A new treatment option for hemodynamic stability during general anesthesia
A prospective study

Background
Hemodynamic responses of laryngoscopy, intubation, and pain are powerful noxious stimulus which should be attenuated by the appropriate premedication, smooth induction, and rapid intubation.
Context
The oral pregabalin may attenuate the hemodynamic pressor response with intraoperative hemodynamic stability.
Aims
The present study was designed to evaluate the clinical efficacy and safety of oral pregabalin for hemodynamic stability.
Settings and Designs
This is a prospective blind randomized controlled cohort observation study.
Materials and Methods
The 80 adult consented patients of ASA grade I and II of either gender aged 24–54 years who met the inclusion criteria were randomized to receive oral pregabalin 150 mg or placebo capsule, given 60–75 min before surgery. Patients were premedicated with metoclopramide (10 mg), glycopyrrolate (0.2 mg), and fentanyl (1 μg/kg). Anesthesia was induced with propofol and rocuronium and maintained with isoflurane, nitrous oxide, and oxygen. Both groups were assessed for preoperative sedation and changes in heart rate and mean arterial blood pressure before and after the induction and 1, 3, 5, and 10 min after laryngoscopy and intubation, then at 5 min intervals till end of surgery along with postoperative complications.
Statistical Analysis
The hemodynamic variables were analyzed by using analysis of variance (ANOVA), Student’s t test, and chi square test as appropriate.

Results
Preoperative sedation was higher with pregabalin with no significant change in heart rate. The mean arterial pressure was attenuated with oral pregabalin to statistically significant value (P<0.007). The requirement of analgesic drug was reduced with no postoperative respiratory depression, nausea, or vomiting and hemodynamic parameters remained stabilized perioperatively.
Conclusions
Oral pregabalin premedication effectively leads to sedation and analgesia with successful attenuation of the adverse and deleterious hemodynamic pressor response.
INTRODUCTION
Direct laryngoscopy and tracheal intubation predictably leads to tachycardia and hypertension which are usually transient and variable. Usually these changes are well-tolerated by healthy individuals, but may be fatal in patients with hypertension and coronary artery disease. The appropriate premedication, smooth induction, and rapid intubation would prevent the associated risk and complication of the hemodynamic pressor responses. These hemodynamic pressor responses may be attenuated by pharmacological methods. Many pharmacological techniques were evaluated either in the premedication or during induction to attenuate the adverse hemodynamic response to laryngoscopy, such as deepening the anesthesia, pretreatment with vasodilators, adrenorecepter blockers, calcium channel blocker, and opioids but with variable results.

More recently antiepileptic drugs have been used for the treatment of acute postoperative pain and to reduce the postoperative opioid requirements. Pregabalin is effective in preventing neuropathic component of acute nociceptive pain of surgery. It is well-absorbed after oral administration and well-tolerated with limited side effects. It has no known clinically relevant drug interactions. Pregabalin undergoes negligible hepatic metabolism and eliminated by renal excretion. It is non-narcotic with clinically important reduction in pain.

The present study was designed as a prospective blind randomized controlled study to find out the efficacy of oral premedication with pregabalin on sedation and changes in mean arterial blood pressure and heart rate observed during laryngoscopy and intubation along with perioperative hemodynamic stability.

Materials & Methods
The study protocol was approved by the Ethical Committee of Institution. This prospective blind randomized control study consisted of eighty normotensive adult consented patients aged 24–56 years of both gender with ASA physical status I and II, scheduled for elective surgery under general anesthesia from September 2009 to August 2010. Patients with anticipated difficult intubation, history of cardiac, pulmonary, or renal disease, and allergy to any anesthetic medication were excluded from the study. Patients with body weight more than 20% of the ideal body weight, and taking antihypertensive drugs, sedatives, hypnotics, and antidepressants, were also excluded from the study. When duration of laryngoscopy exceeded 25 sec or second attempt for intubation was needed, those patients were also excluded from the study. None of the patients had previous experience with general anesthesia.

