Combined Effects of Nitrous Oxide and Propofol on the Dynamic Cerebrovascular Response to Step Changes in End-tidal Pco²in Humans

Thirty-five patients (20 male, 15 female; age, 15–41 yr [mean, 29.3 yr]; height, 165.2 ± 8.2 cm [mean ± SD]; weight, 62.0 ± 9.5 kg) undergoing elective surgery took part in the study. Requirements were fully explained to all participants in writing and verbally, and each gave informed consent before participating in the study. The institutional ethics committee approved the research. Participants were not taking any medication, and none had a known history of cardiovascular, cerebrovascular, respiratory, neurologic, or endocrine disease. They fasted preoperatively for 8–10 h, during which intravenous (800–1,000 ml) fluid replacement was given. No premedication was administered.

The experiment was conducted after the induction of anesthesia and before the start of surgery. To minimize experimental time, subjects were divided into two study groups. The first group was studied during anesthesia with N²O, followed by the addition of an infusion of propofol to the N²O anesthesia. The second group was studied during anesthesia with a propofol infusion, followed by the addition of N²O.

A 2-MHz pulsed Doppler ultrasound system (PC-Dop 842, SciMed, Bristol, UK) was used to measure back-scattered Doppler signals from the right or left middle cerebral artery (MCA). The Doppler signals were transformed to the intensity-weighted mean blood flow velocity (FV^MCA), which was stored on a computer for off-line analysis. FV^MCAwas identified by an insonation pathway through the right or left temporal window using the standard search technique. The transcranial Doppler (TCD) probe was attached securely with a plastic headband at the position where the signal was maximized.

Subjects were placed in a supine position on an operating table with ambient temperature maintained at 25°C. After applying usual anesthetic monitors (pulse oxymetry, a lead II electrocardiograph, noninvasive brachial blood pressure, rectal temperature, and respired gas tensions [O², CO², and N²O]), anesthesia was induced with a bolus injection of 2 mg/kg propofol. Tracheal intubation was facilitated by a bolus injection of 0.2 mg/kg vecuronium. Rectal temperature was maintained within the preanesthetic level ± 0.2°C with a warm air blanket and a water blanket. Expired carbon dioxide tension was monitored continuously with an infrared anesthetic gas monitor (Normocap 200 oxy, Datex, Helsinki, Finland). Airflow was measured by a flow meter to define the end-expiratory phase in the off-line analysis. Carbon dioxide tension and airflow signals were stored on a computer with the TCD signals. Brachial blood pressure was measured every 1 min with an oscillometer throughout the study.

The experimental protocol is shown schematically in figure 1. After the induction of anesthesia, 19 subjects in group 1 were anesthetized with 30% O²+ 70% N²O and mechanically ventilated at a slight hypocapnic level, Petco²of 27–29 mmHg. Neuromuscular block was obtained with a continuous intravenous infusion of vecuronium at a rate of 12 mg/h. The slight hypocapnia was attained by adjusting a tidal volume with keeping the ventilation rate at 10 breaths/min and maintained for at least 15 min for stabilization of respiratory and circulatory condition.

After a 3-min baseline period, hypercapnia was induced suddenly by adding carbon dioxide to the inspiratory gas mixture. By closely observing Petco², the CO²flow rate was manually adjusted breath by breath such that Petco²increased to approximately 45–55 mmHg within a few breaths. The target Petco²level was maintained for the subsequent 5 min. The CO²supplementation was then terminated, and the ventilatory rate was immediately increased to 16 breaths/min, keeping tidal volume constant for about 5–7 breaths to induce a rapid decrease in Petco². The ventilation rate was gradually decreased such that Petco²remained at a constant hypocapnic level for 3 min (recovery period). This resulted in a stepwise Petco²decrease to the baseline Petco²level in several breaths. This measurement session is referred hereafter as the N²O session.

