Tramadol does not modify the Bispectral Index during anaesthesia with sevoflurane and remifentanil

V. Fodale*, C. Praticò, M. Tescione, S. Tanania, T. Lucanto and L. B. Santamaria

Department of Neuroscience, Psychiatric and Anesthesiological Sciences, University of Messina, School of Medicine, Policlinico Universitario ‘G. Martino’, Messina, Italy

* Corresponding author: Department of Neuroscience, Psychiatric and Anesthesiological Sciences, Policlinico Universitario, via C. Valeria, 98125 Messina, Italy. E-mail: vfodale{at}unime.it

Accepted for publication May 6, 2005.


    Abstract
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Background. The aim of this study was to investigate the effects of tramadol administered with ketorolac on the Bispectral Index (BIS) during anaesthesia with sevoflurane and remifentanil.

Methods. Forty-six adult patients, ASA I–III, scheduled for elective minor surgical procedures were studied. Patients were premedicated with remifentanil infusion 0.4 µg kg–1 min–1 and anaesthesia was induced 4–5 min later with propofol 1.5 mg kg–1 and maintained with air–oxygen ( 0.4), remifentanil 0.1–0.15 µg kg–1 min–1 and sevoflurane, adjusted to keep the BIS between 40 and 50. After 20 min of stable anaesthesia, the subjects were allocated randomly to receive i.v. tramadol 1.5 mg kg–1 and i.v. ketorolac 0.3 mg kg–1 (tramadol group) or saline (control group). BIS values, mean arterial pressure, heart rate and end-tidal carbon dioxide were recorded every 5 min for 20 min.

Results. Mean BIS values after tramadol administration were not significantly different from those recorded in patients receiving saline throughout the period of observation. There were no patients who presented explicit recall of events under anaesthesia. No significant changes in mean arterial pressure, heart rate and end-tidal carbon dioxide were noted after tramadol injection.

Conclusion. Tramadol, given with ketorolac to prevent postoperative pain, during anaesthesia maintained with sevoflurane and remifentanil at BIS between 40 and 50, does not modify the BIS value.

Keywords: anaesthesia, depth ; analgesics opioid, tramadol


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Administration of analgesics during anaesthesia to prevent postoperative pain is a recognized trend in practice.1 In particular, studies have shown that preventive analgesia with tramadol prevents the development of strong postoperative pain and notably decreases the request for opioid analgesics.2 3 But intraoperative administration of tramadol was reported to cause dose-dependent activation of the electroencephalogram (EEG) during volatile anaesthesia with isoflurane.4 Therefore, it has been hypothesized that the use of tramadol could increase the risk of awareness during anaesthesia.4 5

The Bispectral Index (BIS) is a processed electroencephalographic monitor introduced to evaluate the depth of anaesthesia and prevent the risk of awareness.6 Nevertheless, there is a lack of data about the effects of tramadol on BIS during anaesthesia. Because tramadol appears to affect EEG activity, the aim of this study was to investigate the effects of tramadol, administered along with ketorolac, on BIS in patients anaesthetized with sevoflurane and remifentanil.


    Methods
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
After institutional review board approval and informed written consent, we enrolled 46 adult patients, ASA I–II, scheduled for minor general surgical procedures, in a prospective, randomized study. Exclusion criteria were central nervous system diseases, haemodynamic instability, ischaemic heart disease, renal or hepatic failure or therapies with drugs affecting EEG activity.

On arrival in the anaesthetic room, standard monitoring was started with continuous ECG, non-invasive arterial blood pressure measurement, pulse oximetry, BIS (BIS® XP, software version 3.12, four-electrode sensor; Aspect Medical Systems, Newton, MA, USA) and capnography. The BIS electrode (four-electrode sensor) was positioned on each patient's forehead as recommended by the manufacturer.

