Yeditepe Medical Journal 2013;7(25): 590-597

EFFECT OF TRAMADOL ON ABSTRACT BISPECTRAL INDEX Purpose: This prospective, randomized, DURING ANESTHESIA double-blind, controlled study was designed to investigate the effects of WITH SEVOFLURANE AND tramadol on the bispectral index (BIS) N2O during anesthesia with sevoflurane and N2O.

Orıgınal Artıcle Methods: 60 ASA class 1 and 2 patients, scheduled for elective lumbar SEVOFLURAN VE N2O İLE microdiscectomy operation under general UYGULANAN GENEL anesthesia, were included in this study. None of the patients were premedicated; ANESTEZİ SIRASINDA anesthesia was induced with thiopental 5 TRAMADOL’ÜN mg.kg-1 and rocuronium 0,6 mg.kg-1, and maintained with 40% N2O-O2 mixture BİSPEKTRAL İNDEKS and sevoflurane. At induction of ÜZERİNE ETKİSİ anesthesia, subjects were randomly allocated into 2 groups to receive either saline (control group), or tramadol 2 mg kg-1 (T group) intravenously. Hemodynamic data and BIS values were Murat Haliloglu then recorded until the completion of the Yeditepe University Hospital, Department of Anesthesiology operation, during which time the concentrations of sevoflurane were not Mehtap Ozdemir modified.

Umraniye Education and Research Hospital, Departman of Anesthesiology Results: The BIS values were significantly different between groups throughout the Ozkan Bozkurt operation. No significant changes in the Umraniye Education and Research Hospital, hemodynamics were noted, except mean Departman of Anesthesiology arterial blood pressure in the T group which was significantly high in the first 5 Nurten Bakan minutes of entubation. Umraniye Education and Research Hospital, Departman of Anesthesiology Conclusıons: There were no patients that has BİS values more than 60 or who presented explicit recall of events under Corresponding Author anesthesia. Tramadol didn’t seem to cause a problem with respect to depth of Murat Haliloglu, M.D. anesthesia and can be safely administered Yeditepe University Hospital, Department of perioperatively. Anesthesiology Istanbul/Turkey e-mail: [email protected] Key Words: bispectral index; awareness; general anesthesia; sevoflurane; tramadol.

590 Yeditepe Medical Journal 2013;7(25):590- 597 Haliloglu M. et al

ÖZET Amaç: Bu prospektif, randomize, çift-kör, anesthesia as it prevents severe kontrollü çalışmada sevofluran ve N20 ile postoperative pain and reduces the uygulanan genel anestezi sırasında demand for opioid analgesic significantly kullanılan tramadolün bispektral indekse (2-4). Hovewer intraoperative olan etkisi araştırıldı. administration of tramadol was reported to cause dose-dependent activation of the Method: Çalışmaya genel anestezi altında electroencephalogram (EEG) during mikrodiskektomi operasyonu geçirecek volatile anaesthesia (5). For this reason, it ASA grup 1 ve 2 olan 60 hasta dahil edildi. has been suggested that the use of Hiçbir hastaya premedikasyon tramadol could increase the risk of uygulanmadı, anestezi indüksiyonu 5 mg awareness (5,6). kg-1 tiopental ile yapıldı, kas gevşetici olarak rokuronyum uygulandı; idame Bispectral index (BIS) provides a N2O-O2 ve sevofloran ile sağlandı. continuous age-independent monitoring of İndüksiyonda hastalar rastgele iki gruba hypnotic state induced by the most widely ayrıldı: tramadol grubuna (T grup) 2 mg used sedative-hypnotic agent and has kg-1 tramadol, kontrol grubuna ise serum been used to asess the induction quality, fizyolojik uygulandı. Hemodinamik ve BİS depth of anesthesia, intraopertive değerleri operasyon boyunca kayıt edildi, requirement of anesthetics, postoperative bu sırada sevofluran değerleri değiştirilmedi. recovery, and to reduce the intraoperative recall awareness. BIS value of 0 Bulgular:Operasyon boyunca BİS represents an isoelectric değerleri tramadol grubunda kontrol electroencephalogram and 100 represents grubundan farklı bulundu. Hemodinamik an awake state, whereas 40 to 60 reflect parametrelerde önemli değişiklikler gözlenmedi, yalnızca entübasyon sonrası adequate hypnotic effect for general ilk 5 dakikada ortalama arter basıncı T anesthesia (7-9). grubunda yüksek seyretti. Tramadol has a risk of intra-operative Sonuç: Hiçbir hasta intraoperatif olayları awareness but there are limited data on hatırladığını belirtmedi ve hiçbirinin BİS this issue. This study aim to identify the değerleri 60’ın üzerinde gözlenmedi. effects of tramadol on the BIS and Tramadolün anestezi derinliği açısından hemodynamic changes during general sorun yaratmayacağı ve güvenli olarak pre inhalational anesthesia using sevoflurane. ve intraoperatif olarak uygulanabileceği sonucuna varıldı. METHODS

