|Year : 2020 | Volume
| Issue : 3 | Page : 412-419
Comparison of oral clonidine and gabapentin premedication for attenuation of pressor response to laryngoscopy and endotracheal intubation
Vaishali Sharma, Kamal Fotedar, Ravi Goel
Batra Hospital and Medical Research Centre, New Delhi, India
|Date of Submission||23-Dec-2020|
|Date of Decision||17-Jan-2021|
|Date of Acceptance||20-Jan-2021|
|Date of Web Publication||22-Mar-2021|
Dr. Vaishali Sharma
Department of Anaesthesiology, Apollo Cradle Royale, Nehru Enclave, New Delhi - 110 019
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: During the administration of general anesthesia, direct laryngoscopy and endotracheal intubation cause an increase in heart rate, arterial pressure, and dysrhythmias in upto 90% of patients. These changes can be particularly hazardous for patients with cerebral or coronary diseases. Both clonidine and gabapentin have been used for anesthetic effects, but a better drug for controlling hemodynamic parameters is being investigated. Aims: The study was done to evaluate and compare the efficacy of oral clonidine 0.3 mg and oral gabapentin 900 mg as a premedication for attenuation of pressor response to laryngoscopy and endotracheal intubation. Materials and Methods: After obtaining approval from the ethics committee, 75 patients, American Society of Anesthesiologists physical status classes I and II between the ages of 18 and 60 years scheduled to undergo elective noncardiac surgical procedure were enrolled in the study. Patients were randomized into three groups of 25 each who received 0.3 mg clonidine, 900 mg gabapentin, and placebo. The hemodynamic parameters were recorded at various time intervals along with any adverse effects. Statistical Analysis: Quantitative variables were compared using unpaired t-test between the two groups and ANOVA for three groups. Qualitative variables were compared using the Chi-square test/Fisher's exact test. P < 0.05 was considered statistically significant. Results: In our study, we found that both clonidine and gabapentin are effective premedicants by oral route 2 h before induction of anesthesia to blunt the hemodynamic response to laryngoscopy and intubation as compared to placebo. Between clonidine and gabapentin, clonidine was found to be more effective with respect to blunting of systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP), although found to be statistically significant only at 15 min with respect to SBP and DBP. Conclusion: Using clonidine or gabapentin, one can effectively provide stable hemodynamic conditions during laryngoscopy and endotracheal intubation, but more so with clonidine.
Keywords: Clonidine, endotracheal intubation, gabapentin, hemodynamic changes, pressor response to laryngoscopy
|How to cite this article:|
Sharma V, Fotedar K, Goel R. Comparison of oral clonidine and gabapentin premedication for attenuation of pressor response to laryngoscopy and endotracheal intubation. Anesth Essays Res 2020;14:412-9
|How to cite this URL:|
Sharma V, Fotedar K, Goel R. Comparison of oral clonidine and gabapentin premedication for attenuation of pressor response to laryngoscopy and endotracheal intubation. Anesth Essays Res [serial online] 2020 [cited 2021 Apr 20];14:412-9. Available from: https://www.aeronline.org/text.asp?2020/14/3/412/311712
| Introduction|| |
During the administration of general anesthesia, direct laryngoscopy and endotracheal intubation cause an increase in heart rate (HR), arterial pressure, and dysrhythmias in upto 90% of patients because of afferent stimulation of the vagus and sympathoadrenal response. These changes can be particularly hazardous for patients with cerebral or coronary diseases. Tachycardia and hypertension resulting from laryngoscopy and endotracheal intubation may lead to myocardial ischemia and prolonged regional myocardial dysfunction in patients with reduced coronary vascular reserve. These changes are also serious in patients of raised intracranial pressure, intracranial aneurysm, and open eye injury.
Various pharmacological and nonpharmacological methods have been investigated to solve this problem of pressor response.
