European Journal of Cardiovascular Medicine

Laryngoscopy and tracheal intubation may cause profound alteration of the haemodynamic state of the patient. Increase in blood pressure and heart rate occurs most commonly from reflex sympathetic discharge in response to laryngotracheal stimulation.1,2 These changes may be associated with morbidity and mortality which are more pronounced in patients with heart disease and hypertension, provoking complications like arrhythmias, increased intracranial pressure.

Pregabalin acts by decreasing the synthesis of neurotransmitter glutamate to act on the central nervous system and possesses analgesic, anticonvulsant, anxiolytic activity.3 Clonidine suppresses induced central noradrenergic hyperactivity to attenuate reflex cardiovascular response to tracheal intubation and to improve stability during surgery.4

Hence the present study is undertaken Compare the efficacy of oral clonidine and oral pregabalin premedication 90 min prior to surgery in attenuating the adverse haemodynamic responses to laryngoscopy and tracheal intubation with respect Systolic blood pressure, Diastolic blood pressure, Mean blood pressure, Rate Pressure Product.

This prospective randomized double blind controlled study was conducted on 100 ASA physical status grade I and II patients of either sex between 18-50 years of age, undergoing elective orthopaedic, spine, otorhinolaryngeal, gynecological and general surgical procedures from October 2012 to May 2014 at  SSIMS&RC, Davangere. Hospital ethics committee clearance was obtained for this study. Informed consent was taken from all the patients

Inclusion Criteria

• Patients aged between 18 to 50 years of age of both genders.
• American Society of Anaesthesiologists grade I and II patients.
• Patients with Mallampati airway grade І and ІІ.
• Patients undergoing elective major or minor surgical procedures under general anaesthesia.

Exclusion Criteria

• Patients’ refusal.
• Age less than 18yrs and more than 45yrs.
• Patients with medical co morbidities like Hypertension, Ischemic Heart Diseases, Arrhythmias, Renal, Respiratory, Cerebral Diseases, Asthmatics and Epileptics.
• Expected difficult intubation.
• If patient is allergic to any of drugs used in the study.
• Patients taking sedatives, hypnotics.
• Emergency procedures.

METHODS:

100 similar looking thick opaque envelopes were randomly divided into 2 equal groups of 50 each (group A or B) and the code name A/B was mentioned on top of the envelope. The pharmacist separated the tablets of Pregabalin(150mg), tablets of Clonidine (0.3 mg) into 2 equal groups of 50 each. He took the tablets out of their sachets & loaded them separately into the envelopes and sealed them in such a way that an envelope was containing either,

Tablets of Pregabalin (150 mg= 2 tablets of 75mg each)

OR

Tablets of Clonidine (0.3 mg=3 tablets of 100 micrograms each)

Thus, 50 envelopes were containing tablets of Pregabalin & had the same code

(A/B) mentioned on them.

50 envelopes were containing tablets of Clonidine with the same code (A/B) mentioned on them. Only the pharmacist was aware of the code identity which was revealed at the end of the study. The patients were randomized by a computer-generated table into 2 equal groups

A/B so that

Group “A” patient received all the tablets from one envelope labelled group “A”.

Group “B” patient received all the tablets from one envelope labelled group “B’.

All patients were assessed the day before surgery. The drug from the closed envelope was drawn and given to the patient by ward nurse with sips of water 90 min prior to surgery. The identity of the tablet was not revealed to the patient and anaesthetist. No other premedication was given other than the study drugs.

ANAESTHETIC TECHNIQUE

On arrival in the operating room, patient’s basal parameters- Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP), Mean Arterial Pressure (MAP), Rate Pressure Product (RPP) and Electrocardiography are monitored using, pulse oximetry, Non-Invasive Blood Pressure (NIBP), and ECG monitor.

