Remifentanil and nitrous oxide reduce changes in cerebral blood flow velocity in the middle cerebral artery caused by pain

I. H. Lorenz*,1, C. Kolbitsch1, M. Hinteregger1, P. Bauer1, M. Spiegel2, T. J. Luger1, C. Schmidauer2, W. Streif3, K. P. Pfeiffer4 and A. Benzer1

1 Department of Anaesthesia and Intensive Care Medicine, 2 Department of Neurology, 3 Department of Paediatrics, 4 Department of Biostatistics and Documentation, University of Innsbruck, A-6020 Innsbruck, Anichstrasse 35, Austria

Corresponding author. E-mail: ingo.lorenz@uibk.ac.at

Accepted for publication: October 17, 2002


    Abstract
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Background. Cerebral blood flow is affected by painful stimuli, and analgesic agents may alter the response of cerebral blood flow to pain. We set out to quantify the effects of remifentanil and nitrous oxide on blood flow changes caused by experimental pain.

Methods. We simulated surgical pain in 10 conscious volunteers using increasing mechanical pressure to the tibia. We measured changes in cerebral blood flow velocity in the middle cerebral artery (CBFVMCA) caused by the pain, using transcranial Doppler sonography. We gave increasing doses of remifentanil (0.025, 0.05 and 0.1 µg kg–1 min–1) or nitrous oxide [20%, 35% and 50% end-tidal concentration (FE'N2O)] and compared these effects on blood flow changes.

Results. Nitrous oxide increased CBFVMCA only when given at 50% FE'N2O. Remifentanil did not affect CBFVMCA. Pain increased CBFVMCA. Both agents attenuated this pain-induced change in CBFVMCA with the exception of nitrous oxide at 20% FE'N2O.

Conclusions. Inhalation of nitrous oxide or adminstration of remifentanil attenuated pain-induced changes in CBFVMCA.

Br J Anaesth 2003: 90: 296–9

Keywords: anaesthetics gases, nitrous oxide; analgesics opioid, remifentanil; brain, blood flow; pain


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
The degree and extent of changes in cerebral blood flow (CBF) caused by pain depends on the characteristics of the stimulus13 and its site of application.3 To investigate the effects of surgical pain on cerebral haemodynamics we used mechanical pressure, which closely mimics surgical pain, in volunteers. We used transcranial Doppler sonography (TCD) to assess pain-induced changes in cerebral haemodynamics.

Analgesics such as remifentanil and nitrous oxide reduce the sensation of pain, so effects on CBF are likely. We measured CBF velocity in the middle cerebral artery (CBFVMCA) when remifentanil or nitrous oxide were given to volunteers experiencing pain caused by increasing mechanical pressure.


    Methods
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
After approval by the local university ethics committee and with written informed consent, 10 right-handed, non-smoking male volunteers (ASA physical status I) with no history of any drug or alcohol abuse took part in this study. The volunteers were randomly assigned by computer (SPSS random function, Version 11.0, SPSS inc., Chicago, IL, USA) to receive remifentanil or nitrous oxide on one day, with the other drug being investigated the next day. Investigation of the effect of the analgesic was preceded by control measurements of CBFVMCA, with and without pain caused by mechanical pressure.

A continuous infusion of remifentanil was given at three doses: 0.025, 0.05 and 0.1 µg kg–1 min–1, in ascending order. Each continuous infusion was preceded by a loading dose (e.g. 25% increased infusion rate for 5 min). After an additional 15 min of steady-state infusion of remifentanil, CBFVMCA was measured with and without pain. Further control measurements were made 20 min after stopping the remifentanil infusion.

The volunteers inhaled three different mixtures of nitrous oxide in oxygen [20%, 35%, 50% end-tidal concentration (FE'N2O)] in ascending order. A minimum of 20 min was allowed for stabilization of the end-tidal concentration before measuring CBFVMCA with and without pain. Further control measurements were made 20 min after stopping nitrous oxide inhalation.

Pain was caused with a locally constructed pneumatic piston (contact area 1.2 cm2), which was fixed to the anterior margin of the left tibia, 5 cm above the ankle. The pressure in the piston was increased by 20 kPa (or 2.4 N) every 5 s. The volunteers were instructed to switch off the device when pain became intolerable. To avoid tissue damage, the pressure was stopped after 90 s. The supply pressure was computer controlled using locally developed software.

CBFVMCA was measured by TCD using a fixed 2-MHz-pulsed TCD device (Multi-Dop-L, DWL, Sipplingen, Germany). The Doppler probe was placed on the right side of the head above the zygomatic arch between the lateral margin of the orbit and the ear, and directed toward the M1 segment of the middle cerebral artery at a depth of 50–55 mm, depending on the quality and stability of the signal.