Nonpharmacological methods include using supraglottic airway devices, McCoy blade, styletscope, and performing brisk and gentle laryngoscopy. Pharmacological methods include deepening plane of anesthesia, omitting cholinergic premedication, pretreatment with lidocaine (oropharyngeal/laryngotracheal/intravenous [i.v.]), vasodilators (nitroglycerine/sodium nitroprusside), beta-adrenergic blockers (esmolol), calcium channel blockers (verapamil/diltiazem), opioids (fentanyl/sufentanil/alfentanil), alpha-2 agonists (clonidine/dexmedetomidine), ACE inhibitors (captopril), GABA mimetics (gabapentin/pregabalin). Remifentanyl, a short-acting opioid, can attenuate the pressor response to the laryngoscopy but it causes bradycardia and hypotension. Also, it needs continuous infusion for providing its effect. Remifentanyl is an expensive drug. These disadvantages are not accompanied when using clonidine or gabapentin.,
Clonidine, the prototypical drug of α2 agonist group, is a selective partial agonist for α2-adrenoreceptors, with a ratio of approximately 200: 1 (α2 to α1). Its antihypertensive effects are caused by central and peripheral attenuation of sympathetic outflow and central activation of noradrenergic imidazoline preferring receptors. It has been shown to suppress central noradrenergic hyperactivity induced by immobilization stress in animals, to decrease the MAC of halothane and the dose of narcotics required to prevent reflex cardiovascular response to laryngoscopy and endotracheal intubation, and to have potent analgesic properties in humans. These characteristics suggest that clonidine might be a useful adjunct to the anesthetic management of patients with preexisting hypertension. Although dose-dependent adverse effects such as hypotension and sedation and idiosyncratic adverse effects such as bradycardia do occur, clonidine does not induce profound respiratory depression and only mildly potentiates opiate-induced respiratory depression., Clonidine, an α2 adrenoreceptor agonist has antihypertensive, sedative, and analgesic effects. The present study is being done to investigate the effectiveness of oral clonidine premedication for attenuation of hemodynamic responses to laryngoscopy and intubation.
Gabapentin, a structural analog of γ-aminobutyric acid, is used as an anticonvulsant drug. Pretreatment with gabapentin can prevent the development of hyperalgesia. Also, gabapentin has a selective effect on the nociceptive process relating central sensitization. Memiş et al. showed that oral administration of gabapentin 800 mg 1 h before induction of anesthesia can attenuate the pressor response to the laryngoscopy and tracheal intubation. Gabapentin is a relatively new drug, which was introduced as antiepileptic but proved to be effective in controlling neuropathic pain. The drug is well tolerated with limited side-effects, as compared with older antiepileptics such as carbamazepine. More recently, gabapentin has been used in randomized controlled trials to treat acute postoperative pain and to reduce postoperative opioid requirements. In addition, it has been shown to be effective in neuropathic pain, diabetic neuropathy, postherpetic neuralgia, and reflex sympathetic dystrophy.,,, Recently, gabapentin was effectively used to attenuate hemodynamic response to laryngoscopy and tracheal intubation, (Fassoulaki et al., 2006; Memis et al., 2006; Kaya et al., 2008). While performing these studies with gabapentin, workers noticed that some patients were hemodynamically stable.
Also, Nishikawa et al. showed that clonidine 4 μg.kg−1, a direct-acting α2 adrenergic agonist, could attenuate blunted catecholamine release and the pressor responses following laryngoscopy and tracheal intubation. Montazeri et al., compared the efficacy of oral clonidine and gabapentin premedication in attenuating the pressor response to laryngoscopy and intubation and found both of them to be equally effective. Marashi et al., also compared oral clonidine and gabapentin premedication and found gabapentin to be more effective than clonidine.
Few data are available comparing the efficacy of gabapentin or clonidine in controlling hemodynamic response throughout the peri-intubation period. We, therefore, conducted this randomized study to compare any possible blunting of cardiovascular effects of laryngoscopy and tracheal intubation by the use of 900 mg gabapentin or 0.3 mg clonidine in comparison with groups that didn't receive any of the above two drugs.
| Materials and Methods|| |
This prospective, randomized, placebo-controlled study was conducted following approval by Hospital Ethics Committee. Seventy-five patients, American Society of Anesthesiologists physical status classes I and II between the ages of 18 and 60 years scheduled to undergo elective noncardiac surgical procedures were enrolled in the study after exclusion criteria have been met and written informed consent obtained. Each patient was examined in the preanesthetic checkup clinic. A detailed history was taken and a thorough physical examination was performed. All patients were kept fasting overnight or a minimum of 6 h. They received oral ranitidine 300 mg, oral tablet alprazolam 0.5 mg at 10 pm the night before surgery. The patients were randomly allocated into three groups of 25 patients each.