After the N²O session was completed, an intravenous bolus of 1 mg/kg propofol was injected, followed immediately by a continuous intravenous infusion of propofol at a rate of 10 mg · kg⁻¹· h⁻¹. The infusion rate was adjusted such that blood pressure was maintained as close to that during the N²O session as possible. In 5 subjects, the infusion rate was reduced to 7–9 mg · kg⁻¹· h⁻¹. Once the infusion rate was determined, it was kept constant throughout the measurement run. Ventilation tidal volume was also adjusted such that the baseline Petco²was identical to that for the N²O session. After a 20-min accommodation period to the new anesthesia, a series of the carbon dioxide loading with measurements was performed as in the N²O session. This measurement run is referred hereafter as the propofol–N²O session.

We took an extreme care to produce a step change in Petco²that was similar in the N²O and propofol–N²O sessions for each subject. However, the manual adjustment could not achieve such precise control as to attain an identical hypercapnic level across all subjects. Therefore, we had to accept interindividual variances in the hypercapnic level ranging as wide as 45–55 mmHg.

After the anesthetic induction and tracheal intubation was performed as mentioned above, 16 subjects in group 2 were anesthetized with a continuous intravenous infusion of propofol, 10 mg · kg⁻¹· h⁻¹. Neuromuscular block was obtained as in study 1. The patients were mechanically ventilated with 30% O²+ 70% N²at the slight hypocapnic level, Petco²of 27–29 mmHg. A series of measurements during stepwise CO²forcing was performed as in study 1 (propofol session). At the completion of the propofol session, the respired gas was switched to 30% O²+ 70% N²O. After a 20-min accommodation period to the new anesthesia, the stepwise carbon dioxide forcing was again performed with measurements (N²O–propofol session).

Data were analyzed off-line using a mathematical package (Splus 2000, MathSoft, Cambridge, MA). End-expiratory phases were determined from the airflow signal. Petco²was obtained from the readings in the expired carbon dioxide signal at the corresponding end-expiratory phases. Mean values of FV^MCAfor every heartbeat and breath-to-breath Petco²were resampled at 1 Hz by a linear interpolation to create a uniform time base. To align interindividual variances in the absolute FV^MCAvalues, FV^MCAwere expressed as percentages of the baseline mean FV^MCAvalue of each anesthesia session for each subject.

We rejected data obtained from subjects who did not present a stable cardiovascular condition throughout the experiment to avoid possible influence of changes in blood pressure on FV^MCA. The stable cardiovascular condition was defined as satisfying the following two criteria: (1) variations of the mean blood pressure remained within a range of the value at the beginning of the experiment ±10 mmHg; and (2) heart rate variations remained within a range of the value at the beginning of experiment ±15 beats/min.

The mathematical model used was described previously. 6,13The model is a simple extension of the steady-state FV^MCA–Petco²relationship, in which the magnitude of change of FV^MCAwas assumed to be proportional to the magnitude of change in Petco². In addition, the dynamic model also considers the speed of change in FV^MCAin response to change in Petco². In the model, therefore, the rate of change of FV^MCAis proportional to the deviation of FV^MCAfrom the value it would obtain in the steady state. Such a dynamic model produces an exponential output (FV^MCA) for a step input (Petco²). It is written in the form:

where the function u(t − Td) defines the variation of Petco²as,

where t is time (s), d/dt  denotes a derivative in terms of time, τ (s) is a time constant, G (%/mmHg) is a gain, and Td (s) is a pure time delay. FV^MCA* (%) and Petco²* (mmHg) are their respective steady-state values before a step change is undertaken.

To allow for asymmetry between the FV^MCAresponse to a step increase (on-response) and to a step decrease (off-response) in Petco², separate parameter values were estimated for the on- and off-responses. This resulted in five variables for estimation: gains for the on- and off-responses (Gon, Goff), time constants for the on- and off-responses (τon, τoff), and a single time delay (Td).

Model fitting for parameter estimation was performed on the on- and off-responses separately. The on-response model was fitted to the data from duration containing the 3-min baseline period and the first 3-min hypercapnic period with a step Petco²increase in the middle. The off-response model was fitted to the data from duration containing the last 3-min hypercapnic period and the 3-min recovery period with a step Petco²decrease in the middle. The best fit models that minimized the sum of square of residuals between the data and model were computed using a grid search technique. 6,13 

Statistical comparisons of FV^MCAand the model parameters between the two sessions in each study were performed using the paired t  test when the normal distribution criterion for each variable or model parameter was fulfilled. Otherwise, the Mann–Whitney U test was used. P < 0.05 was considered significant.

