Does bispectral index monitoring optimize

intravenous anaesthetic drug delivery?

 

Jaap Vuyk

Deparment of Anaesthesiology

Leiden University Medical Center

2300 AA, Leiden, The Netherlands

Email: j.vuyk@lumc.nl

 

The bispectral index monitor has been ongoing developed since 1992 with the premarket approval by the FDA in 1996 (Aspect Medical Systems, Inc., Natick, MA). The bispectral analysis is a further computation of time domain and frequency domain parameters. The bispectral analysis considers the relationship between the sinusoids at two frequencies 1 and 2 and a modulation of these two 1+ 2. For this set of three frequency components the bispectrum can be calculated on the basis of the phase information or bicoherence (BIC 1,2) and the sum of the magnitude of the 3 members known as the real triplet product (RTP 1,2). Finally, the bispectral index then is composed of time domain, frequency domain and higher order spectral parameters. An important feature in the calculation of the bispectral index is that the weight of any of these 4 subparameters (BSR, QUAZI, β-ratio and SyncFastSlow) changes with the level of sedation. The β-ratio weighs heavier in the final computation of BIS at levels of light sedation, the SyncFastSlow parameter dominates at excitation and surgical levels of hypnosis and the BSR and QUAZI are more important in the BIS calculation at the most deep levels of EEG depression. The specific weight of the various subparameters of BIS at various clinical states has been determined, during the development of the BIS by Aspect Medical Systems, on the basis of a body of data gathered from a group of patients that received various anesthetics while EEG and behavioral data were collected. In the end the BIS is determined as a running average of 15-30 seconds of EEG signal collection and visualized as a dimensionless nonlinear parameter between 0-100. With 0 equaling no electrical activity and with 100 defining the awake state. In general, the Bispectral Index Scale (BIS) reflects the awake state at values exceeding 95, a state of sedation at BIS values of 65-85, an arousal state depression suited for general anesthesia at BIS values of 40-65 and burst suppression patterns become evident at BIS levels below 40.

The effect of various anesthetic agents on the bispectral index scale appears to be agent specific. In general, hypnotic agents like propofol, midazolam or thiopental have a strong depressant effect on BIS, inhalational anesthetic agents propagate an intermediate depressant effect on BIS whereas the opioids have little or no influence on the BIS at clinically relevant concentrations. Lastly, nitrous oxide and ketamine appear to have paradoxical effects on the BIS. Altogether, this may be interpreted as BIS relating well to sedation and hypnosis levels but not properly reflecting the level of analgesia or depth of anesthesia.

The most promising application of the bispectral index monitor may be as a monitor of consciousness-sedation-unconsciousness levels. In the absence of central nervous system monitoring hypnotic agents are often administered on the basis of prescribed dosing regimens (12-10-8 mg/kg/h step-down propofol infusion scheme) that may be adjusted to the response of the individual patient. The prescribed dosing regimens do not take into account the pharmacokinetic variability of + 70% or the pharmacodynamic variability of + 300-400% in between patients. This huge interindividual PK/PD variability next to the sometimes poor predictability of the surrogate measures of sedation and anesthesia (haemodynamic parameters, movement responses etc.) are the cause of the frequent over- and under dosing of individual patients during sedation and general anesthesia. The BIS probably is most easily interpreted and may relate best to the actual level of sedation during sedation with a single agent in the absence of painful stimuli. Although no single BIS value exists that will assure an adequate hypnotic level in every patient in the presence of any possible anesthetic agent combination or type of stimulation, the BIS has proven acceptably reliable as a measure of hypnosis during sedation and general anesthesia with most anesthetic agents. Clinically, the optimized focusing of drug administration to the specific needs of the patient with BIS monitoring may result in a reduced agent administration and increased speed of return of consciousness and recovery.

Because the BIS very closely correlates with the level of (un)consciousness it is very tentative to state that the use of bispectral index analysis will reduce or prevent the occurrence of awareness. However, because the incidence of awareness is relatively low and because awareness has been reported in the presence of BIS monitoring, showing that the efficiency of awareness prevention by the BIS is not 100%, to get absolute prove that BIS monitoring would reduce the risk of awareness it would take great numbers of patients.

During the development of the bispectral index monitor agent versus behavioral data have been used to optimize the BIS algorithm. Consequently, when new anesthetic agents arise new data have to be entered and probably the BIS monitor adjusted to enable use with the new agent. As already mentioned some agents like nitrous oxide and ketamine induce their effects by mechanisms that the BIS monitor apparently is unable to track. Adding ketamine or nitrous oxide deepens the anesthetic level but increases the BIS. In the presence of these agents the BIS monitor therefore should not be used.

Electrocautery will make the BIS disappear or increase; pacemakers have been described to increase the BIS as well. EMG activity has been claimed to increase the BIS, but later versions like the recent XP version may be less susceptible to this. Lastly, hypothermia decreases the BIS by 1.12 units per degree Celsius decline in body temperature.