• All the parameters of the study was recorded at following stages –preoperative
• -On arrival in the operating room (baseline)
• -Post induction (1 minute)
• -Immediately after intubation
• -At 1 minute, 3 minutes, 5 minutes and 10 minutes after intubation.
• SBP, DBP, and MBP were recorded post extubation. Any on toward effects related to the drug and anaesthesia were noted and attended to appropriately.
• A fall in mean blood pressure by 30% from the baseline was treated with Mephentermine 6mg boluses. A fall in the heart rate less than 40 beats/min was treated with inj Atropine 0.3mg. Analgesia if deemed necessary was supplemented with inj Fentanyl 1µg/kg IV. Patients were followed up postoperatively at hourly basis till 8 h from drug administration. Any ontoward effects were observed for and noted.
• lactate was started.
• All patients were pre-oxygenated with 100% oxygen for 3 minutes before induction with a tight-fitting face mask.
• All the patients were premedicated with Metoclopramide 10mg, Glycopyrrolate 0.2mg iv, and fentanyl 2mcg/kg.
• After preoxygenation, Patients in each group was induced with Thiopentone sodium 5mg/kg iv slowly till the loss of eyelash reflex. This was followed by vecuronium bromide 0.1mg/kg IV
• Patient’s lungs were manually ventilated with 100% oxygen before orotracheal intubation.
• Direct laryngoscopy performed after 3 minutes by using appropriately sized Macintosh blade and tracheal intubation performed within 15 seconds using appropriately sized cuffed endotracheal tube.
• The patients’ lungs were mechanically ventilated with Tidal volume 10ml/kg and respiratory rate of 12/minute to maintain end tidal PaCo2 at around 36 mmHg.

Data obtained in the study are presented in a tabular manner. Statistical analysis by descriptive data presented as Mean±SD in percentage. Pair wise comparison between the groups was done by “T” test. For all tests a ‘P’ value of <0.05 was considered significant.

Results:  The statistical analysis of changes in the systolic blood pressure at pre induction, post induction, and at different time intervals from the onset of laryngoscopy and intubation in the oral Clonidine and oral Pregabalin groups are presented.

Table 1:  Showing variations in Systolic Blood Pressure (mm Hg)

Clonidine Group (Group A)

The mean preoperative systolic blood pressure in this group was 123.68 ± 13.71. During pre-induction at 90 minutes after premedication, there was a 1.68% fall in systolic blood pressure to 121.60 ± 10.98. During post induction there was a 6.12% further fall in SBP to116.24± 9.99. Immediately after intubation there was a 10.5% increase in SBP was noted with a mean valve of 135.88± 11.68. At 1 minute following laryngoscopy, a decrease in systolic blood pressure was noted with a mean value of 130.76 ± 10.98. At 3-minute following laryngoscopy, decrease in systolic blood pressure was noted with a mean value of 126.20 ±11.92. Starting from 5th minute following laryngoscopy and intubation there was a fall in systolic blood pressure to 0.94% the pre-operative value and 2.91% pro-operative value at 10 minutes, just below the baseline with a mean value of 112.50 ± 12.66 and120.12 ± 11.83 respectively.

ORAL PREGABALIN (GROUP B)           

Pre-operative systolic blood pressure in this group was 121.22 ± 13.71. During pre-induction at 90 minutes after premedication a marginal rise of 3.23% with a mean of 125.14± 10.76 was observed. During post induction there was a 5.15% fall in SBP to114.98± 11.87 was noted.

There was a 16.99% increase in systolic blood pressure following immediate after intubation with mean SBP of 141.82 ± 12.48. 1 minute after laryngoscopy with a mean value of 134.12 ± 13.98. At 3 minutes in systolic blood pressure to 126.14 ± 16.90. Starting from 5th minute following laryngoscopy and intubation there was a fall in systolic blood pressure to 0.49% the pre-operative value and 2.03% pre operative value at 10 minutes, just below the baseline with a mean value of 120.62 ± 17.34 and118.76 ± 16.54 respectively.

There was no significant variation noted in clonidine and pregabalin groups in systolic blood pressure before and 90 minutes after premedication. In comparison to pregabalin group, attenuation of systolic blood pressure is significant in clonidine group immediate after intubation (P 0.01). A rise of systolic blood pressure by 10.5 % was observed in clonidine group as compared to 16.99% in pregabalin group (P 0.01) which is statistically significant.

Clonidine group showed a better attenuation compared to pragabalin group in systolic blood pressure immediately post laryngoscopy. There was not much significance between the two groups statistically in other intervals.

 ANALYSIS OF DIASTOLIC BLOOD PRESSURE

Table 2:   Showing variations in Diastolic Blood Pressure (mm Hg)

In Table 2 the statistical analysis of changes in the diastolic blood pressure at pre induction, post induction, and at different time intervals from the onset of laryngoscopy and intubation in the oral Clonidine and Pregabalin groups are presented.