- Group C (clonidine) - all patients were given oral clonidine 300 μg 120 min before induction of anesthesia
- Group P (placebo) - all patients were given placebo as oral medication 120 min before induction of anesthesia
- Group G (gabapentin) - all patients were given oral gabapentin 900 mg 120 min before induction of anesthesia.
Preoperative vitals like HR, systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial blood pressure were recorded. Overnight fasting was corrected by i.v. crystalloids before induction at 1 mL.kg−1.h−1 after inserting an i.v. line in the preoperative room. In the operating room, standard monitoring electrocardiography (ECG), noninvasive blood pressure, and SpO2 were established, and then baseline HR and blood pressure were recorded. Preinduction, midazolam 0.02 mg.kg−1 intravenously, ranitidine 50 mg i.v., metoclopramide 10 mg i.v., and fentanyl 3 μg.kg−1 i.v. were given.
After preoxygenation, induction with thiopentone 5 mg.kg−1 intravenously was done with endpoint as loss of eyelash reflex. Ability to mask ventilation was checked. After this, injection atracurium besylate 0.6 mg.kg−1 was administered. After ventilation by face mask with 50% N2O and 50% O2 and isoflurane (1 MAC) using a closed circuit for 3 min after injection of atracurium besylate, laryngoscopy was performed and tracheal intubation was done using a cuffed endotracheal tube of appropriate size by an experienced anesthetist. The tracheal cuff was inflated to prevent audible air leak and the endotracheal tube was fixed after confirming the tracheal position of the endotracheal tube by auscultation with a stethoscope and examining the capnograph. All patients were ventilated with 50% N2O + 50% O2 and isoflurane titrated to the MAC of 1.3 for maintenance and the hemodynamic parameters HR, SBP, DBP, mean arterial pressure (MAP) were recorded at intubation and 1, 3, 5, 10 and 15 min after intubation. The patient's lungs were mechanically ventilated to maintain normocarbia (CO2 between 36 and 44 mmHg).
Intraoperatively, multimodal analgesia was given with tramadol 2 mg.kg−1 i.v., 1 g paracetamol i.v. and 75 mg diclofenac IM and supplementing fentanyl 1 μg.kg−1 i.v. after every 45 min.
i.v. crystalloid administration was done for preoperative fluid deficits, maintenance requirement, and ongoing losses if any, according to the 4:2:1 formula. Supplemental neuromuscular blockade was achieved with atracurium besylate 0.12 mg.kg−1 i.v. following assessment of neuromuscular function with train-of-four (TOF) monitoring. The neuromuscular blockade was monitored by TOF stimulation by visual and tactile feel. Residual neuromuscular block was antagonized with neostigmine 0.05 mg.kg−1 and glycopyrrolate 0.01 mg.kg−1 i.v. and patient's trachea was extubated. After shifting the patient to the postoperative care unit, the patient's vitals were monitored and any postoperative nausea vomiting was observed for and treated appropriately with injection ondansetron 4 mg i.v. and if not controlled, then injection dexamethasone 4 mg i.v. was given. Measures to avoid shivering were taken. Postoperative pain was assessed by visual analog scale and treated with narcotics and nonsteroidal anti-inflammatory drugs. Side effects of clonidine like hypotension, nausea, vomiting, and dysrhythmias were observed and noted. Side effects of gabapentin like dizziness, somnolence, nausea, and ataxia were observed and noted. Sedation was scored by Ramsay sedation score which is as follows.