All subjects exhibited normal mean blood pressure (79 ± 6 mmHg [mean ± SD] mmHg) and heart rate (64 ± 4 beats/min [mean ± SD]) at the beginning of the experiment. Four subjects in study 1 and 1 subject in study 2 did not satisfy the stable cardiovascular condition; all of them exhibited increases in blood pressure of greater than 10 mmHg during the hypercapnic period. Therefore, they were discarded from further analysis, and the data obtained from the remaining 15 subjects in each study were analyzed.

Baseline FV^MCAvalues are presented in table 1. In study 1, the continuous infusion of propofol added to the N²O anesthesia decreased the baseline FV^MCAby 31.6 ± 8.6% (mean ± SD;P < 0.001) compared with that for the N²O session. In study 2, the inhalation of N²O added to the propofol anesthesia did not affect the baseline FV^MCA.

Figure 2shows the signals obtained from the subjects and the averages from the subjects. In each anesthesia condition, the manually adjusted carbon dioxide loading produced stepwise changes in Petco², although the step magnitude ranged from 15 to 25 mmHg among the subjects. Petco²steps tended to be faster and greater in the on-response than in the off-response.

Figure 3shows the responses of FV^MCAto step changes in Petco²and the models best fitted to the responses in a representative subject in study 1. Exponential contours in FV^MCAresponse curve to step changes in Petco²were observed in the N²O and propofol–N²O sessions. Model fitting performance was good in all subjects, and the model was able to track the dynamic changes of FV^MCAfor each anesthesia session.

Tables 2 and 3compare the estimated values of the model parameters between the two anesthesia sessions and between the on- and off-responses. The time delay (Td) after which the FV^MCAresponses to step changes in Petco²started was similar in both sessions of each study. In study 1 (table 2), compared with the N²O anesthesia, the propofol–N²O anesthesia increased τon and did not change either Gon or Goff. In study 2 (table 3), compared with the propofol anesthesia, the N²O–propofol anesthesia increased τon and τoff and did not change either Gon or Goff. In both studies, with respect to the comparison between the on- and off-responses, τon was significantly greater than τoff, and Gon was significantly smaller than Goff in any anesthesia session, indicating slower and smaller on-responses than off-responses.

Before interpreting the results of the study, the methods used should be considered. Instead of measuring the true MCA blood flow, this study used FV^MCAas an index of MCA blood flow, which has been done in previous studies. 6,14–16The MCA volume blood flow is theoretically the product of FV^MCAand the cross-sectional area of MCA. Therefore, FV^MCAmay not necessarily represent the volume blood flow if MCA exhibits temporal changes in the cross-sectional area. However, Poulin et al.  13showed that, during CO²-loaded breathing similar to this study, changes in the MCA cross-sectional area were negligible compared with those in the FV^MCA.

The manually adjusted carbon dioxide loading could not produce precise step (square-shaped) changes in Petco²with an identical magnitude across all subjects. The nonuniformity in the carbon dioxide loading pattern among subjects may affect the results. In the previous study, we examined effects of nonuniform step Petco²changes on the dynamic FV^MCAresponse. 6It indicated that the effects of the nonuniformity were negligible on the results in this study, as long as it remained within the extent produced in this study.

We used only a single dose for each anesthetic because of limited experimental time. Furthermore, in 5 subjects in study 1, we reduced the infusion rate of additional propofol to 7–9 mg · kg⁻¹· h⁻¹instead of 10 mg · kg⁻¹· h⁻¹to align blood pressure as closely as possible between the two anesthesia sessions. Therefore, the results of the present study may not be interpreted as the general relationship between the two anesthetics.

The continuous infusion of propofol, when added to the N²O anesthesia, decreased the baseline FV^MCAby 31.6%. It indicates that propofol at the dose used decreased the baseline MCA blood flow. It was suggested that propofol further decreased CBF as a combination of direct vasoconstriction and decreased metabolism. 1,7Although the present study neither controlled nor measured depth of anesthesia, it was likely that the infusion of propofol deepened the level of anesthesia. Therefore, both mechanisms would be responsible for the decrease in the baseline FV^MCAin this study.

