European Journal of Cardiovascular Medicine

Laryngoscopy and endotracheal intubation, performed to secure the airway and administer anaesthetic agents during general anaesthesia, are two frequently encountered stimuli that elicit temporary increases in haemodynamic stress responses.1 Patients having procedures with general anaesthesia have several reflex reactions that contribute to deviations from their baseline haemodynamics.2

The reflex responses result from an increased normal physiological reaction of the autonomic system to stimuli. This covers both parasympathetic reflexes and the overall impact of the sympathetic nervous system. However, parasympathetic responses are more prevalent in the juvenile population than in adults.3 Sympathetic system responses predominate in adults. These reflexes induce diverse problems in human haemodynamics through excessive stimulation of the sympathetic system, frequently resulting in hypertension and tachycardia. These will contribute to perioperative mortality and morbidity in high-risk populations.4

Anaesthesiologists play an essential role in reducing these undesirable stress reactions in order to avoid negative outcomes and lower the associated mortality and morbidity.5 since so many years ago, a great number of approaches and alternatives have been investigated and tested in order to alleviate the stress reaction that is associated with laryngoscopy and intubation.6

Medications from several classifications have been administered to mitigate stress responses. Each of them possesses a distinctive mode of action for mitigating the stress response and has distinct side effects. It is important to take into consideration the features of the patient at the time of medicine selection.7

Clonidine belongs to the class of alpha-2 adrenergic agonists; it was first formulated as a nasal decongestant in the 1960s because of its vasoconstrictive properties, with its central nervous system effects identified subsequently.8 Its antihypertensive impact can be explained by its effect on presynaptic alpha 2 receptors in the brain stem. This action reduces the outflow of central sympathetic nerves, which is the logic behind its utilisation in the process of blunting the intubation and stress response. It also demonstrates activity on peripheral nerve terminals.9

Pregabalin is a unique member of the non-opioid GABA analogues class, exhibiting a pharmacological profile akin to gabapentin, and was approved for medical use by the US Food and Drug Administration (FDA) in December 2004.10 It was previously utilised for the management of neuropathic pain in diabetic peripheral neuropathy. Pregabalin is utilised to mitigate perioperative stress reflexes by altering different excitatory neurotransmitters, including noradrenaline, substance P, glutamate, serotonin, and dopamine, in specific regions of cortical neurones.11

The purpose of this study is to evaluate the efficacy of the two distinct medications stated above in reducing the occurrence of haemodynamic stress reflexes during endotracheal intubation after rigid direct laryngoscopy in patients who are scheduled to have elective procedures under general anaesthesia.

AIMS AND OBJECTIVES

To compare the effect of oral pregabalin 150 mg and oral clonidine 0.2 mg given 90 minutes before surgery, on haemodynamic stress response resulting from laryngoscopy and endotracheal intubation.

Thiswasatype of prospectiveobservational randomizedcomparativestudy performed at elective major operation theatresby Department of Anaesthesia in Sree Mookambika Institute of Medical Sciences, Kulasekharamforone year from April 2021 to May 2022.

Sample size of 60 patients were enrolled in the study after getting a proper written informed consent from all. Patients who gave proper written consent, of specific age group, 18-55 years of both genders, with functional status American Society of Anaesthesiology (ASA) I and II with modified mallampatti score of 1 and 2 on airway assessment, weighing 50-70kg, undergoing various scheduled elective surgeries in general anaesthesia and oral endotracheal intubation with controlled ventilation were enrolled for this study.

Individuals with a history of pregabalin and clonidine allergies, extreme age groups, ASA class ≥ III, modified Mallampatti scores 3 and 4, obesity or weight greater than 70 kg, emergency surgery patients, pregnant and lactating women, patients with cardiovascular, cerebrovascular, respiratory, hepatic, renal, uncontrolled hypertension, diabetes, alcoholics, patients on psychiatric, sedative, or antiarrhythmic medications, and patients on psychiatric medications were not allowed to participate in the study.

A thorough clinical examination was performed on each patient, which included a general examination, a systemic examination of the cardiovascular, pulmonary, gastrointestinal, and central nervous systems, as well as an assessment of the airway to rule out difficult airways. Prior to surgery, computer-based randomisation was used to divide the 60 patients into two groups, A and B, each with a sample size of 30.

All patients have kept nil per oral for a minimum of eight hours prior to the surgery. Alprazolam 0.25 mg, ranitidine 150 mg, and metoclopramide 10 mg were given to the patients as premedication the night before the procedure and the morning of the procedure. Baseline haemodynamic data, such as heart rate (HR) , systolic blood pressure(SBP), diastolic blood pressure(DBP) and mean arterial blood pressure (MAP) were recorded after verifying that all patient information was accurate and reviewing all investigation findings. Unknown coded single dosage of capsule pregabalin 150 mg and tablet clonidine 0.2 mg had administered approximately 90 minutes previous to the induction period with sips of water was given to group A and group B patients accordingly.

All patients have their IV lines secured and linked to multipara monitors that include capnography for EtCO2, noninvasive blood pressure monitoring for SBP, DBP, and MAP, and pulse oximetry for SpO2.