Ramsay sedation score
Significant hemodynamic events were defined as follows
- Tachycardia: HR >100 beats/min or 30% above baseline
- Bradycardia: HR <60 beats/min HR <45 beats/min was treated with atropine 0.6 mg intravenously
- Hypertension: increase in SBP >20% of baseline and was treated by appropriate measures (increasing the inhaled concentration of isoflurane in the inspired gas mixture, supplementation with injection fentanyl 1 μg.kg−1. Any sustained and persistent hypertension was treated with beta-blockers like esmolol or vasodilator like nitroglycerine
- Hypotension: decrease in SBP <20% of baseline and was treated by appropriate measures (decreasing the inhaled concentration of isoflurane in the inspired gas mixture, rapid infusion of crystalloid fluids. Persistent hypotension was treated by bolus doses of ephedrine/mephentermine 6 mg intravenously.
| Results|| |
Data from 75 patients were analyzed. Patients in the three groups were comparable with respect to the baseline demographic characteristics as depicted in [Table 1]. By using ANOVA for 3 groups and independent sample t-test for 2 groups, P > 0.05, therefore there was no significant difference between group clonidine, gabapentin, and placebo with respect to age (years), weight (kg), and sex distribution (female/male). Also, a comparison of the types of surgeries performed in the three groups is depicted in [Table 2].
|Table 1: Comparison of demographic data in groups clonidine, gabapentin, and placebo|
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The results of our study showed that both clonidine and gabapentin reduced HR, SBP, DBP, and MAP for the study period i.e., from induction to 15 min postintubation.
As compared to clonidine, gabapentin reduced HR (decreased more with gabapentin at 1, 3, 5.10 min after intubation, but statistically not significant) as shown in [Table 3] and [Figure 1]. DBP (decreased more with clonidine at 1, 5, 10, 15 min but statistically significant only at 15 min) as shown in [Table 4] and [Figure 2], SBP (decreased more with clonidine at 1, 3, 5, 10, 15 min but statistically significant only at 15 min) as shown in [Table 5] and [Figure 3], MAP (decreased more with clonidine at 1, 5, 10, 15 min but statistically not significant at any time) as shown in [Table 6] and [Figure 4].
|Table 3: Comparison of heart rate in groups clonidine, gabapentin, and placebo|
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|Table 4: Comparison of diastolic blood pressure in groups clonidine, gabapentin, and placebo|
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|Table 5: Comparison of systolic blood pressure in groups clonidine, gabapentin, and placebo|
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|Table 6: Comparison of mean arterial pressure in groups clonidine, gabapentin, and placebo|
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Compared with placebo, gabapentin reduced HR, SBP, DBP, and MBP for the study period i.e., from induction to 15 min postintubation. HR (decreased with gabapentin and statistically significant at 1, 5, 10, 15 min after intubation) as shown in [Table 3], DBP (decreased more with gabapentin at all times but statistically not significant at any time) as shown in [Table 4], SBP (decreased more with gabapentin at all times but statistically not significant at any time) as shown in [Table 5], MAP (decreased more with gabapentin at all times but statistically significant only at 3, 10 min) as shown in [Table 6].
Compared with placebo, clonidine reduced HR, SBP, DBP, and MBP for the study period i.e., from induction to 15 min postintubation. HR (decreased more with clonidine at all times, statistically significant at 1, 5, 10, 15 min) as shown in [Table 3], DBP (decreased more with clonidine at all times, statistically significant at 1, 10, 15 min) as shown in [Table 4], SBP (decreased more with clonidine at all times, statistically significant at all times) as shown in [Table 5], MAP (decreased more with clonidine at all times, but statistically significant only at 1, 10, 15 min) as shown in [Table 6].
There were no cases of bradycardia, tachycardia, arrhythmias, ST-segment, or other ECG changes noted throughout the study as depicted in [Table 7].
|Table 7: Comparison of complications in groups clonidine, gabapentin, and placebo|
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| Discussion|| |
The present study compared the efficacy of oral gabapentin 900 mg and clonidine 0.3 mg administered 120 min before induction of anesthesia for controlling cardiovascular responses to laryngoscopy and tracheal intubation.