By contrast, inhalation of 70% N²O, when added to the propofol anesthesia, did not change the baseline FV^MCA. This is similar to the finding reported by Eng et al.  2These results indicate that vasoconstriction induced by propofol is more potent than N²O-induced vasodilation at the doses used, so that effects of propofol on the cerebral vasculature would manifest.

Compared with the steady-state condition, the dynamic response not only considers the magnitude but also the speed, the gains, the pure time delay, and the time constants, respectively. Neither propofol nor N²O affected Gon or Goff. This indicates that the magnitude of the dynamic response is proportional to the baseline FV^MCAlevel, irrespective of different anesthesia conditions. It would be similar to the steady-state response of CBF to hypocapnia in either inhalational 17–20or intravenous anesthetia. 2,21However, Gon and Goff are approximately twice the magnitude of the steady-state response, which was reported to be 2.1–3.5%/mmHg. This difference may be the result of sustained hypo- or hypercapnia in the steady-state studies, in which gradual adaptation of cerebral vascular regulation toward the baseline level may have occurred. 21–23The difference in the response magnitude between the dynamic and steady-state responses may be reflected on the asymmetry between the on- and off-responses observed in this study. The on-responses were faster (τon < τoff) and smaller (Gon < Goff) than the off-responses in any anesthesia condition. It is comparable with the results of previous studies. 6,13The greater Goff than Gon would be odd because it implies that CBF decreased below the baseline level during the recovery period. It could be attributed to a transient overresponse in the cerebral arteries to a step Petco²decrease, which then fades away in several minutes. 6,13 

As to the speed of the dynamic response, Td represents the time delay after which the FV^MCAresponses to step Petco²changes start. It may be attributed mainly to a circulatory delay between the lung and the brain. The Td values obtained in this study, approximately 7 s, are comparable with those reported in previous studies. 13,24The addition of propofol to the N²O anesthesia increased τon, and the addition of N²O to the propofol anesthesia increased τon and τoff. It indicates that the addition of either propofol or N²O slowed the dynamic FV^MCAresponse to rapid changes in Petco². N²O and propofol induce mutually opposing effects on cerebral vessels, vasodilation and vasoconstriction, respectively. Therefore, the mechanisms slowing the dynamic response may differ between the two anesthetic agents. In the case of the addition of propofol, we wonder if the decrease in the baseline CBF produced by propofol would have delayed changes in the vascular and perivascular factors invoked by sudden changes in Paco², leading to the slowed dynamic response of FV^MCA. Furthermore, cerebral metabolism may be reduced by the additional propofol, 7,25which would also work in a direction to slow the response.

However, it is difficult to extrapolate mechanisms responsible for the slowed dynamic response produced by the addition of N²O to the propofol anesthesia. We had anticipated that the addition of N²O, a cerebral vasodilator, would have accelerated the dynamic FV^MCAresponse. We could only speculate that the additional N²O might modulate carbon dioxide-induced temporal (phase) sequences arising in the vascular and perivascular factors. 21,26–28 

It is beyond the scope of the present study to specify exact mechanisms enrolled in the interaction between N²O and propofol on the dynamic cerebrovascular response to rapid changes in Petco². From a clinical viewpoint, however, the combined use of propofol and N²O may work beneficially for the brain protection, irrespective of the order of administration, because it would dampen the immediate changes in CBF at sudden changes in Paco².

In conclusion, this study examined the effects of propofol and N²O on the cerebrovascular dynamic response to step changes in Petco²when added each other. Despite the directionally opposing effects of the two anesthetics on the cerebral circulation, both induced essentially similar effects. The addition of either anesthetic induced the baseline FV^MCA-dependent dynamic response in magnitude and slowed the dynamic response to step changes in Petco².

The authors thank Rie Kato, M.D., D.Phil. (Department of Anesthesiology, Chiba University Graduate School of Medicine, Chiba, Japan) for constructive criticism in preparing the manuscript.