Perioperative analgesic efficacy of intravenous infusion of preservative-free xylocaine with ketamine or dexmedetomidine as a total opioid-free anesthesia technique

INTRODUCTION

Opioids have been essential components of balanced general anesthesia practice for several decades, enabling anesthesiologists to manage pain, induce sedation, and maintain hemodynamic stability during day surgeries through bolus doses or continuous infusions.^[1] Even with so many advantages of opioids, they produce multiple undesirable side-effects and complications which anesthesiologists encounter in perioperative period such as sedation, vomiting, nausea, urinary retention, ileus, pruritus, confusion, delirium, respiratory distress, and increased morphine consumption, immunosuppression, hyperalgesia, addiction, and abuse.^[2] It leads to undesirable delayed transfer from post-anesthesia care unit, prolonged hospital stay, increased cost of healthcare, and poor patient satisfaction.^[3]

Opioid-free anesthesia/analgesia (OFA) is a multimodal technique that induces anesthesia without the use of perioperative opioids.^[4]

Agents that are more commonly used for multimodal anesthesia include N-Methyl-D-aspartate (NMDA) antagonists such as ketamine, magnesium sulfate, centrally acting alpha 2 agonists- dexmedetomidine, clonidine, non-steroidal anti-inflammatory drugs like Non-steroidal anti-inflammatory drugs, steroids mainly dexamethasone, and local anesthetics – preservative-free xylocaine used as intravenous infusion.^[5,6] Therefore, there is a pressing need to study and evaluate some non-opioid pain medications as part of an OFA technique during elective surgeries, which is integral to an opioid reduction strategy.^[7]

When Xylocaine is used as systemic infusion, it has various non-opioid analgesic properties such as analgesia, anti-hyperalgesia, and anti-inflammation.^[8] It causes blockade of sodium channels and firing of peripheral neurons that are activated by nociceptive stimuli and also inhibits NMDA receptors. Various clinical trials have revealed that infusion of perioperative xylocaine causes a reduction of pain intensity and opioid consumption in the post-surgical period.^[9]

Ketamine prevents postoperative hyperalgesia, and its analgesic effects are mediated at the spinal level. It is characterized by potent analgesic, amnesic, and opioid-free properties. In subclinical doses (doses <0.5 mg/kg), it has good analgesic effects with minimal side effects.^[10,11]

Dexmedetomidine is a highly selective and specific alpha 2 adrenoreceptor agonist with analgesic, sedative, anxiolytic, and sympatholytic properties.^[12] Dexmedetomidine is a centrally acting alpha 2 adrenoreceptor agonist with a good potential for improving analgesia, hemodynamic stability in responses to laryngoscopy and endotracheal intubation. The investigations into the study on dexmedetomidine have shown early recovery after elective surgery, so it is becoming an area of interest in anesthesia practice.^[13]

Hence, this randomized controlled trial was initiated to assess the analgesic requirements postoperatively in adult patients undergoing elective surgeries with preservative-free intravenous infusion of xylocaine and ketamine or dexmedetomidine as a total opioid-free analgesia/anesthesia technique Our hypothesis was that opioid-free anesthesia provided stable hemodynamics, less sedation, and adequate postoperative analgesia and reduced side effects significantly in elective surgeries. The aim of our study was to study the efficacy of infusion of preservative-free xylocaine with ketamine or dexmedetomidine given systemically for intraoperative and postoperative analgesia, and the objectives were to study hemodynamic changes, side effects, and complications of infusion of preservative-free xylocaine, with infusion of ketamine or dexmedetomidine.

MATERIAL AND METHODS

This prospective, randomized, double-blinded, 2 parallel groups clinical trial was conducted at a single tertiary care center. This study was randomized by a computer-generated method. In our study, double-blinding infusion preparation and assessment of Visual Analog Scale (VAS) and Ramsay Sedation score (RSS) were done by an unbiased anesthesiologist not involved in the study, whereas all patients, staff, and involved anesthesiologists were blinded in the whole study. The randomization key was revealed when the study was completed, and then, data were computed.

Exclusion criteria

(i) Non-consenting patients, (ii) patients <18, >70 years, (iii) patients with a history of allergy to any of the study drugs, (iv) prolonged duration surgeries (>1.5 h), (v) body mass index >35kg/m², (vi) history of psychiatric illness and chronic pain, (vii) perioperative anesthetic complications, (viii) loss of follow-up.