Only one side was measured to avoid any variation related to changes in the site of recording. All TCD measurements were made by the same investigator.

During the experiment, the volunteer wore a closely fitting facemask and breathed at a constant FE'CO2 (e.g. 40 mm Hg). This value was sustained by additional verbal command when necessary. To minimize the risk of acid aspiration, volunteers fasted for 6 h before the experiment. To assess sedative side-effects of the two drugs, the bispectral index (BIS) (BISTM Model A-2000TM (v 3.4); Aspect Medical Systems International BV, Leiden, The Netherlands) was measured.

The fraction of inspired and expired oxygen, end-tidal carbon dioxide concentration (FE'CO2), respiratory frequency, non-invasive mean arterial pressure and pulse oximeter haemoglobin saturation (SpO2) were monitored (Compact, Datex, Finland). QUICK CALTM calibration gas (REF: 755582; Datex, Finland) was used to calibrate the monitor.

Statistical analysis
Data are presented as mean (SE). Data were tested for normal distribution using the Kolmogorov–Smirnov test. Pairwise comparison of CBFVMCA values at baseline and with the various doses of both agents with and without pain was performed using ANOVA for repeated measurements. Pain-induced changes in CBFVMCA s–1 ({Delta}-CBFVMCA/duration of pain application in s) were calculated as follows:


P<0.05 was considered statistically significant.


    Results
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
We studied 10 volunteers, mean age 27 (range 18–35) yr; mean weight, 79 (SD 11) kg; mean height: 182 (6) cm without complications. Haemodynamic values (heart rate, mean arterial pressure), respiratory parameters (SpO2, FE'CO2, frequency) and BIS values were not affected by either nitrous oxide or remifentanil.

Control measurements of CBFVMCA before and after administration of nitrous oxide or remifentanil were comparable (Fig. 1). Nitrous oxide increased CBFVMCA with 50% FE'N2O, whereas remifentanil did not influence CBFVMCA (Fig. 1).



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Fig 1 Cerebral blood flow velocity (CBFVMCA) at control (Remi pre; Remi post; N2O pre; N2O post) and during administration of remifentanil (0.025, 0.05, 0.1 µg kg–1 min–1) or nitrous oxide (20%, 35%, 50% FE'N2O). Data are mean (SD); n=10. *P<0.05 compared with control.

 
Pain increased {Delta}-CBFVMCA s–1 at control (Figs 2 and 3). The increase in {Delta}-CBFVMCA s–1 was attenuated during administration of nitrous oxide (35% and 50% FE'N2O; Fig. 2) and all concentrations of remifentanil (Fig. 3).



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Fig 2 Changes in {Delta}-CBFVMCA s–1 at control (N2O pre, N2O post) and during administration of nitrous oxide (20%, 35%, 50% FE'N2O). Data are mean (SD); n=10. *P<0.05 compared with control.

 


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Fig 3 Changes in {Delta}-CBFVMCA s–1 at control (Remi pre, Remi post) and during administration of remifentanil (0.025, 0.05, 0.1 µg kg–1 min–1). Data are mean (SD); n=10. *P<0.05 compared with control.

 

    Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
In our volunteers the increases in CBF caused by pain were reduced by both remifentanil and nitrous oxide.

With TCD, blood flow velocities can be measured non-invasively and continuously through the intact skull.4 Assuming that the diameter of the large cerebral arteries in the circle of Willis (measuring points) does not change greatly, velocity changes will be related to changes in CBF.5 Hence changes in the calibre of the small resistance vessels caused by metabolic changes (e.g. during periods of pain) should cause corresponding velocity changes indicative of changes in CBF.

In a previous TCD study,6 thermal pain (e.g. cold pressor test) decreased CBFVMCA. In a study using positron emission tomography (PET), chemical pain caused by capsaicin decreased global CBF.7 With regard to regional CBF, however, various PET studies found that pain could increase or decrease regional CBF. In fact, variations in both the intensity and the distribution of regional CBF changes have been observed depending on the physical characteristics of the stimulus (e.g. heat vs cold;1 2 chemical vs electrical or laser3) or its site of application (skin vs subcutaneous or muscles). In the present study, pain caused by pressure combined the features of cutaneous, subcutaneous and muscular pain. Surgical pain possesses a combination of these qualities. The intensity of surgical pain depends on the site and stage of the operation. To mimic an episode of increasing pain intensity, we gradually increased pain intensity to the point of intolerance. To account for changes in pain threshold at baseline and during remifentanil or nitrous oxide administration, the duration of pain application was taken into account when we calculated {Delta}-CBFVMCA s–1.