In all patients, induction of anaesthesia was started with a remifentanil infusion at 0.4 µg kg–1 min–1 and 4–5 min later propofol 1.5 mg kg–1. Neuromuscular blockade was obtained with cisatracurium 0.1 mg kg–1. A tracheal tube was inserted and the lungs were ventilated with air and oxygen ( 0.4). Immediately after intubation, remifentanil was reduced to 0.1–0.15 µg kg–1 min–1. Controlled ventilation was adjusted to maintain normocapnia. Anaesthesia was maintained with sevoflurane. The concentration of sevoflurane and the infusion rate of remifentanil were adjusted to maintain the value of BIS between 40 and 50.7 8

Thirty minutes before the end of anaesthesia, the patients were allocated randomly to receive i.v. tramadol 1.5 mg kg–1 and ketorolac 0.3 mg kg–1 (tramadol group), or saline (control group). In a preliminary study (data not shown), administration of ketorolac did not change the BIS values. All haemodynamic and BIS variables were recorded at the following time intervals: before administration of tramadol or saline (0 min) and 5, 10, 15 and 20 min after administration of tramadol (along with ketorolac), as previously described by Coetzee and colleagues.9 After administration of the study medications and during the period of observation, the concentration of sevoflurane and the infusion rate of remifentanil were not modified. During data collection, the investigator was blinded to the group allocation of the patient.

In the postanaesthesia care unit just before transfer to the ward, the patients were interviewed using modified Brice interview;10 this aims to evaluate the possible occurrence of awareness.

Statistics
Data were expressed as mean (SD). Demographic values were analysed with the {chi}2 test and one-way analysis of variance. The values of BIS, heart rate, mean arterial pressure and end-tidal carbon dioxide () were analysed using Student's t-test for independent groups; P<0.05 was considered statistically significant.


    Results
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
The patient characteristics are shown in Table 1. No statistically significant differences among the groups were seen in age, gender, weight, duration of anaesthesia and BIS values. Mean BIS values after administration of tramadol and ketorolac were not significantly different from those recorded in the patients who received normal saline throughout the period of observation (P>0.05) (Table 2). No significant changes were seen in mean arterial pressure, and heart rate after administration of tramadol and ketorolac in comparison with the values before administration (P>0.05). No patients had explicit recall of events under anaesthesia, as assessed by the Brice interview.


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Table 1 Patient characteristics, duration of anaesthesia and Bispectral Index (BIS) values at baseline and after emergence from anaesthesia. Data are mean (range) or mean (SD)

 

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Table 2 Bispectral Index, mean arterial pressure, heart rate and end-tidal carbon dioxide () before (0 min) and after administration of tramadol and ketorolac

 

    Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
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We have shown that the administration of tramadol and ketorolac during stable anaesthesia with sevoflurane and remifentanil does not affect the BIS values. In addition, we were unable to detect any evidence of intraoperative awareness.

There is a lack of data regarding the effects of tramadol on BIS, a processed electroencephalographic monitor introduced to monitor the depth of anaesthesia.6 There is also a lack of data about the effects of tramadol on sedation and hypnosis. Nevertheless, previous clinical studies have speculated on the intraoperative effects of tramadol on EEG activity. Coetzee and colleagues9 reported that, during anaesthesia with isoflurane and nitrous oxide, tramadol caused significant dose-dependent activation of the EEG, as seen by increased frequencies and decreased amplitudes, but these changes were small and probably unimportant. Derived EEG variables did not approach values known to be associated with near-awakening during isoflurane anaesthesia; no patient moved on skin incision and there were no incidences of free recall.9 Later, Coetzee and colleagues5 confirmed that, although tramadol may cause awareness and EEG activation during anaesthesia, it does not antagonize the hypnotic effects of volatile anaesthetics. Vaughan and colleagues4 suggested dose-related activation with tramadol in all EEG variables during anaesthesia with isoflurane and nitrous oxide. EEG changes were not at levels thought to be associated with awareness, indicating that tramadol, whilst causing EEG activation, has no effect on depth of anaesthesia.4

