The Effect of Different Doses of Oral Tizanidine, on the Minimum Alveolar Concentration of Isoflurane and Stress Response

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)

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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). groupIII and 0.7±0.2 in group IV. The Venous blood samples were taken pre- differences between the groups were operative ,after induction of anaesthesia, at statistically significant (P <0.05). (Table 1) the end of surgery and eight hours after No tizanidine-related adverse effects were surgery to determine plasma concentrations of observed throughout the study.Estimated epinephrine, norepinephrine (measured by blood loss never exceeded 300 mL and no HPLC using fluorimetric detection)(18), insulin patient received blood transfusion. and glucose. Plasma concentrations of insulin Pain assessment: The VAS scores were were measured using the Insulin IRMA CT kit lower in groupIII and IV than in the other 2 (Medgenix). Standardized automated labora- groups from the first to the eight hour after tory analyzers measured plasma concent- arrival in the PACU (figure1). In the PACU, 13 rations of glucose. of 20(65%) patients in groupI and 9 of 20 Statistical analysis of the data was fed to patients(45%) in groupII required supple- Microsoft computer programme (SPSS/ 10 for mental analgesics by nalbuphine 10mg. windows). Mean (x) and standard deviation (Table 1) But 2 patients (10%) in groupIII and (SD) were calculated for each group except no patient in group IV required nalbuphine for sedation score and the nalbuphine 10mg. The patients in groupI used 3 times consumed. Analysis was done using one- more supplemental analgesics. (Table 1) way ANOVA(F) to compare the data between The effect on stress response: there were no groups. The intergroups data were analysed statistically significant differences on Plasma using student t-test the placebo group was glucose concentrations throughout the study considered as an independent sample factor. period (Table2) plasma glucose concentration Differences were considered statistically remained within normal range in all of the significant if P < 0.05. The nalbuphine con- studied groups. The Plasma insulin concent- sumed and the sedation score were analyzed rations were not significantly different between using the Mann-Whitney U-test. They were the groups. expressed as mean values with 95% Also, in group I and II the plasma concent- confidence interval. rations of epinephrine were statistically The occurrence of adverse events was significantly increased during surgery and monitored throughout the study and for up to remained elevated thereafter. But the increase 24 h after the end of anaesthesia. An adverse was more in group I than in group II. In group event was defined as any untoward medical III and IV the plasma concentrations of occurrence experienced by the patient. epinephrine were statistically significant

AJAIC-Vol. (8) No. 1 March 2005 Alexandria Journal of Anaesthesia and Intensive Care 70 decreased during surgery and remained In the present study, the 15-min equilibration decreased thereafter. The plasma concent- period represents more than three blood-brain rations of norepinephrine were statistically time constants for isoflurane. Isoflurane MAC was significant increased during and after the 1.3% ± 0.13% in this study. This value was similar operation in the control group only but were to previously published isoflurane MAC deter- statistically significant decreased in the other minations (20,21). these results demonstrated that groups. The decrease was more in group III the MAC of isoflurane was reduced by oral and IV than in group II (Table2). premedication of tizanidine. The oral administration of small-dose tizanidine (2mg) did not Hemodynanic response: in group I and II significantly affect the MAC. Tizanidine 4 mg there were no statistically significant changes decreased the MAC of isoflurane by 27.7%. on the Heart Rate (beat/min.) and the Mean However, large-dose tizanidine(10 mg) reduced Arterial Blood Pressure (MABP in mmHg) isoflurane MAC, nearly doubling the efficacy throughout the study period P > 0.05 (Table2). (46.2% reduction). Therefore, tizanidine could In groupIII and IV the Heart Rate and the reduce volatile anesthetic requirements for skin Mean Arterial Blood Pressure (MABP in mmHg) incision. Clonidine, another α2 agonist, reduced showed statistically significant decrease during the MAC of isoflurane in adults and children and surgery and remained decreased thereafter. P < reduced the induction time of isoflurane in adults 0.05 (Table2). by 34%–47%(22). Premedication with dexmedetomidine, a more selective α2 agonist than DISCUSSION clonidine, reduced the MAC of isoflurane in adults MAC has provided a reliable method of by 47% and reduced the MAC of isoflurane in comparing clinically relevant potencies, drug adults between the ages of 55 and 70 years by interactions, and side effects of volatile 17% (23). anesthetics. Steady-state conditions must be In most of the previous studies done on approximated to provide a reliable estimation tizanidine, plasma concentration in 45 min. to 2 of MAC, allowing equilibration of anesthetic hours, and the elimination half-life of tizanidine concentrations among the alveoli, blood, and in healthy volunteers and patients with multiple brain. (1,2) α2 agonist administration in lower sclerosis or spinal cord injuries ranged from concentrations as adjuvant during the intra- 2.1 to 4.2 hours(24,25). Therefore, the doses operative period has resulted in a reduced of tizanidine were given to all groups 70 requirement for other anesthetic agents, fewer minutes before the induction of anesthesia, interventions to treat tachycardia, and a and a skin incision was taken as a noxious reduction in the incidence of myocardial stimulus 90 minutes after the oral administra- ischemia(19). tion of tizanidine.