Subsequently, midazolam at a dosage of 0.02 mg/kg and glycopyrrolate at 0.04 mg/kg were administered intravenously. Subsequently, preoxygenate with 100% oxygen using a suitably sized anatomical face mask for three minutes. Preferred intravenous drugs for induction include propofol at 2.5 mg/kg, fentanyl citrate at 2 mcg/kg, and the non-depolarizing muscle relaxant atracurium besylate at 0.5 mg/kg. HR, SBP, DBP, and MAP were observed and documented immediately upon induction.

A delicate, smooth, and speedy rigid direct laryngoscopy was performed with appropriately sized Macintosh blades, followed by oral endotracheal intubation using a suitably sized, cuffed, PVC disposable endotracheal tube, all completed within 30 seconds. The endotracheal tube was subsequently attached to a mechanical ventilator for controlled positive pressure breathing, with the settings adjusted to sustain normocapnia (EtCO2 35 - 45 mmHg).

Haemodynamic measures, including SBP, DBP, and MAP, were recorded at the moment of intubation (I) and at one (I+1), three (I+3), and five (I+5) minutes post-intubation.

An adequate deeper plane of anaesthesia was achieved utilising inhalational drugs such as sevoflurane at a MAC value of 1-2%, along with a mixture of nitrous oxide and oxygen in proportions of 66% and 33%, respectively. Intraoperatively administered atracurium besylate 0.1 mg/kg IV and fentanyl 0.5 mcg/kg IV at intervals to sustain an appropriate level of anaesthesia. Administered continuously with intravenous crystalloids, specifically Ringer's lactate, for intraoperative fluid management.

At the conclusion of the surgery, patients were detached from the volatile inhalational agent, sevoflurane. Subsequently, the blocking of neuromuscular connections throughout the body, induced by a non-depolarizing drug, was reversed by administering a mixture of neostigmine at 50 mcg/kg and glycopyrrolate at 10 mcg/kg intravenously. Nitrous oxide was ceased, and the FiO2 was increased to 100%. Extubation was performed.

The patients were subsequently transferred to the recovery room and connected to monitoring devices such as ECG, NIBP, pulse oximetry, and temperature sensors. SBP, DBP, MAP, SpO2, temperature, and urine output were monitored and documented postoperatively.

Patients were monitored for haemodynamic instabilities, complications, and symptoms such as discomfort, shivering, nausea, vomiting, severe drowsiness, headache, visual abnormalities, seizures, respiratory distress, or depression for six hours postoperatively.

Statistical Analysis was carried out using SPSS 20.0 version. For all variables mean and standard deviation derived and interpreted usingtwo samples t-test or unpaired t test. For the test to be statistically significant the p value should be less than 0.05.

The age group of the patients in group A ranged from 18 to 55 years with a mean age of 39.63±9.61 years and in group B ranged from 18 to 54 years with mean age of 39.96±10.11years. AmongthepatientsingroupA,12(40%)weremalesand 18 (60%)werefemales while in groupB,21 (70%)weremalesand 9 (30%)werefemales.

In HR variability, patients in the pregabalin group (Group A) demonstrated elevated mean values compared to the clonidine group (Group B). A 9.24% increase from the baseline mean value observed one minute post-intubation. However, the mean HR values of participants in the clonidine group remained on the lower side during induction. A significant decrease of 9.1% from the baseline recorded after induction. Statistically significant p-values less than 0.05 were recorded across all time intervals. (Fig 1)

Fig 1: Comparison of variation in mean HR

The mean SBP of patients in the pregabalin group was consistently greater than that of group B during all post-intubation testing times. The highest mean SBP, exhibiting a departure of +9.86% from baseline, was observed one minute after intubation. The mean SBP in the clonidine group remained consistently lower than the baseline value. The maximum decrease of 15.62% (111.66 mmHg) from baseline was recorded during the 5 minutes following the induction phase. (Fig 2)

Fig 2: Comparison of MeanSBP

Both groups exhibited a declining trend in DBPduring all testing intervals following intubation. A highest decline of 7.85% and 26.06% from baseline mean DBP levels was recorded in groups A and B, respectively. Patients in the clonidine group exhibited the greatest reduction compared to those in the pregabalin group.(Fig 3)

Fig 3: Comparison of MeanDBP

The clonidine group was able to limit the increase in MAP linked to the stress response, whereas the pregabalin group was unable to do so. The pregabalin group was able to reduce the mean MAP by a maximum of 4.15% post-induction from the baseline value, whereas the clonidine group achieved a reduction of up to 21.6% five minutes post-induction from the baseline mean MAP value. (Fig 4)

Fig 4: Comparison of mean of MAP

Among the patients, 67% in the pregabalin group and 70% in the clonidine group tolerated the drugs well with no adverse effects. Thirteen percent of both groups experienced dizziness. (Table 1)

Table 1: Comparison of side effects

This prospective observational comparison study aimed to evaluate the efficacy of oral pregabalin and oral clonidine in mitigating sympathoadrenal reactions triggered during laryngoscopy and endotracheal intubation. Despite numerous studies and experiments conducted over several decades, none have shown to be optimal. Despite conventional stiff direct laryngoscopy and oral endotracheal intubation remaining the prevalent techniques during general anaesthesia, the detrimental consequences of sympathetic stress responses on different systems related to intubation are unavoidable. This needs the development of the optimal strategy for eliminating the pressure response during laryngoscopy and intubation.