Anahtar kelimeler: Bispektral indeks; After obtaining approval from the farkındalık; genel anestezi; sevofluran; Institutional Ethics Committee (Date: tramadol. 11.01.2011 Chairperson: Ahmet Göçmen, MD) and written informed consent, a total INTRODUCTION of 60 adults, 18 to 65 years ofage, physical status ASA (American Society of Tramadol is a synthetic, centrally acting Anesthesiologists) I and II, scheduled for opioid analgesic with a potent opioid an elective single space lumbar disc metabolite (1). surgery under general anesthesia were included in this study. All of the surgical It has been frequently used for pain procedures were performed by the same control during administration of inhaled surgical team. The demographic data of

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Yeditepe Medical Journal 2013;7(25):590- 597 Haliloglu M. et al the patients and their ASA values were After 5 minutes of preoxygenation with recorded. 100% O2, anesthesia was induced with thiopental sodium 5 mgkg-1and Exclusion criteria were history of rocuronium 0,6 mgkg-1 was given as hearing loss, language or communication muscle relaxant. Manual ventilation was difficulties, chronic pain on analgesic done with sevoflurane 2 vol %, O2 1,5 L medications, allergy to any drugs used in -1 -1 min , N2O 2 L min . After 3 minutes the study, central nervous system larngoscopy was done with Magill diseases, hemodynamic instability, laryngoscope blade and trachea was ischemic heart diseases, renal or hepatic intubated with cuffed polyvinyl chloride failure, therapies with drugs affecting EEG tube size 7,5 mm for female and 8,0 mm -2 activity, body mass index˃35kg m . In internal diameter for male. Controlled the preoperative stage, all patients were ventilation was adjusted to maintain informed about visual analog scale (VAS) normocapnia. Anesthesia was maintaned (0=no pain at all to 10=intolerable pain). with 66% nitrous oxide in oxygen and the All enrolled patients were randomly sevoflurane vaporizer was adjusted to divided into group C (controle), or group T maintain an end-expired sevoflurane (tramadol) (n=30 in each group) concentration of 1,7%. During according to SNOSE way (10). At the intraoperative stage, muscle relaxation induction of anesthesia before was maintained with 10 mg rocuronium. intratracheal intubation, one of two study In addition, a 2 µg kg-1 fentanyl bolus was solutions was slowly given to patients by planned for use in cases when the mean the first author of this study according to arterial pressure and heart rate rose 20% a randomised, double-blinded and above basal values. All hemodynamic and placebo-controlled protocol. The study BİS variables, ETCO2 (mmHg), SpO2, were solutions (C, T) were prepared by hospital recorded at following time interval: at pharmacist within two 10 ml syringes, so baseline and 1,3,5,15,30,45,60,90 that C, T syringes contained 10 ml serum minutes after intubation; at this time, the -1 physiologic as placebo, 20 mg ml concentration of inhaled anesthetics was tramadol respectively. The syringes were not adjusted. At the termination of marked only with a coded label to surgery, sevoflurane and N20 were maintain the double-blind nature of the discontinued and the residual study. Thus, while 30 patients in group-C neuromuscular block was reversed and received 1ml saline per 10 kg, and 30 extubation was done when patients were patients in group-T received 1ml tramadol awake and respiration was regular and -1 per 10 kg (2 mg kg ); these syringes adequate. were consecutively used. Injection of these solutions was done within at least 3 In the recovery area, all patients min advocated by Radburch et al (11). received 35% oxygen by mask. Pain intensity was assessed by the patient and None of the patients were premedicated anesthesist on arrival recovery room and for preoperative sedation and hypnosis, every 15 minutes thereafter using a visual and after they arrived at the operating analogue scale. In addition, the presence room, we monitored their of nausea and vomiting was recorded and electrocardiograms, non-invasive blood the success of antiemetic therapy noted. pressure and peripheral oxygen saturation Patients who requested additional pain - (SpO2). We attached the BIS (BIS A-2000, relief were given meperidine 0,5 mg kg software version 3.30, Aspect Medical 1i.v. Nausea was treated with ondansetron Systems, USA) at the frontal area of head 4 mg i.v. Data were recorded for 90 according to the way recommended by the minutes min in the recovery area or until manufacturing company and with more patients received additional analgesia. than 95 on the signal quality index (SQI), BIS values were measured and recorded.