When attention is directed towards or away from a painful stimulus, this can affect electrocortically evoked potentials8 9 as well as pain-induced changes in regional CBF.10 In the present study, attention was directed towards the increasing pain, and the volunteers had to actively discontinue this stimulus when the pain became intolerable. We can assume that mechanical pain increased {Delta}-CBFVMCA s–1 not only by its specific physical characteristics but also because of the high level of attention present. The importance of such attention is clear in the effects of non-painful cognitive tasks, which increase CBFVMCA in volunteers.11

In this study, both nitrous oxide and remifentanil reduced the pain-induced increase in {Delta}-CBFVMCA s–1. One possible explanation for this is that the state of attention of the subjects could have been altered by the agents. BIS monitoring and clinical impression, however, gave no indication of changes in vigilance and or attention in any volunteers at any time during the experiment. Thus, decreased pain perception with no obvious change in attention probably explains the decrease in {Delta}-CBFVMCA s–1 during administration of nitrous oxide or remifentanil. Alternatively, the observed changes in {Delta}-CBFVMCA s–1 could merely reflect pain-induced changes in systemic haemodynamics. In the present study, nitrous oxide and remifentanil did not cause any changes in arterial pressure or heart rate. Reliable non-invasive measurements during the relatively short periods of increasing pain (<90 s) were not possible. Cerebral autoregulation is maintained with these doses of remifentanil.12 Therefore, changes in arterial pressure (e.g. during increasing pain) are unlikely to have caused the observed changes in CBFV. However, nitrous oxide at 50% FE'N2O does affect autoregulation,13 so the observed changes in {Delta}-CBFVMCA s–1 could have been caused by circulatory effects.

The effect of the agents on CBFVMCA in the absence of pain is of interest. In the absence of pain, remifentanil had no effect on CBFVMCA. Similarly, in a previous study, Paris and colleagues14 showed that an even higher dose (e.g. 2 µg kg–1) of remifentanil did not affect CBFVMCA in anaesthetized patients. In spontaneously breathing volunteers, however, remifentanil (0.1 µg kg–1 min–1) increased regional CBF, especially at brain sites rich in opioid receptors, at a dose comparable to that used in the present study.15

In the absence of pain, nitrous oxide increased CBFVMCA only at the highest dose used (50% FE'N2O). Nitrous oxide increases CBFVMCA when given to normocapnic volunteers.16 Hyperventilation counteracted this nitrous oxide-induced increase in CBFVMCA.16 17 Thus, pain-induced hyperventilation could have reduced CBFVMCA when nitrous oxide was given during increasing pain. In the present study, however, normocapnia was meticulously maintained using FE'CO2, which correlates well with PaCO2.1820 In some cases, the changes in ventilation caused by pain were too short (e.g. duration of <60 s) to significantly alter PaCO2. Therefore, it is unlikely that changes in PaCO2 were responsible for the changes observed in {Delta}-CBFVMCA s–1, whether during administration of nitrous oxide or remifentanil alone or during the painful stimulus and administration of analgesic. This is all the more important because cerebrovascular reactivity to carbon dioxide remains intact during administration of remifentanil21 and nitrous oxide.22

In conclusion, we found that mechanical pain increases CBFVMCA in human volunteers. These pain-induced changes in {Delta}-CBFVMCA s–1 were attenuated during inhalation of nitrous oxide or adminstration of remifentanil.


    Acknowledgements
 
The authors thank all volunteers at Innsbruck University Hospital whose participation made this study possible.


    References
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
1 Casey KL, Minoshima S, Berger KL, Koeppe RA, Morrow TJ, Frey KA. Positron emission tomographic analysis of cerebral structures activated specifically by repetitive noxious heat stimuli. J Neurophysiol 1994; 71: 802–7[Abstract/Free Full Text]

2 Casey KL, Minoshima S, Morrow TJ, Koeppe RA. Comparison of human cerebral activation pattern during cutaneous warmth, heat pain, and deep cold pain. J Neurophysiol 1996; 76: 571–81[Abstract/Free Full Text]

3 Svensson P, Minoshima S, Beydoun A, Morrow TJ, Casey KL. Cerebral processing of acute skin and muscle pain in humans. J Neurophysiol 1997; 78: 450–60[Abstract/Free Full Text]