The study encompassed two distinct pharmacological groups to examine their effects on stress responses during laryngoscopy and intubation. Each medication possessed a distinct mode of action in reducing sympathetic stress responses. The authors attempted to evaluate which one was more effective in reducing the pressure response.

The study results indicated that the clonidine group effectively reduces key haemodynamic measures of sympathetic stress response, including HR, SBP, DBP, and MAP without any adverse effects. Although the pregabalin group did not outperform the clonidine group, it possesses notable properties for attenuating haemodynamic stress responses. Both groups did not demonstrate any notable adverse effects, except from nausea, vomiting, and dizziness. Previously so many studies found to be done on this same subject using same medications.

Mohanty S et al.¹² conducted a study including 100 ASA (I/II) patients scheduled for elective procedures under general anaesthesia to examine the efficacy of oral clonidine and oral pregabalin in mitigating the stress response associated with laryngoscopy and tracheal intubation. The research indicated that both medications were helpful in mitigating the haemodynamic stress response associated with laryngoscopy and tracheal intubation. Post-operative analgesia was superior in the pregabalin group, while the clonidine group resulted in reduced sedation. A separate study conducted by Mohapatra AK et al.¹³ in 60 patients scheduled for posterior fossa procedures under general anaesthesia revealed analogous results.

Kaur H et al.¹⁴ noted that in the pregabalin group, the mean HR consistently remained below baseline for the majority of time intervals, but exhibited a rise over baseline immediately following intubation (T0i) and one minute post-intubation (T1i), with increases of just 1.488±1.20% and 0.45±1.16%, respectively, above baseline. In both the pregabalin and clonidine cohorts, the mean SBP and mean MAP consistently remained below the baseline value (Tb) across all time intervals from T0.5 to T10i. Both clonidine and pregabalin offered sufficient anxiolysis and drowsiness, with pregabalin demonstrating more significant sedation and anxiolysis compared to clonidine.

Compared to the present study, Suryawanshi et al.¹⁵ reported that the mean HR after one hour of medication administration in the Clonidine group and the Pregabalin group were 58.03±4.94 and 64.13±5.5, respectively (p value <0.05). Following drug delivery, the heart rate in the Clonidine group was considerably lower than that in the Pregabalin group at all intervals. SBP, DBP, and MAP were equivalent at baseline and 30 minutes before to medication delivery. Systolic, diastolic, and mean arterial pressures were significantly elevated in the Clonidine group (p < 0.05).

In a similar study, Prathibha H et al.¹⁶ noted a substantial reduction in HR across all time intervals in the oral clonidine group. The oral pregabalin group shown no significant reduction in the haemodynamic response concerning HR. Clonidine is superior to pregabalin in mitigating unfavourable haemodynamic responses, particularly regarding HR, during direct laryngoscopy and tracheal intubation.

Pal RK et al.¹⁷ performed a study to evaluate the efficacy of oral clonidine (200 mcg) versus oral pregabalin (150 mg) in mitigating the haemodynamic surge response associated with direct laryngoscopy, endotracheal intubation, and pneumoperitoneum in patients scheduled for elective laparoscopic cholecystectomy under general anaesthesia. The research indicated that the HR were markedly reduced in the clonidine group at 1, 2, 3, 4, and 5 minutes post-laryngoscopy and at 15 minutes following pneumoperitoneum. MAP and SBP were markedly reduced in the clonidine cohort at 3, 4, and 5 minutes post-laryngoscopy and intubation. Adverse symptoms such as nausea, vomiting, shivering, and xerostomia were similar between the two groups.

In contrast to the present study, Murari T et al.¹⁸ found no significant difference at baseline in mean (SD) HR, SBP, DBP, and MBP between the two groups (p>0.05). The mean (SD) HR was considerably reduced in group A (clonidine group) compared to group B (pregabalin group) before induction and at 1, 3, 5, 10, and 15 minutes (p < 0.05). The mean (SD) SBP and MBP were considerably lower in group A than in group B before induction, immediately after intubation, and at 1, 3, and 5 minutes (p < 0.05). Bradycardia was more prevalent in the clonidine group, but sedation was more pronounced with pregabalin administration.

Administering 0.2 mg of tablet clonidine and 150 mg of capsule pregabalin 90 minutes prior to general anaesthesia as premedication mitigates the sympathetic stress response during laryngoscopy and intubation. Pregabalin demonstrated a limited attenuating action. Oral clonidine shown superior efficacy as a premedication in reducing elevated HR, SBP, DBP, and MAP during laryngoscopy and intubation for procedures conducted under general anaesthesia, in comparison to oral pregabalin.

FINANCIAL SUPPORT AND SPONSORSHIP: Nil.

CONFLICTS OF INTEREST:

There are no conflicts of interest

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