Direct laryngoscopy and endotracheal intubation lead to increasing blood pressure and HR. Mechanism of cardiovascular response to intubation is considered to be a reflex sympathetic response to the mechanical stimulation of the larynx and trachea. Significant increase in serum levels of norepinephrine and epinephrine subsequent to laryngoscopy with and without tracheal intubation have been described.,, Various anesthetic methods and drugs are used for controlling the hemodynamic response to the laryngoscopy and intubation. The technique or drug of choice depends on the necessity and duration of operation, choice of the anesthetic technique, route of administration, and medical condition of the patient.,
Our results show that with respect to decrease in HR, clonidine is more effective than placebo at all times which is statistically significant at 1, 5, 10, 15 min but less effective than gabapentin at 1, 3, 5, 10 min and better at 15 min which is statistically not significant at any time. Also, gabapentin is better at all times as compared to placebo which is statistically significant at 1, 5, 10, 15 min. With respect to decrease in SBP, clonidine is more effective than placebo at all times which is statistically significant too and also, better than gabapentin at all times but statistically significant only at 15 min. Also, gabapentin is better at all times as compared to placebo which is statistically not significant at any time. With respect to decrease in DBP, clonidine is more effective than placebo at all times but statistically significant only at 1, 10, 15 min and also, better than gabapentin at all times but statistically significant only at 15 min. Also, gabapentin is better at all times as compared to placebo which is statistically not significant at any time. With respect to decrease in MAP, clonidine is more effective than placebo at all times but statistically significant only at 1, 10, 15 min and also, better than gabapentin at 1, 5, 10, 15 min but statistically not significant at any time. Also, gabapentin is better at all times as compared to placebo but statistically significant only at 3, 10 min.
The results of our study were not in agreement with the results of studies by Fassoulaki et al., Tsuchiya et al. and Kaya et al. as far as the effect of gabapentin on change in HR is concerned. Fassoulaki et al. showed that pretreatment with gabapentin 1600 mg at 6 hourly intervals starting the day (noon) before surgery attenuates the pressor response to laryngoscopy and intubation of the trachea. They emphasized that gabapentin had no effect on the changes in HR. They induced anesthesia with propofol, which produces bradycardia. Therefore, tachycardia resulting from intubation may have been attenuated by propofol in both groups concealing such a possible effect of gabapentin on the HR. Tsuchiya et al. showed that induction of anesthesia with thiopental increased HR due to reducing cardiac parasympathetic tone. It is possible that tachycardia induced by thiopental inhibited the beneficial effect of gabapentin on HR. This is also in agreement with Kaya et al. study that reported gabapentin blocked the increase in the MAP but not the HR associated with tracheal intubation.
In our study, gabapentin had a significant effect on the changes in HR. We used thiopental for induction of anesthesia. This is probably because we used co-induction with fentanyl and midazolam in our study in all three groups which is not the case with other studies. Also, in our study, in the placebo group, there was no effect on HR, so the decrease in HR can be attributed to gabapentin. In our study, none of the patients had hypotension before induction of anesthesia. Also, none of the patients in Group G or Group C exhibited severe hypotension compared with the control group. Consistent with our study protocol during the induction period, we had to administer ephedrine if systolic arterial pressure (SAP) remained less than 20% from baseline. Nonetheless, none of our patients needed active treatment for hypotension during the study period. These data documented the safety of gabapentin administration. The mechanism by which gabapentin attenuates the pressor response to laryngoscopy and intubation is unidentified. The drug inhibits membrane voltage-gated calcium channels, therefore acting in a manner like calcium channel blockers.
As far as clonidine is concerned, the results of our study are in agreement with the results of studies by Ghignone et al., Raval and Mehta, and Engelman et al.
