ORAL CLONIDINE PRE MEDICATION FOR ATTENUATION OF HAEMODYNAMIC RESPONSE TO LARYNGOSCOPY AND INTUBATION.

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1 IJA No. A49/2k Indian 124 J. Anaesth. 2002; 46 (2) : INDIAN JOURNAL OF ANAESTHESIA, APRIL ORAL CLONIDINE PRE MEDICATION FOR ATTENUATION OF HAEMODYNAMIC RESPONSE TO LARYNGOSCOPY AND INTUBATION. Dr. Dipak L. Raval 1 Dr. Malini K. Mehta 2 SUMMARY A study on 100 ASA Gr I-II patients between 18 and 65 years of age was conducted to compare effectiveness of oral clonidine as a premedicant and also for attenuation of haemodynamic responses to laryngoscopy and endotracheal intubation with oral diazepam and placebo. The patients were divided into three groups. Groups C (n=40) received tablet clonidine 4g kg -1 (maximum 0.2 mg). Group D (n=40) received tablet diazepam 0.2 mg kg 1 and Group P (n=20) received tablet placebo (antacid) with sip of water, about 90 minutes prior to induction of anaesthesia. Clonidine produced marked sedation and better anxiolysis as compared to placebo but less sedation and same level of anxiolysis as compared to diazepam. There were no changes in respiratory rate in either group. Clonidine provided extra advantage over diazepam and placebo by blunting haemodynamic responses during laryngoscopy and endotracheal intubation and also by its antisialagogue effect. Keywords : Premedication: oral clonidine, diazepam. Haemodynamic response: laryngoscopy, intubation, clonidine. Introduction Preanaesthetic medication forms an integral part of anaesthetic management and some form of premedication is universally administered before any anaesthesia. The ideal premedicant should be effective and pleasant to be taken orally, have analgesic and non emetic properties, should not impair cardiovascular stability or depress respiration, should have antisialagogue effect and should effectively alleviate apprehension of the patient. Alpha-2 adrenoceptor agonists have been used as premedicants because of their beneficial properties in anaesthesia. The only clinically available alpha-2 adrenergic agonist in our country is clonidine, which is mainly used as an anti hypertensive agent, but has many properties of ideal premedicant and also has beneficial effects on haemodynamics during stressful conditions like laryngoscopy and endotracheal intubation 1,2. This study was undertaken to evaluate effectiveness of oral clonidine as a preanaesthetic medicant and as a drug to attenuate the haemodynamic responses associated 1. D.A.,Assistant Professor Of Anaesthesiology. M.P.Shah Medical College. Jamnagar. 2. D.A., M.D,Professor And Head, Department Of Anaesthesiology Govt. Medical College Rajkot. Correspond to : Dr Dipak L Raval, Assistant Professor, C/21-A Doctors Qts, M.P.Shah Medical College Campus, GGH, Jamnagar , Gujarat. with laryngoscopy and endotracheal intubation and its effects were compared with commonly used premedicant diazepam as well as placebo (tablet antacid) in the patients undergoing elective surgery. Material And Methods This study was conducted on 100 patients aged from 18 to 65 years of either sex, belonged to ASA I or II scheduled for routine surgery. All the patients were thoroughly examined. Patients taking drug treatments known to affect heart rate, blood pressure or hormonal stress responses were excluded from the study. The patients were divided into three groups according to the premedication they received. Group C (n=40) -received tablet clonidine 4 g kg -1 (up to a maximum of 0.2mg) Group D (n=40) -received tablet diazepam 0.2mg kg -1 Group P (n=20) -received tablet antacid. All the drugs were given with sips of water about 90 minutes prior to induction of anaesthesia. No anticholinergic drug was given either before or at the time of induction of anaesthesia. In the preanaesthetic room, the assessment was done just before and 90 minutes after administration of the drug. The degree of sedation and anxiolysis was graded as follows:

2 RAVAL, MEHTA : ORAL CLONIDINE FOR ATTENUATION OF PRESSOR RESPONSE 125 i. Sedation scoring 0. point patient awake and talkative. 1. point patient awake but uncommunicative. 2. point patient drowsy, quiet and easily arousable. 3. point patient asleep. ii. Anxiety Scoring: 0. patient quiet and comfortable. 1. patient uneasy. 2. patient worried or anxious. 3. patient very worried or very upset. 4. patient frightened or terrified. The heart rate, blood pressure (systolic, diastolic and mean arterial pressure) were recorded with non invasive monitor (pacetech, vitalmax 800). Respiratory rate, status of tongue (dry or moist) and any undesirable effects were also noted. On arrival in the operation theater, an intravenous line was set up and anaesthesia was induced with 2.5% thiopentone 4-6 mg kg -1 bw after preoxygenation for 3 minutes, followed by suxamethonium 2 mg kg -1 bw. During laryngoscopy and endotracheal intubation, heart rate and blood pressure were recorded and designated as I and continued at 1 minute interval after endotracheal intubation upto 5 minutes and designated as I 1,,,, and. Any patient who strained or took more than 15 seconds for intubation or required a second attempt of laryngoscopy and intubation was excluded from the study. Anaesthesia was maintained with O 2 and N 2 O without the addition of any narcotic or inhalational agent up to 5 minutes after endotracheal intubation. Thereafter pancuronium bromide and 0.5% halothane were supplemented. After completion of surgery, neuromuscular blockade was antagonised, patients were extubated and shifted to recovery room. Results Patients characteristics are shown in table I. Clonidine provided an acceptable level of sedation in comparison to placebo but it was less sedative than diazepam (p<0.05) (Table II). The differences in the anxiety scoring before and after premedication with clonidine as well as with diazepam were highly significant, but that after placebo was not significant (Table III). Sedation Score In Different Groups After 90 minutes of Premedication Table I : Age, weight and sexwise distribution (mean values) Clonidine Diazepam Placebo Group C Group D Group P (n=40) (n=40) (n=20) Age (Year) (18-56) (18-65) (18-55) Weight (Kgs) Sex M:F M:F M:F (M:F) 26:14 11:29 10:10 65%:35% 27.5% :72.5% 50%:50% Table II : Sedation scoring in different groups Sedation score Mean SE Group Score P ± SD ( x 1 - x 2 ) Value Clonidine (Group C) 42.5% 47.5% 5% 5 % ± Diazepam (sig) (Group D) 22.5% 60% 12.5% 5% ± 0.70 Placebo (Group P) (100%) ± 0.00 Score 0 Patient awake and talkative Score 1 Patient awake but uncommunicative Score 2 Patient drowsy, quiet and easily arousable Score 3 Asleep sig. Significant.

3 126 INDIAN JOURNAL OF ANAESTHESIA, APRIL 2002 Table III Anxiety scoring in different groups Group Anxiety Score Mean score Difference P value Group C of x ±SEM Before Premedication (17.5%) (42.5%) (37.5%) (2.5%) 1.75 <0.01 After Premedication (85%) (12.5%) (2.5%) - - ± 0.14 (HS) Group D Before Premedication (32.5%0 (27.5%) (40.0%) <0.01 ± 0.14 (H>S) After Premedication (80%) (15%) (5%) - - Group P Before Premedication (55%) (30%) (15%) >0.05 ± (N.S) After Premedication (50%) (30%) (20%) - - Score 0 patient quiet and comfortable ; Score 1 patient uneasy; Score 2 patient worried or anxious; Score 3 patient very worried or very upset; Score 4 patient frightened or terrified; H.S. Highly significant N.S. Not significant On inter group comparison, statistically insignificant difference was observed in the anxiety score between clonidine and diazepam (p>0.05) whereas when placebo was compared with clonidine and diazepam, the difference were statistically highly significant (p<0.01) and significant (p<0.05) respectively (Table IV). Table IV : Comparison of anxiety scores after premedication in different groups Group Mean+SD SE (x 1 -x 2 ) P value Clonidine >0.05 (Group C) (N.S) Diazepam <0.05 (Group D) S Placebo <0.01 (Group) ± (H.S) N. S. - Not significant S. - Significant H. S. - Highly significant 90 min after premedication, the decrease in the pulse rate in clonidine group was statistically highly significant whereas increase in the pulse rate after diazepam and placebo was statistically significant and highly significant (Table V). On inter group comparison, after 