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Anesth Analg 2003;97:1040-1045
© 2003 International Anesthesia Research Society

ANESTHETIC PHARMACOLOGY

Electroencephalographic Burst Suppression Versus Loss of Reflexes Anesthesia with Propofol or Thiopental: Differences of Variance in the Catecholamine and Cardiovascular Response to Tracheal Intubation

Seppo T. Mustola, MD*, Gerhard A. Baer, MD PhD{dagger}, Juhani K. Toivonen, MD PhD*, Anne Salomäki, Sc.lic.{ddagger}, Mika Scheinin, PhD§, Heini Huhtala, MSc||, Pekka Laippala, PhD, and Ville Jäntti, MD PhD#

*Department of Anesthesia, South Carelia Central Hospital, Lappeenranta, Finland; {dagger}Department of Anesthesia, Tampere University Hospital, Tampere, Finland; {ddagger}Department of Chemistry, Tampere University Hospital, Tampere, Finland; §Department of Pharmacology, University of Turku, Turku, Finland; ||School of Public Health, University of Tampere, Tampere, Finland; ¶School of Public Health, Research Unit, Tampere University Hospital, Tampere, Finland; and #Ragnar Granit Institute, Tampere University of Technology, Tampere, Finland

Address correspondence and reprint requests to Seppo T. Mustola, MD, Department of Anesthesia, South Carelia Central Hospital, Valto Käkelän Katu 1, FIN-53130 Lappeenranta, Finland. Address e-mail to seppo.mustola{at}ekshp.fi


   Abstract
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 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
The electroencephalographic burst suppression pattern (BSP) might indicate the brain’s effect-site concentration of anesthetics more precisely than clinical signs and thus eliminate bias from studies on the reaction to tracheal intubation after different induction drugs. To test this hypothesis, we compared the catecholamine and cardiovascular responses and their variances to tracheal intubation when either BSP was induced by infusion of propofol (30 mg · kg-1 · h-1; n = 14) or thiopental (75 mg · kg-1 · h-1; n = 14) or anesthesia by repeated bolus doses until loss of reflexes (LR), initially of propofol 2.5 mg/kg (n = 15) or thiopental 5 mg/kg (n = 15). The standard deviations were more often smaller in the BSP than in the LR groups, but the results of Levene’s test for differences of variance were insignificant. At the LR level, propofol attenuated catecholamine, arterial blood pressure, and heart rate responses to intubation better than thiopental, but at the BSP level, only the norepinephrine response was better attenuated. Cp50 concentrations of propofol and thiopental at the onset of BSP were 9.65 and 31.60 µg/mL, respectively.

IMPLICATIONS: Our results did not support the hypothesis that the responses to tracheal intubation can be more accurately predicted when unconsciousness is controlled with the aid of an electroencephalographic burst suppression pattern. Significant differences were found in the reactions between propofol and thiopental. At the burst suppression level, the catecholamine response was abolished with propofol.


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Propofol attenuates, more efficiently than thiopental, the hemodynamic response to tracheal intubation and the subsequent increase of catecholamines, whether bolus doses (1,2) or infusion regimens (3,4) are used. Depth of anesthesia in all studies was controlled by analysis of clinical signs. We hypothesized that more precise information might be obtained on the reaction to tracheal intubation when unconsciousness is controlled by aid of the electroencephalographic (EEG) burst suppression pattern (BSP). BSP represents very abnormal cortical activity, where 95% of cortical cells are silent during suppression (5), and therefore patients are deeply unconscious during BSP. Furthermore, healthy brain BSP is produced only by large concentrations of anesthetic (6–8). Inhaled anesthetics induce BSP at approximately 1.5 minimum alveolar anesthetic concentration (8,9), whereas thiopental and propofol induce BSP near the plasma concentration, which abolishes the reaction to a noxious stimulus in 50% of patients (Cp50) (6,7,10,11). This shows that at BSP level, patients are at the same depth of anesthesia with propofol and thiopental, but it is a different depth compared with inhaled anesthetics. However, different anesthetics produce different BSPs (9,12,13), indicating their different mechanisms of action.