In our study, premedication with clonidine 0.3 mg administered 120 min prior to surgery significantly reduced HR, diastolic arterial pressure (DAP), SAP, MAP changes for 15 min after endotracheal intubation. Our data confirmed the results of the above studies that HR, SAP, DAP, MAP significantly differ with regard to groups and to times. The risk of undesirable side effects is very important in evaluating the overall safety of preanesthetic medication. The potentially beneficial effect of α2 agonists may be counteracted by bradycardia and hypotension. Our data showed that hypotension may be expected. This hypotensive effect has been described in other investigations in which clonidine was used either in its i.v. form or as an oral dose of 4 or 5 μg.kg-1. In our study, nevertheless, hypotension occurred in 2 patients only after the induction of anesthesia in spine surgeries when the patient was turned lateral. This finding is in agreement with a previous study in elderly patients undertaking ophthalmic surgery under local anesthesia, in which 30% of the patients premedicated with 300 μg clonidine, but no patient in the other groups (150 μg clonidine or placebo), were treated at least once for hypotension. Another author has also described severe hypotensive episodes in at least 10% of patients premedicated with 300 μg of clonidine. The above-mentioned studies together with the results of our study advocate caution in the use of clonidine 300 μg as a general premedicant. We preferred a dose of 4 μg.kg−1 clonidine in the present study because previous studies showed that administration of 4 μg.kg−1 clonidine blunted catecholamine release during intubation and surgery and that larger clonidine doses were not more effective. Smaller doses, nevertheless, were not adequate to blunt the reaction to laryngoscopy. Additionally, the maximum dose of clonidine is limited by its action on peripheral α-adrenoceptors. Larger doses might cause peripheral α stimulation, which could result in an increase in blood pressure. In most human researches, 4 μg.kg−1 clonidine was applied without signs of peripheral α stimulation. Some mechanisms by which clonidine blunt the HR and blood pressure response to the instrumentation of the airway have been proposed. Activation of central α2-adrenoceptors, which causes both a decrease in peripheral sympathetic tone and an increase in vagally induced reflex bradycardia, and stimulation of peripheral presynaptic α-adrenoceptors, which leads to the diminished release of norepinephrine from the nerve endings toward the vasculature and to a reduction in peripheral sympathetic tone, are amongst probable explanations.
When we compared the effects of oral clonidine and gabapentin premedication for attenuation of pressor response to laryngoscopy and intubation in our study, we found almost comparable efficacy of oral clonidine and gabapentin in attenuating pressor response to laryngoscopy and intubation, but more so with clonidine. Also, a study by Seyed et al., showed almost comparable efficacy of oral clonidine and gabapentin in attenuating pressor response to laryngoscopy and intubation, more so with gabapentin. Our results vary with the above study probably because we used 0.3 mg of clonidine and Seyed et al., used 0.2 mg of clonidine. Also, the mean weight in our study (in Group C -58.48 kg, in Group G - 60.52 kg) was less as compared to the study by Seyed et al. (in Group C - 67.88 kg, in Group G - 71.32 kg). So, per kilogram body weight, the dose used in our study was higher which might have accounted for the above difference.
We did not quantify stress mediators such as endogenous plasma catecholamines or cortisone. These can be regarded as limitations of our study. We studied patients up to 60 years as elderly patients take more often drugs such as antidepressants, hypnotics, and antihypertensives. Older patients also demonstrate increased sensitivity to drugs and the cardiovascular effects of gabapentin were not investigated extensively. Elderly patients should be included in a different group for the study where doses of gabapentin should be adjusted according to age. Accordingly, its optimal dosing and side effects for the older population require more study before planning a similar study.
The advantages of using gabapentin or clonidine premedication for attenuation of cardiovascular responses to the laryngoscopy are easy administration, no significant side effects, and availability with low price. Also, both drugs have antinociceptive effects that may be beneficial for controlling postoperative pain.
Our study showed that oral gabapentin 900 mg or clonidine 0.3 mg, given 2 h before the operation, comparably blunted the pressor response to laryngoscopy and endotracheal intubation, but more so with clonidine.
| Conclusion|| |
We conclude that both clonidine and gabapentin are effective premedicants by oral route 2 h before induction of anesthesia to blunt the hemodynamic response to laryngoscopy and intubation as compared to placebo and by using clonidine or gabapentin to manipulate central monoaminergic pathways that are involved in the sympathetic response to noxious stimuli, one can effectively provide stable hemodynamic conditions during laryngoscopy and endotracheal intubation, but more so with clonidine.
Financial support and sponsorship
This study was financially supported by senior faculty.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]