Table1: Patient characteristic, duration of surgery, end-tidal isoflurane and the analgesics requirements: GroupI GroupII GroupIII GroupIV P value n=20 n=20 n=20 n=20 (placebo) 2mg tizanidine 4mg tizanidine 10mg tizanidine Age(yr) 46±13 43±11 44±12 44±11 0.13 Sex M/F 6/14 7/13 12/8 9/11 Weight (Kg) 60±10 61±7 63±5 58±12 0.27 Hieght(cm) 160±8 162±6 159±10 157±6 0.14 Duration of surgery(min.) 55±20 60±12 48±22 62±17 0.22 *Isoflurane conc.(vol٪) 1.3±0.13 1.24±0.1 0.94±0.2* 0.7±0.2* 0.004 *Nalbuphin req. (No.(%)) 13(65٪) 9(45٪) 2(10٪) 0(0%) 0.001 Sedation score (No.( %)) 0 19(95%) 17(85%) 8(40%) 5(25%) 0.001* 1 1(5%) 3(15%) 12(60%) 15(75%) 0.001* Values are mean±SD. . * Statistically significant decrease. P< 0.05

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Figure1:VAS of the tested groups

120

100

80 groupI score groupII 60 groupIII groupIV 40

0 1 23456 789 1011121314151617181920 No. of patients

Table2: Hemodynanic variables and plasma concentration of epinephrine, glucose and insulin before, during and after surgery.

preoperativ Intraoperative postoperative t-test e I II Heart rate (b/min.) 30 60 P1 P2 P3 minutes minutes GrI 86±13 88±19 91±16 92±12 0.1 0.1 0.3 GrII 84±11 90±14 91±16 89±16 0.2 0.2 0 GrIII 82±12 64±15* 65±15* 62±11* 0.00* 0.00* 0.00* GrIV 84±5 58±14* 55±12* 63±17* 0.00* 0.00* 0.00* F 0.4 21 29 25 P value 0.7 0.00* 0.00* 0.00*

MABP (mmHg) GrI 96±13 101±10 100±9 99±10 0.1 0.1 0.2 GrII 94±13 91±11 92±9 90±11 0.2 0.6 0.2 GrIII 94±6 82±14* 79±15* 77±19* 0.00* 0.00* 0.00* GrIV 90±5 78±16* 71±12* 74±19* 0.00* 0.00* 0.00* F 1.12 23 2410 P value 0.3 0.00* 0.00* 0.00*

