Alexandria Journal of Anaesthesia and Intensive Care 67 The Effect of Different Doses of Oral Tizanidine, on the Minimum Alveolar Concentration of Isoflurane and Stress Response. Montaser S. Abo Elkassem,MD Lecturer of Anesthesia, Faculty of Medicine, Menoufiya University. ABSTRACT α2-ADRENERGIC receptor agonists bind to peripheral and central nervous system sites modulating autonomic nervous system function. These effects may explain the clinically observed attenuation of sympathetically mediated responses to perioperative stress. They also have an antinociceptive effect in animals. In humans premedicated with oral tizanidine an α2-adrenoceptor agonist, attenuated the increase in blood pressure associated with laryngoscopy and intubation and the amount of midazolam required for loss of consciousness was significantly reduced. We speculated that the oral administration of tizanidine might reduce the minimum alveolar anesthetic concentration (MAC) of isoflurane. Eighty ASA physical status I–II patients, aged 24–56 yr, were randomly allocated into 4 groups ( 20 for each): a Control group and a 2mg Tizanidine group, 4mg Tizanidine group, 10mg Tizanidine group. As premedication, the Control group received a placebo, and the Tizanidine groups received oral tizanidine 70 min. before surgical skin incision. Anesthesia was induced in all patients by propofol 2-2.5 mg/kg intravenously mixed with lidocaine 0.3 mg/kg, given over 30s. until loss of eyelid reflex (determined every 15 s). After loss of consciousness, appropriate size of laryngeal mask was introduced by Brain method. Then administration of isoflurane was begun; the patients were spontaneously ventilated using a non—rebreathing system. MAC was determined by a technique adapted from the conventional up-down method for quantal responses. The MAC of isoflurane was 1.3±0.13in the Control group, 1.24±0.1 in group II, 0.9±0.2 in groupIII and 0.7±0.2 in group IV. In group III and IV the plasma concentrations of epinephrine and norepinephrine were statistically significantly decreased during surgery and remained decreased thereafter. The oral administration of tizanidine successfully reduced the MAC of isoflurane, decreased the release of stress hormones and decreased the postoperative analgesic requirements in human adults. INRODUCTION tizanidine pretreatment(12). Furthermore, oral The minimum alveolar anesthetic concent- premedication with tizanidine prolongs tetra- ration (MAC) is that anesthetic end-tidal caine spinal anesthesia(13). The influence of concentration at which 50% of subjects move tizanidine on volatile anesthetic MAC has not in response to skin incision(1). Introduced in been investigated. This study was designed to 1963, MAC remains the standard for determine the influence of different doses of comparing potencies among different inhaled oral tizanidine directly on isoflurane MAC and anesthetics (2). Interactions between anesthe- indirectly on the stress response. tics and other drugs have been investigated through their effect on MAC(3-5). For example, PATIENTS AND METHODS small-dose opioids reduce volatile an-esthetic Informed consent was obtained from all requirements(6-8). Although tizanid-ine has patients, and the study was done in the been used for many years as an α2- Menoufiya University Hospital. Eighty patients adrenoceptor agonist that has an antinoci- of both sexes, ASA class I–II, (table 1) ceptive effect in animals(9-11), in humans oral scheduled for elective lower abdominal tizanidine was used as a premedication. The surgical operations (herniorhaphy or varicec- increase in mean blood pressure that accom- tomy) where muscle relaxation was not panies laryngoscopy and tracheal intubation needed. was attenuated(12) and the amount of mida- All patients had intravenous access, which zolam required for loss of consciousness was was heparinised and plugged. We excluded significantly less in patients who received the patients with any history of cardiopulmonary or AJAIC-Vol. (8) No. 1 March 2005 Alexandria Journal of Anaesthesia and Intensive Care 68 neurological disorders and diabetes mellitus After the target end-tidal isoflurane con- and those receiving medication which might centration had been stable for at least 15 min., affect the cardiovascular and nervous systems. a skin incision at the site of surgery (of at least Patients with renal or hepatic impairment as 2 inches) was made. A positive response was well as concomitant administration of drugs defined as movement of limbs, head, or body that prolong Q-T interval were also excluded within 60 s of skin incision. Coughing, chewing, from the present study. The patients were or swallowing was not considered movement. asked to fast for at least 8 h before the oral Hemodynamic data within 2 min before and 4 premedication. min after intubation and incision were extracted The patients were randomly allocated into 4 from the automatic recordings for comparison groups according to the premedication with among groups. tizanidine used: a Control group (placebo), Patients received a balanced electrolyte 2mg Tizanidine group, 4mg