Clonidine Group (Group A)

The mean preoperative diastolic blood pressure in this group was 74.2.68 ± 3.68. During pre induction at 90 minutes after premedication, there was a 2.13% fall in diastolic blood pressure to 72.70 ± 9.24. During post induction there was a 5.04% further fall in DBP to70.54± 7.87. Immediately after intubation there was a 16.56% increase in DBP was noted with a mean valve of 86.58± 8.13. At 1 minute following laryngoscopy, a decrease in diastolic blood pressure was noted with a mean value of 82.64 ± 8.25. At 3 minute following laryngoscopy, decrease in diastolic blood pressure was noted with a mean value of 79.84 ±8.29. It decreased to 75.88± 9.11 at 5 minutes, 74.58 ± 8.52 at 10 minutes.

ORAL PREGABALIN (GROUP B)

Diastolic blood pressure in pregabalin group before premedication was 74.1 ±4.29. During pre induction (90 minutes after premedication) 3.7% rise DBP to 76.84± 6.42 was noted. During post induction there was a 5.75% further fall in DBP to 69.84± 8.36. Immediately after intubation there was a 28.66% increase in DBP was noted with a mean valve of 95.34± 11.35. At 1 minute following laryngoscopy, a decrease in diastolic blood pressure was noted with a mean value of 84.32 ± 9.92. At 3-minute following laryngoscopy, decrease in diastolic blood pressure was noted with a mean value of 78.38 ±11.91. It decreased to 74.94± 12.57 at 5 minutes and 73.64 ± 11.23 at 10 minutes.

A maximum rise 16.56% in clonidine group and a rise of 28.66% were noted in pregabalin groups following immediate after intubation.

Attenuation of diastolic blood pressure by clonidine as compared to pregabalin group was significant following pre induction (P 0.011) and  immediate after intubation (P < 0.001) where it was statistically significant.

ANALYSIS OF MEAN BLOOD PRESSURE:

Table 3:  Showing variations in Mean Blood Pressure (mmHg)

In Table 3 the statistical analysis of changes in the Mean Blood Pressure at pre induction, post induction, and at different time intervals from the onset of laryngoscopy and intubation in the oral Clonidine and Pregabalin groups are presented.

ORAL CLONIDINE (Group A)

In clonidine group, the baseline MAP was 90.70 ±4.70 mmHg. During the pre-induction period there was 0.82% fall in MAP with mean of 89.96±7.87 mmHg. During post induction there was a 4.72% further fall in MAP to 86.42±7. Immediately after intubation mean MAP was 103.38 ±7.84mmHg representing 13.98% rise from baseline. The increase in MAP during intubation compared to baseline value was statistically significant (p<0.01). Subsequently the elevated MAP started settling down. By 1 min it was 99.28±7.60, 3 min it was 95.72±7.65 mmHg, by 5 min it was 92.06±8.68mmHg. By 10 min mean MAP was 90.42±8.43 mmHg which is less than the baseline value.

ORAL PREGABALIN (GROUP B)           

In this group, the baseline MAP was 90.22±4.58 mmHg. During intubation it was 111.68±11.16mmHg. There was a 23.79% increase from baseline. The elevated MAP started settling down. By 1 min 101.48±10.16, 3 min it was 95.22±12.38mmHg, by 5 min 91±12.69 mmHg, by 10 min 89.52±11.23mmHg.

A maximum rise 13.98% in clonidine group and a rise of 23.79% were noted in pregabalin groups following immediate after intubation.

Attenuation of mean blood pressure by clonidine as compared to pregabalin group was significant following pre induction (P 0.009), immediate after intubation (P < 0.001) and 5 mins after intubation (P 0.009).

  ANALYSIS OF RATE PRESSURE PRODUCT

Table 4:  Showing variations in Rate Pressure Product

In Table 4, the statistical analysis of changes in the Rate Pressure Product at pre induction, post induction, and at different time intervals from the onset of laryngoscopy and intubation in the oral Clonidine and Pregabalin groups are presented.