The aim of this study was to test our hypothesis by investigating plasma catecholamine and hemodynamic responses to tracheal intubation during BSP induced by steady infusion and after bolus doses until loss of reflexes (LR) with either propofol or thiopental. In addition, we measured the plasma concentrations of 3,4-dihydroxyphenylethylenglycol (DHPG), an intracellular metabolite of norepinephrine, and plasma concentrations of propofol and thiopental to estimate their BSP concentrations.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
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The Ethics Committee of South Carelia Central Hospital approved the study, and written, informed consent was obtained from all patients. We studied 60 ASA physical status I–II patients, aged 20 to 60 yr, scheduled for elective surgical procedures. We excluded patients with a body mass index >30 kg/m2, cardiac diseases, and arterial hypertension and those who take drugs which affect the central nervous system. Patients were randomly allocated by selection of sealed envelopes to one of four groups: LR with propofol (P-LR) or thiopental (T-LR) and BSP with propofol (P-BSP) or thiopental (T-BSP).

Premedication and anticholinergics were omitted. After arrival in the operating theater, an infusion of acetated Ringer’s solution was started via a large vein on a forearm. A radial artery cannula served for continuous recording of arterial blood pressure and drawing of blood samples.

The electrocardiogram chest lead 5, systolic and diastolic arterial blood pressure, heart rate, end-tidal CO2, peripheral oxygen saturation, and peripheral and endonasal body temperatures were monitored with an S/5 monitor (Datex-Engström, Espoo, Finland) and collected on the hard disk of a portable personal computer at 10-s intervals. The EEG was monitored with a Neuropak 8 (Nihon Kohden, Tokyo, Japan) evoked potential measuring system. The EEG signal was obtained from a pair of silver cup electrodes placed in the middle of the head (Cz) and behind the left ear (A1). Electrode impedance was kept <5 k{Omega}.

Anesthesia was induced in the LR groups either with propofol 2.5 mg/kg or thiopental 5 mg/kg, injected over 20 s. If the eyelash or pupillary light reflex was still present 60 s after the injection, additional doses of propofol 0.5 mg/kg or thiopental 1 mg/kg were given at 30-s intervals until both reflexes were abolished. An abolished pupillary reflex meant a small pupil with no reaction to light. In the BSP groups, induction was with infusion of either propofol 30 mg · kg-1 · h-1 or thiopental 75 mg · kg-1 · h-1 until burst suppression was achieved. EEG was evaluated visually. The onset of BSP was stated when 2–4 s of EEG suppression had been noted. After onset of BSP, the infusion of propofol was decreased to 20 mg · kg-1 · h-1 and that of thiopental to 37.5 mg · kg-1 · h-1. Infusion programs had been chosen according to a pilot study. The aim was to maintain the BSP (2- to 5-s suppressions between bursts) until the trachea was intubated. One minute after the last bolus dose or 1 min after the onset of BSP, rocuronium 0.6 mg/kg was used to facilitate tracheal intubation. The duration of intubation was recorded.

After intubation in the BSP groups, the lungs were ventilated with 30% oxygen in air, and anesthesia was continued with propofol 15 mg · kg-1 · h-1 or thiopental 25 mg · kg-1 · h-1 for 5 min. Thereafter, anesthesia was continued with 65% nitrous oxide in oxygen, fentanyl, and isoflurane, which was also the maintenance regimen in the LR groups.

Arterial blood samples (9 mL) for catecholamine estimations were collected into prechilled EDTA tubes at times presented in Table 1 and were maintained at 0°C in an ice bath. Transfer to the laboratory was performed within 10 min, where the samples were immediately centrifuged at 0°C and stored at -70°C until they were analyzed by high-performance liquid chromatography with coulometric electrochemical detection (14). Epinephrine, norepinephrine, and DHPG interassay coefficients of variation were 11.8% (mean, 0.24 nM; n = 10), 8.2% (mean, 1.17 nM; n = 10), and 9.1% (mean, 4.84 nM; n = 10) with quantitation limits of 0.05, 0.05, and 0.5 nM, respectively. Arterial blood for plasma concentrations of propofol and thiopental was collected into EDTA tubes at times presented in Table 2. Transfer was performed within 30 min; plasma was separated and stored at -20°C until analysis by high-performance liquid chromatographic methods (15,16). Propofol and thiopental intraassay coefficients of variation were 5% and 4%, with quantitation limits of 3 ng/mL and 0.3 µg/mL, respectively.