Unlike previous clinical studies, our data did not show any evidence of BIS modification when tramadol was given in clinical doses to prevent postoperative pain. Therefore, the significance of previous findings of EEG activation by tramadol is difficult to interpret. Nevertheless, several hypotheses are possible. In the studies by Vaughan and colleagues4 and Coetzee and colleagues,9 low concentrations of volatile anaesthetic with nitrous oxide were administered. It is likely that the EEG-activating effect of tramadol may also depend on the concentration of the volatile anaesthetics. This is supported by the fact that the British National Formulary did not recommend the use of tramadol during light anaesthesia.11

Also, the presence of nitrous oxide could have played a role in the excitatory property of tramadol. In animals, an increase in EEG activity has been shown when nitrous oxide is added to low concentrations of isoflurane,12 with a potentially facilitating activation effect of tramadol. In particular, the difference between modification of EEG patterns and evoked potential shown by Vaughan and colleagues4 after tramadol administration contradicts a possible role of nitrous oxide, since a different effect on EEG and cortical somatosensory evoked potentials (SEP) was seen when nitrous oxide was added to isoflurane anaesthesia.13 In addition, different anaesthetic drugs can produce different electroencephalographic patterns. Increases in delta activity are interpreted as signs of modification of depth of anaesthesia. These EEG patterns are sometimes also found in frontal leads after surgical stimulation during isoflurane anaesthesia, which leads to the conclusion that, to avoid incorrect anaesthetic management under EEG monitoring, this phenomenon of ‘paradoxical arousal’ must be taken into consideration.14

Finally, the dosage of tramadol could also have played a role, since we administered clinical doses of the drug. This hypothesis is consistent with previous studies in which excitatory effects in the central nervous system were observed only when tramadol was given at doses exceeding the therapeutic range.15

This study has some limitations. First, the small number of patients may have hidden some true variation. But the number of patients included in each group was higher than in previous studies evaluating the EEG effects of tramadol during anaesthesia.4 9 Secondly, there are limitations in the study protocol. It reflects our daily clinical practice, in which we maintain BIS values between 40 and 50. Tramadol did not change the BIS value in this deep hypnotic state. Nevertheless, the effect of tramadol on patients under relatively light anaesthesia might cause an arousal reaction, and furthermore it might increase the presence of explicit memory. The light general anaesthesia (with sufficient analgesia) could otherwise reflect the daily clinical practice of other anaesthetists. In addition, we administered tramadol during surgery, whereas Vaughan and colleagues4 tested the drug before surgery. Surgery stimulation plays an important role in the modification of the depth of anaesthesia, or occurrence and recall of intraoperative awareness. However, our study reflects the common clinical practice of giving analgesics intraoperatively to prevent postoperative pain. Thirdly, tramadol was administrated along with ketorolac. But ketorolac does not act on the central nervous system, and therefore in our study the results could not have been modified by the co-administration of ketorolac. Moreover, co-administration of ketorolac reproduces a method of treatment of postoperative pain commonly applied during anaesthesia.16

The use of the BIS in monitoring EEG modification could also be criticized, compared with previous studies.4 9 Nevertheless, electroencephalographic parameters evaluated during nitrous oxide and isoflurane anaesthesia are well correlated with BIS at surgical levels,17 and BIS is known to give more information than power spectrum-based analysis.18

In conclusion, administration of tramadol, together with ketorolac, to prevent postoperative pain does not further modify the values of BIS during anaesthesia with sevoflurane and remifentanil when the BIS is kept between 40 and 50.


