vmca or cerebrovascular CO2 response during propofol anesthesia.
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© 2000 International Anesthesia Research Society
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