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  		Table 1. Plasma Concentrations (nmol/L) of Epinephrine and Norepinephrine: Values Are Mean (95% Confidence Limits)
 

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  		Table 2. Plasma Concentrations (µg/mL) of Propofol (P) and Thiopental (T) During and After Infusion: Values Are Mean (sd)
 
Levene’s test (17) was used to compare the equality of the variances. The comparison between the P and T groups was based on analysis of variance for repeated measurements and Tukey’s procedure for the post hoc testing. One-way analysis of variance was used for demographic data. Wilcoxon’s signed rank test was used for within-group differences before and after tracheal intubation. Results are presented as mean (SD) 95% confidence limits (CL), unless specified otherwise; P < 0.05 was considered statistically significant. The computation was performed with SPSS for Windows (Version 10.1) software (SPSS Inc., Chicago, IL). The power calculations were made with Solo Power Analysis software. The purpose was to detect a 20% difference between the means at a two-sided significance level of 0.05.


   Results
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 Abstract
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 Results
Discussion
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At the end of the study, data from one patient each of groups P-BSP and T-BSP were incomplete and were excluded from further analysis. Demographic data and induction details are presented in Table 3. Eight patients of Group P-LR and seven patients of Group T-LR needed one extra bolus to abolish reflexes; additional boluses were not needed. BSP could be maintained in all patients of the BSP groups until tracheal intubation. Five minutes after tracheal intubation (end of infusion), some patients of Group P-BSP did not preserve BSP, but all of Group T-BSP did. In the recovery room, no patient recalled anything about tracheal intubation.


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  		Table 3. Demographic Data, Duration of Anesthetic Infusion and Intubation, and Time to Reach Electroencephalographic Burst Suppression Pattern (BSP); Values Are Mean (sd or Range)
 
A significant difference for the variances of catecholamines was found between the combined (P and T) LR and BSP groups in 2 of 15 possible instances (Table 4). Levene’s test between the combined LR and BSP groups in cardiovascular response showed significant differences in 11 of the tested 21 pairs, but only in 5 pairs was significance due to smaller SD% in the BSP group in both pairs, i.e., in favor of our hypothesis (Table 5). The power was satisfactory (>0.99) for each of these variables.


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  		Table 4. Levene’s Test of Equality of Error Variances for Catecholamines (P Values) Between Combined (Propofol and Thiopental) Loss-of-Reflex and Burst Suppression Groups
 

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  		Table 5. Results of Levene’s Test (P Values) for Differences of Variance in Hemodynamic Data Between Combined (Propofol and Thiopental) Loss-of-Reflex (LR) and Burst Suppression (BSP) Groups
 

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  		Table 6. Systolic (SAP) and Diastolic (DAP) Arterial Blood Pressure and Heart Rate (HR) in Loss-of-Reflex (LR) and Burst Suppression (BSP) Groups with Propofol (P) and Thiopental (T): Values Are Mean (sd) (95% Confidence Limits)
 
Arterial concentrations of epinephrine and norepinephrine are presented in Table 1. There were no significant differences between or within groups in arterial concentrations of DHPG, varying from 5.29 to 7.00 nmol/L (0.99–2.85 nmol/L) in all groups.

Systolic and diastolic arterial blood pressure and heart rate increased significantly (P < 0.002) in all groups after tracheal intubation compared with the values before intubation. Between-group differences are presented in Table 6.

Cp50 (95% CL) concentrations of propofol and thiopental at the onset of BSP were 9.65 µg/mL (9.03–10.27 µg/mL) and 31.60 µg/mL (27.32–35.88 µg/mL), and Cp95 (95% CL) values were 10.82 µg/mL (10.19–11.14 µg/mL) and 42.78 µg/mL (38.49–47.06 µg/mL), respectively. Group T-BSP had much wider range of plasma concentrations (11.70–44.35 µg/mL) than Group P-BSP (7.26–11.06 µg/mL) at the onset of BSP. Plasma concentrations of propofol and thiopental at other points are presented in Table 2.