Randomization and treatment
Eighty healthy adult patients were randomly assigned to one of the two treatment groups of 40 patients each. Control group I received placebo capsule and Group II received pregabalin 150 mg, given orally with sips of water about 60–75 min before induction of general anesthesia. Group allocations were done by an anesthetist who was unaware of the study protocol and was not involved in the study.

Anesthetic technique
On arrival in the operating room, monitors were attached and baseline heart rate, systolic, diastolic and mean arterial blood pressure, pulse oximetry, and ECG were recorded. Preoperative level of sedation was assessed by Ramsay sedation score: 1=anxious, agitated, or restless; 2=co-operative, oriented, and tranquil; 3=respond to command; 4=asleep with brisk response to stimulus; 5=asleep with sluggish response to stimulus; and 6=asleep with no response.

A crystalloid intravenous infusion of 6–8 ml/kg was started and patients were premedicated with metoclopramide (10 mg), glycopyrrolate (0.2 mg), and fentanyl (1 μg/kg). After 3 min of preoxygenation, anesthesia was induced with propofol (2 mg/kg) in a dose sufficient to abolish the eyelash reflex. The laryngoscopy and intubation was facilitated with rocuronium 0.8 mg/kg, and of minimum possible duration. It was being similar to all patients. Anesthesia was maintained with MAC of 0.8% isoflurane, nitrous oxide 60% in oxygen. The patients were mechanically ventilated to maintain the normocapnia (CO2 between 35–40 mm Hg). Supplemental neuromuscular blockade was achieved with rocuronium 0.1 mg/kg. At the end of surgery, the residual neuromuscular block was antagonized with appropriate doses of neostigmine (0.05 mg/kg) and glycopyrrolate (0.01 mg/kg) and the extubation was performed when respiration was adequate.

The heart rate, mean arterial blood pressure, ECG, SpO2, and EtCO2 levels were continuously monitored and recorded before and after induction, immediately after intubation and cuff inflation and 1, 3, 5, and 10 min, thereafter at every 5 min intervals till end of surgery. Patients were observed for complications like hypotension, hypertension, arrhythmias, hypoxemia, and bronchospam.
Postoperative follow-up
The patients were transferred to postanesthesia care unit and monitored until there was no signs of any drug-induced effects. Any side effects were noted and treated as required. The need for postoperative opioid analgesic medication and incidence of nausea and vomiting along with requirement for rescue antiemetic were also noted.
Study population size
Preliminary sample size was decided in consultation with statistician and was based on initial pilot observations, indicated that approximately 20–23 patients should be included in each group in order to ensure power 0.80 for detecting clinically meaningful reduction by 10–20% in heart rate and mean arterial blood pressure. Assuming a 5% dropout rate, the final sample size was set at 80 patients.

Statistics
The results obtained in the study are presented in tabulated manner and analyzed using Microsoft Excel, and SPSS software for windows. Hemodynamic variables were represented by mean±SD. Statistical significance in mean difference was done by using analysis of variance (ANOVA), Student’s t test, and chi square test as appropriate. A P value of <0.05 was considered significant and <0.001 as highly significant.

Results
Eighty patients, 40 in each group, were evaluated. Both groups were comparable with respect to the demographic and operational factors. No significant differences were found between groups with respect to age, sex, weight, time between oral premedication of pregabalin administration to anesthetic induction, duration of laryngoscopy, and surgical procedure time. Duration of anesthesia did not differ among the study groups.(table-1)

Table1: Demographic profile, duration of laryngoscopy, and types of surgery.

Preoperative sedation level
The degree of sedation before premedication was comparable between the groups. A clear increase in sedation was observed with pregabalin as compared to control. Onset of action for level 2 sedation was seen after 15 min in 5(12.5%) patients of pregabalin group while at 60 min 31 (77.5%) patients of group II fell asleep with sluggish response (level 5). Only seven (17.5%) patients have shown level 6 sedation after 75 min of oral premedication [Figure 1].

Figur 1: Onset of different sedation level.

Cardiovascular effects
There was no significant difference in the heart rate and mean arterial blood pressure values in groups before and after premedication. Immediately after induction and laryngoscopy, the heart rate increased significantly in both groups but the increase was less in pregabalin group. Maximum increase in heart rate from baseline was observed after 1 min of laryngoscopy. There was no statistically significant attenuation of heart rate in premedicated group but it remained stabilized in comparison to control group [Table 2].
Table 2: Heart rate changes during laryngoscopy.