Tizanidine group, solution (Lactated Ringer's solution) was 10mg Tizanidine group. The anesthesiologist infused intravenously at a rate of 10 ml/kg/hr. was blinded to the study groups. All patients If significant hypotension occurred, we could received premedication (in the form of 50ml increase the rate of intravenous fluids. If there water) 70 min. before the induction of was no correction of hypotension aliquots of 5- anesthesia. Sedation before anesthesia induc- 10mg ephedrine HCl were given. tion was scored according to the scale End-tidal concentrations of CO2 (ETCO2) described by Kulka et al,(14) : 0, patient is and isoflurane (ETiso), and arterial hemo- awake; 1, patient is sedated, but awake; 2, globin oxygen saturation (SpO2) were patient is asleep but reacts immediately to continuously measured using a Capnomac verbal commands; 3, patient is asleep, and Ultima. (Datex, Helsinki, Finland). The ECG reaction to verbal commands is delayed; and (lead II) was recorded5 min. (preoperative, 4, patient is asleep and does not react to after induction, after skin incision and post- verbal commands. operative) for electronic calculation of heart Preoperative medication consisted of 0.5 mg rate, and mean arterial blood pressure (MBP) atropine sulfate intramuscular one hour was measured with Finapress (Finapress preoperatively and 1-2 µg/kg fentanyl intra- Ohmeda, Louisville, CO). The monitors were venously immediately before induction in all incorporated onto the anaesthetic machine. groups. General anesthesia was induced with MAC was initially determined by using propofol 2-2.5 mg/kg intravenously mixed with Dixon's up/down method.(16) The initial end- lidocaine 0.3 mg/kg, given over 30s. until loss tidal isoflurane concentration was estimated for of eyelid reflex (determined every 15 s). After the first patient in each group. The initial loss of consciousness, appropriate size of isoflurane concentration used in each group laryngeal mask was introduced by Brain was 1.8%, and the isoflurane concentration method.(15) was changed on the basis of the patient’s Administration of isoflurane was begun; the response to the noxious stimulus. patients were spontaneously ventilated using a If that patient moved in response to skin non-rebreathing system (Servo 900; Siemens- incision, then the target end-tidal isoflurane Elema, Sweden) with oxygen in air(1:1) with concentration was increased by 10% for the FIO2=0.5. End-tidal isoflurane concentrations next patient in that group. If the patient did not were determined using a multigas gas analyzer move, then the next patient received a 10% calibrated daily against an enflurane/CO2 reduction in the target isoflurane concentration. standard mixture provided by the manufacturer After skin incision, anesthesia was main- and were adjusted breath-to-breath to maintain tained with isoflurane in oxygen and nitrous the target concentration at which the patient is oxide (FIO2, 0.3—0.4) Administration of stable hemodynamically and not respond to isoflurane was discontinued at the end of the any noxious stimuli and this was considered operation. During the preanaesthesia work-up, the target concentation. Body temperature was each patient was informed of the pain visual maintained >35.5°C by maintaining room analog scale (VAS) consisting of a 100 mm temperature at 25°C and warming of the line with 0 equal to “no pain” and 100 the infused fluids. “worst possible pain”.(17) AJAIC-Vol. (8) No. 1 March 2005 Alexandria Journal of Anaesthesia and Intensive Care 69 The protocol for postoperative analgesia was standardized in all groups.2grams pro- RESULTS paracetamol hydrochloride(diluted in 100 cc The four patient groups were similar with normal saline) (PRO-DAFALGAN 2G - respect to physical characteristics, the duration Laboratories UPSA-FRANCE) intravenous and the types of surgery (table1). None of the infusion were administered over 10 min, 30 patients were excluded from the study. min before surgical closure and repeated Sedation scoring: During the preinduction every six or eight hours. period sedation scoring was as the following: If paracetamol was ineffective, post- 19 patients in the Control group had a sedation operative pain, defined by patient complaint or score of 0,one patient had a score of 1. In VAS > 50 mm, was treated, in all groups, with groupII 17 patients had a sedation score of 0, 10 mg nalbuphine HCL (Nalufin-AMOUN 3patients had a sedation score of 1, in groupIII PHARMACEUTICAL CO.-EGYPT) intraven- 8 patients had a score of 0 and 12 patients had ousssly and repeated every hour if necessary. a sedation score of 1.In group IV 5 patients Pain and analgesia in the postoperative period had a score of 0 and 15 patients had a were assessed: sedation score of1. The difference between the 1) VAS was noted every hour at rest during groups was highly significant (P < 0.05). eight hours postoperatively. The effect on MAC: The isoflurane 2) nalbuphine requirement in the eight hours concentration percent was 1.3±0.13in the after arrival in the postanaesthesia care unit Control group, 1.24±0.1 in groupII, 0.9±0.2 in (PACU).