90 min of premedication, highly significant changes in pulse rate (p<0.01) was observed after clonidine as compared to diazepam and placebo but no significant changes (p>0.05) was observed between diazepam and placebo group (Table V). The rise in pulse rate during laryngoscopy and intubation from basal value was statistically highly significant in diazepam group and placebo group (P<0.01) but it was not significant in clonidine group (P>0.05) (Table V). After 1 min of intubation pulse rate in clonidine group returned to the basal value and remained lower than the basal value upto 5 min of intubation, whereas in diazepam and placebo group pulse rate did not return to the basal value even after 5 min of intubation and as compared to the basal value a statistically highly significant difference in pulse rate was observed at the end of 1,2,3,4, and 5 min after intubation (I 1,,, and ) respectively in patients of diazepam as well as placebo group (Table V). Table V: Mean values (beats/minute) of pulse rate atvarious intervals Group C b, a,+ * + + Mean Sd Group D a, * Mean SD Group P b, Mean SD Denotes P<0.01 (highly significant) * Denotes P<0.05 (significant) a Denote P<0.01(highly significant) b Denote P<0.01(highly significant) basal value (B1) within a gro other group value at same time

4 RAVAL, MEHTA : ORAL CLONIDINE FOR ATTENUATION OF PRESSOR RESPONSE 127 After 90 min of premedication systolic, diastolic and mean blood pressure was decreased in patients of clonidine and diazepam group, whereas it was increased in patients of placebo group. On inter group comparison no significant changes in systolic blood pressure were observed between clonidine and diazepam group. Statistically highly significant changes were observed in both diastolic and mean arterial pressure when each group is compared with other two groups (Table-VI, VII and VIII). Table VI: Mean values of systolic arterial pressure (mm of Hg) at various intervals : Group C +, b Mean SD Group D a, Mean SD Group P a, b, Mean SD Denotes P<0.05(highly significant) *Denotes P<0.01(significant) a Denote P<0.01(highly significant) b Denote P<0.01(highly significant) Table VII : Mean values of diastolic arterial pressure (mm of Hg) at various intervals Group C a, b, Mean SD Group D a, c, basal value (B1) within a group other group value at same time. Mean SD Group P b, c, Mean SD Denotes P<0.01(significant) basal value (B1) within a group. a) b) c) Denotes P<0.01 other (highly significant) group value at same time. Table VIII : Mean values of diastolic arterial pressure (mm of Hg) at various intervals Group C a,b, Mean SD Group D a,c,+ + + Mean SD Group P a,c, Mean SD Denotes P<0.01 (significant) a,b,c Denotes P<0.01(highly significant) basal value (B1) within a group. other group value at same time. During laryngoscopy and endotracheal intubation, decrease in systolic, diastolic and mean arterial pressure in clonidine group was not significant whereas rise in the systolic, diastolic and mean arterial pressure from the basal value was statistically highly significant in both diazepam as well as placebo groups (Table VI, VII, VIII). Systolic, diastolic and mean arterial pressure remained lower than the basal value upto 5 min of endotracheal intubation in clonidine group. Whereas all these values returned to the basal value after 3 min of intubation in diazepam group but did not return to the basal value even upto 5 min of intubation in placebo group. As compared to basal values statistically highly significant difference in systolic, diastolic and mean arterial pressure were observed at the end of 1,2,3,4 and 5 min of intubation in patients of both clonidine and placebo groups (Table VI, VII, and VIII). No statistically significant decrease in respiratory rate was observed after 90 min of premedication in any of the group (Table IX). Table IX: Changes in respiratory rate in different groups Group Before 90 minutes after P value Premedication Premedication Clonidine 16.74± ±0.96 >0.05 (Group C) (N.S) Diazepam 16.45± ± 1.17 >0.05 (Group D) (N.S) Placebo 16.65± ±1.15 >0.05 (Group P) (N.S>) N.S. = Not significant.