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Yeditepe Medical Journal 2013;7(25):590- 597 Haliloglu M. et al

In the postanesthesia care unit just before transfer to the ward, the patients A) were interviewed using modified Brice interview (12); this aims to evaluate the 160 possible occurrence of awareness. 140

120 STATISTICS * 100 * 80 For statistical data, we used NCSS 60 (Number Cruncher Statistical System) Tramadol MAP(mmHg) 40 2007 & PASS (Power Analysis and Sample 20 controle Size) 2008 Statistical Software (Utah, 0 USA) and the results were expressed as mean ± standard deviation. We analyzed sex using chi-square test and age, body mass index using one-way ANOVA. The Time (min) chance of each variable in each group according to time was analyzed with repeated measures ANOVA and Post-hoc B)

Comparison, Bonterroni was used. We

judged statistically significant when 120

P˂0.05. 100 80 RESULTS 60

40 The two groups were similar in relation Tramadol

Heart (BPM)rate 20 to age, sex, weight, duration of surgery, Controle and baseline Bispectral Index (Table 1). 0

Time (min)

C)

100

99

(%)

2

SPO 98 Tramadol Table-1: Demographic variables of patients involved Controle in the study, duration of surgery and baseline 97 Bispectral index values.

Time (min)

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Yeditepe Medical Journal 2013;7(25):590- 597 Haliloglu M. et al

D) There were no significant changes in SpO2, EtCO2, heart rate. Mean arterial 34 pressure at third and fifth minutes and BIS values throughout the anesthesia 33 were significantly higher in tramadol group compared with the control group. 32 There were no patients in whom BIS

(mmHg) values were more than 60 or who 2 2 Tramadol 31 presented explicit recall of events under

EtCO Controle anesthesia, as assessed by the Brice 30 interview in the recovery room (Figure-1) Opioid requirements in the operation and 29 early postoperative period were 0 3 15 45 90 significantly lower in patients with Time (min) tramadol group as compared with the control group (p˂ 0,01). 12 patients

(40%) in the tramadol group and 28 E) patients (93,3%) in the control group required supplementary analgesia in the 100 90 recovery room (p=0,001). Eight and seven patients suffered nausea and

80 70 vomiting (N/V) in the tramadol and 60 controle groups, respectively (p=0,76). 50 * (Table 2) 40 * * * * * * * Tramadol

30 Bispectralindex 20 Controle Tramadol Control P- 10 value

0 Intraoperative 0 (0%) 4 (12.9 0.038

1 5 60 30 fentanyl need %) Postoperative 12 (40%) 28 0.001 Baseline meperidine (93.3%) Time (min) need