4 Aaslid R, Markwalder TM, Nornes H. Noninvasive transcranial Doppler ultrasound recording of flow velocity in basal cerebral arteries. J Neurosurg 1982; 57: 769–74[ISI][Medline]

5 Bishop CC, Powell S, Rutt D, Browse NL. Transcranial Doppler measurement of middle cerebral artery blood flow velocity: a validation study. Stroke 1986; 17: 913–15[Abstract]

6 Micieli G, Tassorelli C, Bosone D, Cavallini A, Viotti E, Nappi G. Intracerebral vascular changes induced by cold pressor test: a model of sympathetic activation. Neurol Res 1994; 16: 163–7[ISI][Medline]

7 Coghill RC, Sang CN, Berman KF, Bennett GJ, Iadarola MJ. Global cerebral blood flow decreases during pain. J Cereb Blood Flow Metab 1998; 18: 141–7[CrossRef][ISI][Medline]

8 Siedenberg R, Treede RD. Laser-evoked potentials: exogenous and endogenous components. Electroencephalogr Clin Neurophysiol 1996; 100: 240–9[CrossRef][Medline]

9 Garcia-Larrea L, Peyron R, Laurent B, Mauguiere F. Association and dissociation between laser-evoked potentials and pain perception. Neuroreport 1997; 8: 3785–9[ISI][Medline]

10 Peyron R, Garcia-Larrea L, Gregoire MC, et al. Haemodynamic brain responses to acute pain in humans: sensory and attentional networks. Brain 1999; 122: 1765–80[Abstract/Free Full Text]

11 Harders AG, Laborde G, Droste DW, Rastogi E. Brain activity and blood flow velocity changes: a transcranial Doppler study. Int J Neurosci 1989; 47: 91–102[ISI][Medline]

12 Warner DS, Hindman BJ, Todd MM, et al. Intracranial pressure and hemodynamic effects of remifentanil versus alfentanil in patients undergoing supratentorial craniotomy. Anesth Analg 1996; 83: 348–53[Abstract]

13 Girling KJ, Cavill G, Mahajan RP. The effects of nitrous oxide and oxygen on transient hyperemic response in human volunteers. Anesth Analg 1999; 89: 175–80[Abstract/Free Full Text]

14 Paris A, Scholz J, von Knobelsdorff G, Tonner PH, Schulte am Esch J. The effect of remifentanil on cerebral blood flow velocity. Anesth Analg 1998; 87: 569–73[Abstract]

15 Lorenz IH, Kolbitsch C, Schocke M, et al. Low-dose remifentanil increases regional cerebral blood flow and regional cerebral blood volume, but decreases regional mean transit time and regional cerebrovascular resistance in volunteers. Br J Anaesth 2000; 85: 199–204[Abstract/Free Full Text]

16 Hormann C, Schmidauer C, Haring HP, Schalow S, Seiwald M, Benzer A. Hyperventilation reverses the nitrous oxide-induced increase in cerebral blood flow velocity in human volunteers. Br J Anaesth 1995; 74: 616–18[Abstract/Free Full Text]

17 Hormann C, Schmidauer C, Kolbitsch C, Kofler A, Benzer A. Effects of normo- and hypocapnic nitrous-oxide-inhalation on cerebral blood flow velocity in patients with brain tumors. J Neurosurg Anesthesiol 1997; 9: 141–5[ISI][Medline]

18 Young WL, Prohovnik I, Ornstein E, Ostapkovich N, Matteo RS. Cerebral blood flow reactivity to changes in carbon dioxide calculated using end-tidal versus arterial tensions. J Cereb Blood Flow Metab 1991; 11: 1031–5[ISI][Medline]

19 Campbell FA, McLeod ME, Bissonnette B, Swartz JS. End-tidal carbon dioxide measurement in infants and children during and after general anaesthesia. Can J Anaesth 1994; 41: 107–10[Abstract]

20 Bongard F, Wu Y, Lee TS, Klein S. Capnographic monitoring of extubated postoperative patients. J Invest Surg 1994; 7: 259–64[Medline]

21 Ostapkovich ND, Baker KZ, Fogarty-Mack P, Sisti MB, Young WL. Cerebral blood flow and CO2 reactivity is similar during remifentanil/N2O and fentanyl/N2O anesthesia. Anesthesiology 1998; 89: 358–63[CrossRef][ISI][Medline]

22 Aono M, Sato J, Nishino T. Nitrous oxide increases normocapnic cerebral blood flow velocity but does not affect the dynamic cerebrovascular response to step changes in end-tidal P(CO2) in humans. Anesth Analg 1999; 89: 684–9[Abstract/Free Full Text]