5 128 INDIAN JOURNAL OF ANAESTHESIA, APRIL 2002 The change in status of tongue from moist to dry was statistically highly significant in clonidine group but it was statistically not significant in diazepam and placebo groups (Table X). Table X : Changes in status of tongue (antisialogue effect) in different groups Group Before Premedi- 90 minutes after P value Moist cation Moist Premedication Dry Dry Clonidine <0.001 (Group C) 95% 5% 20% 80% (H.S) Diazepam >0.01 (Group D) 92.5% 7.5% 77.5% 22.5% (N.S) Placebo >0.1 (Group P) 80% 20% 70% 30% (N.S.) H.S. Highly significant N.S.Not significant. Discussion The effects of clonidine on sedation and haemodynamic variables are dose related and increasing the dose to more than 4 mcg kg -1 does not further enhance efficacy 3. 5 mcg kg -1 oral clonidine was not sufficient to blunt the response to laryngoscopies that exceeds 15 seconds duration 4. In this study oral clonidine 4 mcg kg -1 produced both sedation and anxiolysis. The degree of sedation is less as compared to diazepam and there was no difference in anxiety scoring between them. The sedative effect of clonidine may be due to decreased tonic activity of the locus coeruleus which modulates the stimuli arriving in the central nervous system 5. Sedation and anxiolysis caused by clonidine are elicited at central alpha-2 adrenergic receptors, hence it can be considered as an anaesthetic adjuvant. Similar study was carried out by Rudra A et al (1994) 6, Das A.K. and Rudra R (1995) 7. They observed less sedation with 3 mcg kg -1 oral clonidine, as compared to 0.2 mg kg -1 oral diazepam and no statistically significant difference in the anxiety scoring between the two groups. 90 minutes after clonidine, decrease in the pulse rate was statistically highly significant. The decrease in the pulse rate after clonidine is due to the reduction of the sympathetic outflow, the simultaneous increase of parasympathetic tone of central origin and the influence of clonidine on neurons which receive baroreceptor afferents (Sleight p et al). 90 minutes after oral clonidine and diazepam, the fall in systolic, diastolic and mean arterial pressure was highly significant. Clonidine is an alpha 2 adrenoceptor agonist, which interacts with the catecholaminergic neuronal system which modulates tonic and phasic (reflex) blood pressure control and reduces the release of norepinephrine from nerve endings both centrally and peripherally and causes reduction in arterial pressure. Sympathoadrenal activation associated with laryngoscopy and endotracheal intubation causes rise in arterial blood pressure and tachycardia. Carabine et al suggested that cardiovascular responses by short lasting laryngoscopies can be attenuated with very low doses of oral clonidine. Prevention of tachycardia in response to laryngoscopy and intubation and the slowing of the heart rate induced by clonidine share a complex underlying mechanism. It consists of at least three different components, centrally the activation of alpha-2 adrenoceptors causes both a reduction in peripheral sympathetic tone and an increase of vagally induced reflex bradycardia, peripherally stimulation of presynaptic alpha adrenoceptors leads to diminished release of norepinephrine from the nerve endings towards the vasculature and to a reduction in peripheral sympathetic tone towards the heart. Concern might be expressed regarding the risk of clonidine withdrawal and associated hyperdynamic cardiovascular states. This has not occurred in this study, during the first 24 post operative hours, since no evidence of an overshoot of sympathetic activity was observed in human subjects after a single dose of clonidine (Wing L.M.H.et al) 10. Several reports had shown that short term administration of clonidine does not induce withdrawal syndrome. Rebound phenomena or untoward haemodynamic events after the sudden withdrawal of clonidine therapy can occur only after 6-30 days of clonidine treatment. There is little physiological basis for alpha-2 adrenergic receptor stimulation induced respiratory depression. Clonidine premedication is accompanied by a substantial degree of dryness of mouth, this is due to the effect of drug on presynaptic alpha adrenoceptors in the brain stem as well as on parasympathetic nerves which supplies the salivary glands. It is concluded that premedication with oral clonidine produced less sedation and same level of anxiolysis as compared to diazepam and placebo with regards to its antisialogague effect and by blunting haemodynamic responses during laryngoscopy and endotracheal intubation.