 

Conclusion.

Bispectral index monitoring is useful for the intraoperative tracking of the level of unconsciousness especially during high hypnotic-low opioid anesthesia. It allows for an improved titration of hypnotic agent requirement and may lead to a reduced agent use and improved recovery. No data yet provide sufficient prove that BIS may predict anesthetic depth or may be used to predict patient responses to noxious stimulation. BIS monitoring may be useful for guidance of sedation e.g. in the ICU but more data are required to judge its value in this setting. Lastly, no data yet provide sufficient proof that bispectral index monitoring reduces the incidence of awareness.

 

References.

1. R.Caton, The electrical currents of the brain., British Medical Journal 2:278 (1875).

2. F.Gibbs, E.Gibbs, and W.Lennox, Effect on the electroencephalogram of certain drugs which influence nervous activity., Archives of Internal Medicine 60:154-66 (1937).

3. I.J.Rampil, A primer for EEG signal processing in anesthesia, Anesthesiology 89:980-1002 (1998).

4. L.T.Breimer, A.G.Burm, M.Danhof, P.J.Hennis, A.A.Vletter, J.W.de Voogt, J.Spierdijk, and J.G.Bovill, Pharmacokinetic-pharmacodynamic modelling of the interaction between flumazenil and midazolam in volunteers by aperiodic EEG analysis, Clin.Pharmacokinet. 20:497-508 (1991).

5. L.T.Breimer, P.J.Hennis, A.G.Burm, M.Danhof, J.G.Bovill, J.Spierdijk, and A.A.Vletter, Quantification of the EEG effect of midazolam by aperiodic analysis in volunteers. Pharmacokinetic/ pharmacodynamic modelling, Clin.Pharmacokinet. 18:245-53 (1990).

6. J.C.Scott, J.E.Cooke, and D.R.Stanski, Electroencephalographic quantitation of opioid effect: comparative pharmacodynamics of fentanyl and sufentanil, Anesthesiology 74:34-42 (1991).

7. J.C.Scott, K.V.Ponganis, and D.R.Stanski, EEG quantitation of narcotic effect: the comparative pharmacodynamics of fentanyl and alfentanil, Anesthesiology 62:234-41 (1985).

8. K.Kuizenga, C.J.Kalkman, and P.J.Hennis, Quantitative electroencephalographic analysis of the biphasic concentration-effect relationship of propofol in surgical patients during extradural analgesia, Br.J.Anaesth. 80:725-32 (1998).

9. V.Billard, P.L.Gambus, N.Chamoun, D.R.Stanski, and S.L.Shafer, A comparison of spectral edge, delta power, and bispectral index as EEG measures of alfentanil, propofol, and midazolam drug effect, Clin.Pharmacol.Ther. 61:45-58 (1997).

10. M.Buhrer, P.O.Maitre, O.R.Hung, W.F.Ebling, S.L.Shafer, and D.R.Stanski, Thiopental pharmaco-dynamics. I. Defining the pseudo-steady-state serum concentration-EEG effect relationship, Anesthesiology 77:226-36 (1992).

11. D.R.Stanski, Pharmacodynamic modeling of anesthetic EEG drug effects, Annu.Rev.Pharmacol.Toxicol. 32:423-47 (1992).

12. M.Buhrer, P.O.Maitre, C.Crevoisier, and D.R.Stanski, Electroencephalographic effects of benzodiazepines. II. Pharmacodynamic modeling of the electroencephalographic effects of midazolam and diazepam, Clin.Pharmacol.Ther. 48:555-67 (1990).

13. H.Schwilden, J.Schuttler, and H.Stoeckel, Quantitation of the EEG and pharmacodynamic modelling of hypnotic drugs: etomidate as an example, Eur.J.Anaesthesiol. 2:121-31 (1985).

14. J.W.Johansen and P.S.Sebel, Development and clinical application of electroencephalographic bispectrum monitoring, Anesthesiology 93:1336-44 (2000).

15. M.T.Alkire, C.J.Pomfrett, R.J.Haier, M.V.Gianzero, C.M.Chan, B.P.Jacobsen, and J.H.Fallon, Functional brain imaging during anesthesia in humans: effects of halothane on global and regional cerebral glucose metabolism, Anesthesiology 90:701-9 (1999).

16. M.T.Alkire, Quantitative EEG correlations with brain glucose metabolic rate during anesthesia in volunteers, Anesthesiology 89:323-33 (1998).

17. P.S.Glass, M.Bloom, L.Kearse, C.Rosow, P.Sebel, and P.Manberg, Bispectral analysis measures sedation and memory effects of propofol, midazolam, isoflurane, and alfentanil in healthy volunteers, Anesthesiology 86:836-47 (1997).