PONV 8 7 0.766 (25.8%) (23.1%) Fig. 1. Changes of mean arterial blood pressure (A), heart rate (B), SPO2 (C), EtCO2 (D), bispectral index Table-2: The analgesic requirement and (E) among the two groups. All data are presented as postoperative N/V incidence. mean ± SD. *p<0,05 **p<0,01 compared to the control group. DISCUSSION

Tramadol is a central acting opioid agonist widely used in anesthesiology and suitable for preventive analgesia due to its unusual mode of action (1,2,4). Tramadol has lower affinity for the µ-opioid receptor than morphine resulting in analgesic

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Yeditepe Medical Journal 2013;7(25):590- 597 Haliloglu M. et al potency which is 10 times weaker than and depth of anesthesia (20-22). This morphine. However, only 40% of the study used the BIS to monitor the effect analgesic effect of tramadol is antagonized of tramadol on the changes in awareness by naloxone, pointing to an additional in EEG. non-opioid mechanism which contributes to tramadol’s analgesic activity. This Previous studies have speculated on the second mechanism is related to the intraoperative effects of tramadol on EEG activation of the descending activity. Coetze et al. reported that, antinociceptive system and consists in during anesthesia with isoflurane and both inhibition of the reuptake of nitrous oxide, tramadol caused dose noradrenaline, serotonin and an increased dependent activation of the EEG, but such release of serotonin. Houmes et al. change was not enough to induce showed that tramadol seems to be as awareness and there was no movement in effective and safe as morphine for response to skin incision or no treatment of postoperative pain (13). postoperative recall (23). Later, Coetz et Potential advantages of administering al. confirmed that tramadol did not tramadol for postoperative pain relief antagonize the hypnotic effect of include long duration of action and limited inhalation anesthetics, but it may cause respiratory depressing effects (13-15). awareness and EEG activation during Maximum analgesia occurs 1-2 hours after anesthesia (6). Vaughan et al. reported intravenous administration, therefore that tramadol changed EEG activity in a tramadol should be given during operation dose-dependent manner during anesthesia because administration after inhalation with isoflurane and nitrous oxide (5). anesthesia has been shown to provide However when anesthetic depth was inadequate postoperative pain relief measured by using auditory evoked (14,16). However, it has been potential, it does not antagonize the hypothesized that the use of tramadol hypnotic effect of inhalation anesthetic could increase the risk of awareness (5). Our study results confirm the findings during anesthesia (5,6). of the previous studies, and show that BIS values were significantly higher in Intraoperative awareness is an tramadol group troughout the anesthesia unpleasant experience and may result in period. None of the patients participating sleep disorders, nightmares, anxiety and in the study had BIS values higher than recall after surgery in addition to intra- 60, or explicit recall of events under operative pain or fear of no movement anesthesia. during surgery. Therefore it is very important to monitor depth of anesthesia. Cuvas et al. reported that when 100 mg to (17,18). In the past, variables used to of tramadol was administered under predict awareness and anesthetic depth, general anesthesia, the mean arterial were hemodynamic changes, movement, pressure increased for the initial 5 respiratory effort and pupil size (18,19). minutes and then decreased, and heart However, after a muscle relaxant was rate decreased for 35 minutes, but it did widely used clinically, it is hard to not influence anesthetic depth (24). We evaluate such symptoms along with a observed that mean arterial pressure muscle relaxant, and to use them to significantly higher in tramadol group at 3, predict the risk of intra-operative 5 minutes during the operation. We awareness and light anesthetic state (18). assumed that early increase of blood Due to such reasons, devices to monitor pressure was resulted from the intra-operative awareness and anesthetic enhancement of noradrenalin and depth is developed and introduced into serotonin concentration due to interfering clinical practice. Among them, the BIS is with their reuptake and release shown to be very useful to analyze the mechanisms. EEG of cerebral cortex, monitor sedation

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