Epinephrine (pg/mL) GrI 36±17 120±46** 135±59** 220±70** 0.00** 0.00** 0.00** GrII 43±19 95±39** 92±24** 109±12** 0.00** 0.00** 0.00** GrIII 42±4 28±12* 25±14* 33±15* 0.00* 0.00* 0.00* GrIV 45±3 24±17* 27±15* 25±13* 0.00* 0.00* 0.00* F 1.6 45 50 117 P value 0.18 0.00* 0.00* 0.00* Values are mean±SD. ** Statistically significant increase. P<0.05 * Statistically significant decrease. P<0.05 Intraoperative I= after induction of anesthesia. Intraoperative II= at the end of surgery. P1=between preoperative and post induction. P2= between preoperative and at the end of surgery. P3=between preoperative and postoperative.

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Table3: Plasma concentration of norepinephrine, glucose and insulin before, during and after surgery. preoperative Intraoperative postoperative t-test I II Norepinephrine (pg/mL) P1 P2 P3 GrI 180±36 310±36** 390±44** 392±35** 0.00** 0.00** 0.00** GrII 220±25 180±18* 185±16* 190±17* 0.00* 0.00* GrIII 210±44 88±22* 78±32* 80±31* 0.00* 0.000* 0.00* GrIV 178±34 91±25* 75±41* 78±37* 0.00* 0.00* 0.00* F 7 316 352 458 P value 0.2 0.00* 0.00* 0.00*

Glucose (mgl/dL) GrI 86 ± 16 90.5±14.5 87± 19 92± 17 0.2 0.1 0.4 GrII 93± 14 102± 9 101.4±19 95±6.5 0.2 0.1 0.4 GrIII 88.3± 18 88.5±14 90±17 92±9 0.3 0.1 0.2 GrIV 85.5± 6 100±9 98±13 89±11 0.1 0.2 0.7 F 0.7 2.2 2.5 0.8 P value 0.5 0.09 0.06 0.4

Insuline(µU/mL) GrI 6.4±1.8 6.5± 2.8 7.1±2.4 7.2±1.2 0.5 0.1 0.07 GrII 7±2.1 5±1.8 6.3±3.1 6.8±2.5 0.3 0.2 0.6 GrIII 5.6±1.9 5.2±.8 6±0.9 6±1.8 0.3 0.6 0.9 GrIV 5.6±3.8 6.4±4 6.2±2.4 7±1.4 0.2 0.5 0.08 F 1.5 1.1 0.5 1.4 P value 0.2 0.3 0.6 0.2 Values are mean±SD. ** Statistically significant increase. P<0.05 * Statistically significant decrease. P<0.05 Intraoperative I= after induction of anesthesia. Intraoperative II= at the end of surgery. P1=between preoperative and post induction. P2= between preoperative and at the end of surgery. P3=between preoperative and postoperative.

Although α2-adrenergic agonist, per se, has a mediated via α2 adrenoceptors, rather than modest antinociceptive activity, in animal opioid receptors, and may involve inhibition of studies, in humans,analgesic interactions bet- the release of aspartic and glutamic acids or ween α2-adrenergic agonist and opioids and substance P (a putative transmitter in primary the analgesic effect is more pronounced afferent fibers that relays information about (26,27). In the present study, oral administ- noxious stimuli to the central nervous system) ration of tizanidine reduced postoperative . Also, Wajima et al, (30) postulated that the analgesic requirement determined by IV primary site of antinociceptive activity seems nalbuphine after abdominal surgery. In to be at the spinal level. This investigation accordance with this study, Segal et.al (28). may support the finding of the present study suggested that oral followed by transdermal that the patients of group III and IV did not clonidine administration resulted in approxi- require further analgesia postoperative. mately 50% reduction of the postoperative As regard the hemodynamic measure- PCA morphine requirement after abdominal ments, MAP and heart rate, did not show any surgery . significant differences among treatment Ono et al,(29) on their study at various groups I and II. Inspite of the significant animal models suggested that a dose- decrease in the hemodynamic variables in dependent antinociceptive effect of tizanidine groupIII and IV, heart rate and MAP changes has been observed. This effect seems to be remained adjusted within 20% of awake