6 RAVAL, MEHTA : ORAL CLONIDINE FOR ATTENUATION OF PRESSOR RESPONSE 129 Acknowledgement We are thankful to the department of preventive and social medicine, Government Medical College, Surat for the guidance to carry out statistical analysis of this study. References 1 Ghignone M., Quintin L., Duke P.C., Kehle C.H. and Callvillo O. Effects of clonidine on narcotic requirements and haemodynamic response during induction of fentanyl anaesthesia and endotracheal intubation Anaesthesiology 1986; 64; Nishikawa T., Taugchi M, Kimura T., Taguchi N, Sato Y. and Dai M. Effects of oral clonidine premedication upon haemodynamic changes associated with laryngoscopy and tracheal intubation Masui 1991; July 40(7) Kulka peter J., Tryba Michael and Zenz Micheal. Dose response effects of intravenous clonidine on stress responses during induction of anaesthesia, Anaesthesia and Analgesia 1995;80; Laurito C.E., Baughman V.L. Becker G.L., Cunningham F., Pyaon B.H. and Citron G.M.Oral clonidine blunts the haemodynamic responses to brief but not prolonged laryngoscopy. Journal Clni Anaesth. 1993; Jan Feb 5(1) Autret A.et al (1977) Quoted from Kumar A., Bose S., Bhattacharya A., Tandon O.P. and Kundra P. : Oral clonidine premedication for elderly patients undergoing intraocular surgery. Acta anaesthesiol Scand 1992; 36: Rudra A., Das A.K. and Chaudhari S. Evaluation of clonidine as a premedicant during ketamine anaesthesia journal of Anaesthesiology and clinical pharmacology 1994;11; Das A.K. and Rudra R. Clinical efficacy of oral clonidine a preanaesthetic medicant. Indian Journal of Anaesthesia 1995; 43; Sleight P. et al (1975) Quoted from Kumar A., Bose S., Bhattacharya A., Tandon O.P. and Kundra P. Oral clonidine premedication for elderly patients undergoing intraocular surgery. Acta Anaesthesiol scand. 1992;35; Carabine U.A., Wright P.M.C and Moore J. Preanaesthetic medication with clonidine: A dose response study. British Journal of Anaesthesia 1991;67; Wing L.M.H et al (1977) Quoted from Das A.K. and Rudra R. Clinical efficacy of oral clonidine as a preanaesthetic medicant. Indian Journal of Anaesthesia 1995; 43; JOIN ISA! Benefits. 1) Free, preferred, communication on all conferences, educational programmes, career advancement schemes, etc. 2) Exposure to career advancement programme and sponsorship of ISA when needed. 3) Access to compete for various medals an 4) d awards of ISA every year. 5) Eligibility to elect your association leaders. 6) Eligibility to contest at election to become ISA office bearer of your choice at branch level, state level and national level. 7) Reduced delegate registration charge at all ISA sponsored CME, workshop, conference in India for your life time (city level, state level, zonal level and national). 8) Complimentary conference registration to members aged over 75 years and their spouses. 9) Access to family benefit scheme of ISA and incentive card of FBS 10) Regular free delivery of Indian Journal of Anaesthesia, news letter, etc. 11) Enjoy the status as corporate member of Society of Anaesthesiologists of World (WFSA). 12) Eligibility to attend any ISA branch meeting in India with prior intimation. 13) To become a member of proposed Indian College of Anaesthesiologists and receive honour. 14) Communication support and legal assistance in accidental anaesthetic mishaps where member is involved or incriminated. 15) Right to publish your scientific article in our journal. Dr. B. Radhakrishnan. - Secretary ISA. (National)