18. R.Flaishon, A.Windsor, J.Sigl, and P.S.Sebel, Recovery of consciousness after thiopental or propofol. Bispectral index and isolated forearm technique, Anesthesiology 86:613-9 (1997).

19. J.Vuyk, T.Lim, F.H.Engbers, A.G.Burm, A.A.Vletter, and J.G.Bovill, The pharmacodynamic interaction of propofol and alfentanil during lower abdominal surgery in women, Anesthesiology 83:8-22 (1995).

20. T.Katoh, H.Bito, and S.Sato, Influence of age on hypnotic requirement, bispectral index, and 95% spectral edge frequency associated with sedation induced by sevoflurane, Anesthesiology 92:55-61 (2000).

21. M.E.Ausems, J.Vuyk, C.C.Hug, Jr., and D.R.Stanski, Comparison of a computer-assisted infusion versus intermittent bolus administration of alfentanil as a supplement to nitrous oxide for lower abdominal surgery, Anesthesiology 68:851-61 (1988).

22. C.Lysakowski, L.Dumont, M.Pellegrini, F.Clergue, and E.Tassnyi, Effects of fentanyl, alfentanil, remifentanil and sufentanil on loss of consciousness and bispectral index during propofol induction of anaesthesia., Br.J.Anaesth. 86:523-7 (2001).

23. H.M.El Kerdawy, E.E.Zalingen, and J.G.Bovill, The influence of the alpha2-adrenoceptor agonist, clonidine, on the EEG and on the MAC of isoflurane, Eur.J.Anaesthesiol. 17:105-10 (2000).

24. T.Sakai, H.Singh, W.D.Mi, T.Kudo, and A.Matsuki, The effect of ketamine on clinical endpoints of hypnosis and EEG variables during propofol infusion, Acta Anaesthesiol.Scand. 43:212-6 (1999).

25. C.C.Wu, M.S.Mok, C.S.Lin, and S.R.Han, EEG-bispectral index changes with ketamine versus thiamylal induction of anesthesia, Acta Anaesthesiol.Sin. 39:11-5 (2001).

26. G.Barr, J.G.Jakobsson, A.Owall, and R.E.Anderson, Nitrous oxide does not alter bispectral index: study with nitrous oxide as sole agent and as an adjunct to i.v. anaesthesia, Br.J.Anaesth. 82:827-30 (1999).

27. G.D.Puri, Paradoxical changesin bispectral index during nitrous oxide administration., Br.J.Anaesth. 86:141-2 (2001).

28. W.T.Denman, E.L.Swanson, D.Rosow, K.Ezbicki, P.D.Connors, and C.E.Rosow, Pediatric evaluation of the bispectral index (BIS) monitor and correlation of BIS with end-tidal sevoflurane concentration in infants and children, Anesth.Analg. 90:872-30 (2000).

29. M.Renna and R.Venturi, Bispectral index and anaesthesia in the elderly, Minerva Anestesiol. 66:398-402 (2000).

30. T.J.Gan, P.S.Glass, A.Windsor, F.Payne, C.Rosow, P.Sebel, and P.Manberg, Bispectral index monitoring allows faster emergence and improved recovery from propofol, alfentanil, and nitrous oxide anesthesia. BIS Utility Study Group, Anesthesiology 87:808-15 (1997).

31. K.Kurehara, T.Horiuch, M.Takahash, K.Kitaguchi, and H.Furuya, [A case of awareness during propofol anesthesia using bispectral index as an indicator of hypnotic effect], Masui 50:886-9 (2001).

32. M.F.O'Connor, S.M.Daves, A.Tung, R.I.Cook, R.Thisted, and J.Apfelbaum, BIS monitoring to prevent awareness during general anesthesia, Anesthesiology 94:520-2 (2001).

33. G.Barr, R.E.Anderson, A.Owall, and J.G.Jakobsson, Being awake intermittently during propofol-induced hypnosis: A study of BIS, explicit and implicit memory, Acta Anaesthesiol.Scand. 45:834-8 (2001).

34. C.De Deyne, M.Struys, J.Decruyenaere, J.Creupelandt, E.Hoste, and F.Colardyn, Use of continuous bispectral EEG monitoring to assess depth of sedation in ICU patients, Intensive Care Med. 24:1294-8 (1998).

35. M.M.Struys, T.De Smet, L.F.Versichelen, D.Van, V, B.R.Van den, and E.P.Mortier, Comparison of closed-loop controlled administration of propofol using Bispectral Index as the controlled variable versus "standard practice" controlled administration, Anesthesiology 95:6-17 (2001).

36. M.Luginbhl, T.W.Schnider, Detection of awareness with the bispectral index: two case reports, Anesthesiology 96: 241-3 (2002).

37. A.R.Absalom, N.Sutcliffe, G.N. Kenny, Closed-loop control of anesthesia using bispectral index, Anesthesiology 96: 67-73 (2002).