No significant difference was observed in the mean arterial pressure (MAP) before and after premedication in both groups. After induction and laryngoscopy, the attenuation of mean arterial blood pressure in premedicated group was statistically significant as to control group [Table 3].
Table 3: Mean arterial blood pressure changes during laryngoscopy.

Intraoperative heart rate and mean arterial blood pressure values were attenuated and remained stabilized to base levels without requirement of any other medication. In the postanesthesia care unit, heart rate and MAP remained at a lower level in premedicated group than in control group.
Anesthetic and analgesic requirements with other intraoperative interventions
Decreased amount of propofol and fentanyl was required for induction in premedicated groups as compared to control group. Intraoperatively, the control group was supplemented by bolus doses of fentanyl (0.5 μg/kg) when there was more than 20% increase in heart rate or mean arterial blood pressure. No analgesic supplement was needed for pregabalin group. Rapid intravenous infusion was needed in five patients of pregabalin group to treat hypotension. None of the patients had persistent or severe hypotension, thus vasoactive drugs were not used.

Recovery and postoperative follow up
There were no differences between both groups with respect to awakening and recovery times. They were well oriented and able to obey commands in the postoperative care unit. Postoperative analgesic need was much less with pregabalin group as compared to control. No significant complication has occurred after use of oral premedication with pregabalin in our study. Postoperative nausea and vomiting were not found in any group during our study.
DISCUSSION
The study evaluated the oral premedication with pregabalin for hemodynamic stability during laryngoscopy and observed the sedative effect of oral pregabalin without any significant respiratory depression. Hemodynamic pressor response was attenuated by pregabalin with minimal effect on heart rate. The increase in hemodynamic values in control group may be due to inadequate sedation and analgesia. Near-stable hemodynamic variables in the present study was an indication of adequate analgesia and sedation with oral pregabalin. In our study we have used oral premedication with pregabalin 150 mg and found it to be effective for perioperative hemodynamic stability. The hemodynamic results of our study were in agreement with recent results with gabapentin. The pregabalin possesses several properties to make it valuable premedicant to attenuate the hemodynamic response of laryngoscopy and intubation.

Reid et al., first described the hemodynamic response to laryngoscopy and intubation, probably due to intense sympathetic discharges caused by stimulation of epipharynx and laryngo-pharynx.[1] Shribman et al. reported that laryngoscopy alone or with tracheal intubation increases arterial blood pressure and catecholamine levels while intubation significantly increases heart rate.[2] Hassan et al., reported high incidences of cardiac arrhythmias, myocardial ischemia, acute left ventricular failure, and cerebrovascular accidents following intubation in hypertensive patients. Hypertension may affect perioperative morbidity through the extent of end organ damage.[3]

Hemodynamic responses to laryngoscopy and laparoscopy should be attenuated due to associated risk of myocardial ischemia or cerebral hemorrhage. If no specific measures are taken to prevent hemodynamic response, the heart rate can increase from 26% to 66% and systemic blood pressure can increased from 36% to 45%, which may be due to variation in balance of sympathetic and parasympathetic outflow or receptor hypersensitivity. These hemodynamic changes can be detrimental in elderly and hemodynamically compromised patients.[4,5] More recently, Aronson and Fontes found that among the various component of blood pressure, preoperative pulse pressure was independently and significantly associated with postoperative stroke, renal failure, and mortality in patients undergoing coronary artery bypass. Rise in pulse pressure as few as 10 mmHg in both normotensive and hypertensive individual is associated with 20% or more increased risk of renal, coronary, and cerebral events.[6]