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The variances of the catecholamines of the combined groups were significantly different between the LR and BSP groups in only 2 of 15 instances, and that of the cardiovascular values in 11 of the tested 21 pairs. However, the latter was due to differences in favor of our hypothesis in only five pairs (Table 5). Thus, our results do not support the hypothesis that a well defined BSP would cause smaller variances of mean values than the LR level.

Hemodynamic reactions were less pronounced in both BSP groups than in the LR groups. Additionally, the catecholamine response to tracheal intubation was nearly totally blocked in Group P-BSP. These differences of the hemodynamic responses to tracheal intubation between the LR and BSP groups may be explained by two different mechanisms. First, with bolus doses, there is a relatively high contribution of direct depression of the cardiovascular system because of large peak concentrations. Second, during drug infusion, such large peak concentrations are not achieved, and depression of the central nervous system becomes more prominent. Some of the differences between bolus doses and an infusion regimen may be related to the half-time of equilibrium between blood and the effect site.

In the LR groups, propofol more efficiently attenuated plasma catecholamine responses to tracheal intubation than thiopental, but neither totally blocked the plasma norepinephrine response to intubation, which is in accordance to previous studies (1,2). During BSP, propofol attenuated the norepinephrine response to tracheal intubation more efficiently than thiopental. Lindgren et al. (2) speculated that differences in the norepinephrine response to tracheal intubation between propofol and thiopental compared with a previous study (18) might be in the sampling site. Norepinephrine is metabolized in the lungs. Coley et al. (18) collected samples from the antecubital vein, Lindgren et al. (2) from central mixed venous blood, and we from arterial blood. Because our results are in accordance with those of Lindgren et al. (2) and of other studies (19) in which samples were collected from a peripheral line (1), the reason for the different results of Coley et al. (18) cannot be in the sampling site.

In this study, we confirmed that serum levels of norepinephrine’s metabolite DHPG do not change when norepinephrine is changing (15). Thus, it seems useless to monitor DHPG levels in future similar studies.

The better attenuation of the hemodynamic response to intubation seen after propofol than thiopental may be partly due to 1) a stronger effect on pharyngeal and laryngeal mechanoreceptors, as documented in good intubation conditions after propofol alone (20,21); 2) a specific central effect of propofol (22); 3) a specific peripheral effect (23); or 4) a longer-lasting hypotensive effect (24).

The infusion regimen in this study resulted in steady plasma concentrations of thiopental, whereas plasma concentrations of propofol decreased after intubation; some patients did not preserve BSP until the end of the propofol infusion. The propofol infusion rate of 20 mg · kg-1 · h-1 must be maintained longer to preserve the BSP (7).

We noticed large individual deviations in plasma concentrations of thiopental. They do not disturb the monitoring of certain EEG changes, but they do disturb the results of a study when certain EEG changes are correlated with plasma concentrations of thiopental. Cp50 concentrations of propofol and thiopental at the BSP level were in accordance with those in previous studies (7,10).

Drug effects on the brain are reflected in the EEG, and recently univariate indexes have been attained to measure the hypnotic component of anesthesia, for instance, the bispectral index (25). Bispectral index is not good at predicting a patient’s movement in response to pain, and it has problems detecting BSP or unconsciousness (26,27). BSP is a sign of intermittent suppression of cortical cells (6), and there are no reports of recall during BSP. Deep anesthesia is unnecessary for routine surgery, but short suppressions are frequently seen during the induction of anesthesia with bolus dosage. Therefore, we chose the BSP of the EEG; its level is easily defined as suppression durations between bursts. Automatic detection of BSP (28) might increase its value for research, but the results of this study show that cardiovascular reflexes are still highly variable.

In conclusion, smaller variances in the results of the easier-to-define BSP level compared with the LR level were statistically insignificant and do not explain why attenuation of catecholamine and hemodynamic responses to tracheal intubation is better in both BSP groups compared with the LR groups. Thiopental attenuated the hemodynamic response to intubation, as well as propofol, during BSP, but propofol more efficiently attenuated the catecholamine response.


   Acknowledgments
 
Supported by the Medical Research Fund of Tampere University Hospital and the Tuberculosis Foundation of Vyborg.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication May 16, 2003.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2003 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press