    References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
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1 Osipova NA, Petrova VV, Beresnev VA, Dolgopolova TV, Zhelezkina NV. Preventive analgesia: a new trend in anesthesiology. An idea born and developed at the P.A. Herzen Institute of Oncology. Anesteziol Reanimatol 1999; 6: 13–8[Medline]

2 Wordliczek J, Banach M, Garlicki J, Jakowicka-Wordliczek J, Dobrogowski J. Influence of pre- or intraoperational use of tramadol (preemptive or preventive analgesia) on tramadol requirement in the early postoperative period. Pol J Pharmacol 2002; 54: 693–7[ISI][Medline]

3 Hartjen K, Fischer MV, Mewes R, Paravicini D. Preventive pain therapy. Preventive tramadol infusion versus bolus application in the early postoperative phase. Anaesthesist 1996; 45: 538–44[CrossRef][ISI][Medline]

4 Vaughan DJ, Shinner G, Thornton C, Brunner MD. Effect of tramadol on electroencephalographic and auditory-evoked response variables during light anaesthesia. Br J Anaesth 2000; 85: 705–7[Abstract/Free Full Text]

5 Coetzee JF, van Loggerenberg H. Tramadol or morphine administered during operation: a study of immediate postoperative effects after abdominal hysterectomy. Br J Anaesth 1998; 81: 737–41[Abstract/Free Full Text]

6 Rosow C, Manberg PJ. Bispectral index monitoring. Anesthesiol Clin North Am 2001; 19: 947–66[Medline]

7 Wuesten R, Van Aken H, Glass PS, Buerkle H. Assessment of depth of anesthesia and postoperative respiratory recovery after remifentanil-versus alfentanil-based total intravenous anesthesia in patients undergoing ear-nose-throat surgery. Anesthesiology 2001; 94: 211–7[CrossRef][ISI][Medline]

8 Johansen JW, Sebel PS. Development and clinical application of electroencephalographic bispectrum monitoring. Anesthesiology 2000; 93: 1336–44[CrossRef][ISI][Medline]

9 Coetzee JF, Maritz JS, du Toit JC. Effect of tramadol on depth of anaesthesia. Br J Anaesth 1996; 76: 415–8[Abstract/Free Full Text]

10 Enlund M, Hassan HG. Intraoperative awareness: detected by the structured Brice interview? Acta Anaesthesiol Scand 2002; 46: 345–9[CrossRef][ISI][Medline]

11 British National Formulary. September 1999; 38: 210

12 Roald OK, Forsman M, Heier MS, Steen PA. Cerebral effects of nitrous oxide when added to low and high concentrations of isoflurane in the dog. Anesth Analg 1991; 72: 75–9[Abstract]

13 Porkkala T, Jantti V, Kaukinen S, Hakkinen V. Nitrous oxide has different effects on the EEG and somatosensory evoked potentials during isoflurane anaesthesia in patients. Acta Anaesthesiol Scand 1997; 41: 497–501[ISI][Medline]

14 Litscher G, Schwarz G. Is there paradoxical arousal reaction in the EEG subdelta range in patients during anesthesia? J Neurosurg Anesthesiol 1999; 11: 49–52[ISI][Medline]

15 Freye E, Latasch L, Von Bredow G, Neruda B. The opioid tramadol demonstrates excitatory properties of non-opioid character—a preclinical study using alfentanil as a comparison. Schmerz 1998; 12: 19–24[CrossRef][ISI][Medline]

16 Pieri M, Meacci L, Santini L, Santini G, Dollorenzo R, Sansevero A. Control of acute pain after major abdominal surgery in 585 patients given tramadol and ketorolac by intravenous infusion. Drugs Exp Clin Res 2002; 28: 113–18[ISI][Medline]

17 Morimoto Y, Hagihira S, Koizumi Y, Ishida K, Matsumoto M, Sakabe T. The relationship between bispectral index and electroencephalographic parameters during isoflurane anesthesia. Anesth Analg 2004; 98: 1336–40[Abstract/Free Full Text]

18 Hagihira S. Bispectral analysis gives us more information than power spectral-based analysis. Br J Anaesth 2004; 92: 772–3[Free Full Text]





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