In order to reduce the incidence and severity of the hemodynamic responses of laryngoscopy and intubation, many pharmacological methods were evaluated either in the premedication or during induction, to attenuate these adverse hemodynamic responses with controversial results. Tachycardia and rhythm disturbances can be attenuated by omitting atropine as premedicants. Intranasal nitroglycerin attenuated the hypertensive response to laryngoscopy and intubation but tachycardia was observed.[7] Many studies have reviewed the impact of different drugs on hypertension following laryngoscopy. The most important were lidocaine, esmolol, sodium nitroprusside, and fentanyl.[8] Intravenous lidocaine prevented the increase in mean arterial blood pressure but had no effect on the heart rate. Among opioids, remifentanil (1 μg/kg), alfentanil (10–20 μg/kg), or fentanyl (0.5–1.0 μg/kg) were reported to have the most stable effect on hemodynamic response to laryngoscopy and tracheal intubation but they prolonged the recovery time.[9]

When assessing techniques to lessen the cardiovascular responses to intubation, the induction agents may influence the results. We induce anesthesia with propofol, which produces bradycardia. Thus tachycardia resulting from intubation may have been attenuated by propofol in both groups. Beside, propofol produces hypotension more than thiopental and bradycardia, which may compensate in part the cardiovascular changes attributable to laryngoscopy and tracheal intubation.

More recently antiepileptic drugs have been used for the treatment of acute postoperative pain and to reduce the postoperative opioid requirements.[10] While using pregabalin as adjuvant to prevent acute and chronic postoperative pain, we investigated whether the same pretreatment may attenuate the hemodynamic response to intubation and laryngoscopy. Pregabalin, an antiepileptic drug, is effective in controlling neuropathic component of acute nociceptive pain of surgery by inhibiting membrane voltage-gated calcium channels, thus reducing the release of several neurotransmitters including glutamate, nor adrenaline and substance P. It does not interact with GABA receptors. However, only few data are available in the literature regarding the effect of pregabalin on the cardiovascular system. Its analgesic and anticonvulsant activity make it a useful oral premedicant.[11] Salivary and tracheobronchial mucus secretions necessitate prophylactic administration of an antisialagogue agent. Glycopyrrolate, which does not penetrate the blood-brain barrier, was the rational choice.

The incidence of nausea and vomiting after general anesthesia has been reported to be as high as 24%. Metoclopramide has been shown to be an effective and safe antiemetic for both prevention and treatment of postoperative nausea and vomiting. Intravenous antiemetic such as ondansetron, often with dexamethasone, may be given during surgery.[12] In the present study, the metoclopramide was used as it acts both centrally and peripherally, speeds gastric emptying time, and increases the tone of the lower esophageal sphincter. Postoperative nausea and vomiting were not found in any group of our study.

We studied patients up to 59 years as elderly patients take drugs more often such as antidepressants, hypnotics, and antihypertensive with increased sensitivity to drug. The safety and effectiveness of pregabalin in pediatric patients below the age of 12 years and adolescents has not been established.

Preincisional analgesia has been shown to be more effective in control of postoperative pain by protecting the central nervous system from deleterious effects of noxious stimuli and resulting allodynia and increased pain. Pregabalin has antiallodynic and antihyperalgesic properties useful for treating neuropathic pain and may also be beneficial in acute postoperative pain.[13]

To our knowledge no randomized controlled study has been done to evaluate the hemodynamic response after oral pregabalin premedication during laryngoscopy and intubation. Several studies have reported the usefulness of pregabalin as postoperative analgesic with higher patient satisfaction. In our study, oral premedication with pregabalin has been found effective for attenuation of laryngoscopy and intubation pressor response with perioperative hemodynamic stability. No arrhythmia, myocardial ischemia, or any other complication was observed in any group of our study. Within the context of an integrated approach, attempts have been recently made to introduce adjuvant with the intention to facilitate early recovery with decreased side effects related to opioids. Further studies are needed to determine the long-term benefits.

CONCLUSION
Pregabalin is emerging as an effective oral premedication drug with safe and multimodal drug profile as it causes sedation and analgesia with successful attenuation of the adverse and deleterious hemodynamic stress response of laryngoscopy and intubation. It has shown efficacy in decreasing the perioperative analgesic requirement. Its hemodynamic stability may be beneficial in obese, hypertensive, and cardiac compromised patients. As there was no postoperative respiratory depression, it may be used in asthmatic and compromised airway patients.

Footnotes
Source of Support: Nil
Conflict of Interest: None declared.

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Abstract