AJAIC-Vol. (8) No. 1 March 2005 Alexandria Journal of Anaesthesia and Intensive Care 73 baseline values either by giving Ringer's In the present study there were no lactate solution or ephedrine sulphate. change in blood glucose level and also in Whereas most of the studies done on plasma insulin level. In contrast, Dorman et clonidine postulated that clonidine signifi- al,(38) speculated that clonidine administ- cantly decrease the hemodynamic para- ration of 3 mg/kg caused a pronounced meters. Park et al,(31) and Benhamou et increase in glucose plasma concentration al,(32) showed significantly lower mean during abdominal hysterectomy without blood pressure and heart rate values, affecting pituitary hormone secretion or respectively, in clonidine-treated patients plasma cortisol. Although insulin plasma than placebo-treated patients after surgery. concentrations were not measured, the Toru et al,(33) in their study, reported that hyperglycemic action of clonidine observed blood pressure and heart rate values after in this study was attributed to the inhibitory surgery were not affected by clonidine effect of clonidine upon the B cells of the premedication, this difference could be pancreas and decreased insulin release. attributed to the single dose of clonidine However, other mechanisms have also used in their study. been proposed to be responsible for the From the previous studies we can hyperglycemic action of clonidine, such as postulated that tizanidine can be used more increased gluconeogenesis or glycogeno- safer than clonidine as a premedication. lysis, mediated via stimulation of α2 The present study investigated the effect adrenergic receptors located in the central of tizanidine premedication on the stress nervous system(39) . response in patients undergoing anesthesia In summary, the study was scheduled and surgery. Due to its sympatholytic action, for measurement of isoflurane MAC with or α2 agonist suppresses parts of the without oral tizanidine 2,4,10mg as a pre- endocrine surgical stress response (34). In medicaltion in surgical patients. Oral the present study, low dose of oral tizanidine premedication in a dose of 4 and tizanidine premedication (2 mg) did not 10 mg decreased the MAC of isoflurane, but significantly affect the sympathoadrenergic more decrease occurred with 10 mg and hemodynamic responses to surgery tizanidine. Also, tizanidine decreased the indicating that the sympatholytic effect of release of stress hormones and decreased tizanidine is dose-dependent. SO, in the the postoperative analgesic requirements. In present study premedication with tizanidine, spite of the increased dose of tizanidine orally at doses of 4 and 10 mg has been (10mg) there were no tizanidine-related reported to blunt increases in catecholamine adverse effects observed throughout the plasma concentrations during surgery. study, such as hypotension (which some- The study done by Charles et al,(35) on times occurs when clonidine is used). healthy volunteers, found that dexmedeto- Therefore, we believe that tizanidine can be midine at concentrations similar to those a safer and cost-effective alternative indicated for patient sedation decreases anesthesia premedication. systolic blood pressure and heart rate. This was accompanied by an approximate 30% REFERENCES reduction in plasma concentrations of norepinephrine. They also reported that the 1. Eger EI II, Saidman LJ, Brandstater B. unique pharmacology of α2-adrenergic Minimum alveolar anesthetic concent-ration: receptor agonist drugs results in sedation a standard of anesthetic potency. and analgesia without depression of Anesthesiology 1965; 26:756-63. respiration (35). By attenuating surgical 2. Quasha AL, Eger EI II, Tinker JH. stress-induced sympathetic activation, these Determination and applications of MAC. Anesthesiology 1980; 53:315-34. drugs also increase perioperative hemo- 3. Tsunoda Y, Hattori Y, Takatsuka E, et al. dynamic stability and decrease risk for Effects of hydroxyzine, diazepam, and myocardial ischemia (36,37) . pentazocine on halothane minimum alveolar

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