Clonidine Group (Group A)

In clonidine group, the baseline RPP was 10521.72±1252.24. During the pre-induction period there was 23.96% fall in RPP with mean of 8000.58±1422.03. During post induction there was a increase in RPP to 8373.88±1359.03. Immediately after intubation mean RPP was 11511 ±2006.19 representing 9.4% rise from baseline. The increase in RPP during intubation compared to baseline value. Subsequently the elevated RPP started settling down. By 1 min it was 10491.10±159214, 3 min it was 9697.40±1546.40, by 5 min it was 9118.38±1559.19. By 10 min mean RPP was 8616.86±1362.33 which is less than the baseline value.

ORAL PREGABALIN (GROUP B)           

In this group, the baseline RPP was 10256.02±1673.89. During intubation it was 14649.90±2203.51. There was a 42.84% increase from baseline. It increased further by 1 min 15525.56±17185.35, the elevated RPP started settling down by 3 min 11823.58±2436.04, 5 min it was 10749.36±2050.33, by 10 min 10462.77±2408.77.

The difference in the RPP between clonidine (Group A) and Pregabalin (Group B) group remain highly significant at all times of assessment (p < 0.001).

Maximum increase in RPP in clonidine group was at immediate post laryngoscopy which was far less than the pregabalin group.

The RPP response between clonidine and pregabalin was very significant at all times starting from pre-op to 10 minutes (p<0.001) where it is significant with clonidine showing a favourable response towards attenuation of RPP.

In clonidine group systolic blood pressure reduced by 1.68% 90 minutes after premedication but there was 3.23% marginal rise in the pregabalin group. It increased 10.5% above pre operative valves immediate after intubation and came to baseline at 5 minutes following laryngoscopy and intubation. With pregabalin group, the maximum rise in systolic blood pressure was 16.99% above the preoperative values (during premedication) immediate after intubation and it reached to baseline after 5 minutes following laryngoscopy and intubation.

Attenuation of sympatho adrenal response to laryngoscopy and intubation was observed by Pouttu et al.5 Clonidine showed a better drug to attenuate rise in systolic blood pressure comparing it to pregabalin immediately post laryngoscopy (p<0.01).

DIASTOLIC BLOOD PRESSURE

Maximal rise in diastolic blood pressure was 16.56% in clonidine group and in pregabalin group it was 28.66% (p<0.001). In clonidine group as well as in Pregabalin group the diastolic blood pressure almost reached the baseline by the end of 5 minutes following laryngoscopy and intubation. None of the patients in the clonidine group suffered from bradycardia and hypotension.

MEAN ARTERIAL PRESSURE

In our study there was a significant difference (p<0.001) in the mean arterial pressure with oral Clonidine and Pregabalin immediate after intubation period. Maximum rise in mean blood pressure, above the baseline, was 13.98% for oral Clonidine and 23.79% for oral Pregabalin group.

RATE PRESSURE PRODUCT

Rate pressure product (RPP) is an indirect measure of Myocardial oxygen consumption (MVO2). Myocardial oxygen consumption is correlated with the rate-pressure product (heart rate x systolic blood pressure) and this hemodynamic parameter has been shown to follow a circadian pattern similar to that observed with cardiovascular events.6

In our study the difference in rate pressure product between oral Clonidine and oral Pregabalin groups was statistically significant at all times preoperative to 10 min. Attenuation of maximum rise in the rate pressure product by clonidine is evident and statistically highly significant when compared with pregabalin group (p < 0.001).

Kumkum Gupta showed that clonidine was superior to pregabalin for attenuation of the hemodynamic responses to laryngoscopy.

Our study in contrary to Kumkum Gupta study showed significant attenuation of pressor response in clonidine group immediate to laryngoscopy & intubation in blood pressure compared to pregabalin group. But there was highly significant attenuation in heart rate and rate pressure product.

Both Clonidine and oral pregabalin effectively attenuates the haemodynamic response to laryngoscopy and intubation of trachea. Of the two, oral clonidine is effective in attenuation compared to oral pregabalin.

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2. Fassoulaki A, Melemeni A, Paraskeva A, Petripoulos G. Gabapentin attenuates the pressor response to direct laryngoscopy and intubation. Br J Anaesth 2006;96(6):769-73.
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6. WB White. Heart rate and the rate-pressure product as determinants of cardiovascular risk in patients with hypertension. Am J Hypertens. 1999 Feb;12(2 Pt 2):50S-55S.