In our study, the total number of patients enrolled was 80. The patients were allocated randomly to either of the two groups of 30 each (group I and group II), with the help of computer-generated random number. Figure 1 shows a consort diagram showing enrolment of patients.

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Figure 1:

Consort diagram. ASA: American Society of Anaesthesiologist.

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Groups I: Intravenous infusion of preservative-free xylocaine 1.5 mg/kg/h over 15 min before tracheal intubation and then 0.5 mg/kg/h or titrated as required till the closure of the wound and intravenous infusion of ketamine 0.5 mg/kg over 15 min before tracheal intubation and continued at rate of 0.25 mg/kg/h till 10 min before the closure of wound. Group II: Intravenous infusion of preservative-free xylocaine 1.5 mg/kg/h over 15 min before tracheal intubation and then 0.5 mg/kg/h or titrated as required till the closure of wound and intravenous infusion of dexmedetomidine 0.5 mcg/kg over 15 min before tracheal intubation and continued at rate of 0.2 mcg/kg/h till 10 min before the closure of wound. Table 1 shows the protocol of drug infusion of xylocaine, ketamine, and dexmedetomidine.

Table 1: Table showing group drugs infusion protocol.

Group	Drugs	Start (15 mins before induction)	Intubation	Maintenance (Post intubation)	Stoppage of infusion
I	Xylocaine	1.5 mg/kg	Standard GA techniques, except opioids	0.5 mg/kg/hr.	Skin closure
	Ketamine	0.5 mg/kg		0.25 mg/kg/hr.	10 mins before wound closure
II	Xylocaine	1.5 mg/kg		0.5 mg/kg/hr.	Skin closure
	Dexmedetomidine	0.5 mcg/kg		0.2 mcg/kg/hr.	10 mins before wound closure

GA: General anaesthesia

RESULTS

Eighty patients were evaluated for eligibility. After exclusion of unsuitable patients, the remaining 66 participants who satisfied the inclusion and exclusion criteria were randomized into two groups. Final total patient number was 60 [Figure 1].

DISCUSSION

The indiscriminate use of opioids has resulted in a global prescription-precipitated opioid abuse epidemic. As a result of this major crisis, there has been a paradigm shift in the way the intraoperative and postoperative analgesia should be managed. More and more impetus is being provided to the concept of “opioid-free anaesthesia/opioid sparing strategy” (OFA/OSS). This study was one such an attempt.

This study was conducted with the main aim of finding a suitable technique of OFA out of the 2 easily available drugs and comparing them. The study demonstrated that administration of pre-incisional and intraoperative intravenous infusion of preservative-free xylocaine and ketamine (group I) and preservative-free xylocaine and dexmedetomidine (group II) improved post-operative analgesia by completely avoiding total opioid consumption over a 24-h period and decreased pain scores in patients undergoing procedures under general anesthesia.

Some of the adverse effects such as delayed wound healing, deep vein thrombosis, respiratory problems, poor rehabilitation, hyperglycemia, prolonged hospital stays, and development of chronic pain may occur with inadequate post-operative analgesia.^[14] Reduced intraoperative analgesic requirement is due to the fact that when administered systemically, xylocaine has analgesic, anti-hyperalgesic, and anti-inflammatory properties which are effective in post-surgical period even after stopping the infusion at the end of surgery. Hence, during surgeries, xylocaine infusion can be given systemically as an adjunct in multimodal analgesia regimen, which is being used widely. Xylocaine and ketamine have a potential for altering central sensitization by modification of neurochemistry in the dorsal horn of the spinal cord.^[15]

Our study shows that preincisional and intraoperative infusion of xylocaine and dexmedetomidine is more effective as postoperative analgesia as compared to preservative-free xylocaine and ketamine, although both produced satisfactory analgesia. The key findings of our analysis revealed that the group II (xylocaine and dexmedetomidine) showed a lower mean VAS score (P < 0.5) than group I (xylocaine and ketamine) in post-surgical period at 0 h (immediately postoperative), 1 h, 4 h, 8 h, 12-h, 24 h as described in Table 6.

Dexmedetomidine, ketamine, and lidocaine have an analgesic effect without causing significant respiratory depression and having post-operative opioid sparing effect, thereby reducing the risk of opioid related postoperative complications.^[16]

There was no significant difference between the groups in hemodynamic data, SBP, DBP, MAP, and heart rate. In group 1, SBP and DBP were 120.06±7.4 and 72.16±6.8, respectively, and in group II, SBP and DBP were 118.4 ± 9.8.and 73.93 ± 9.3, respectively. Heart rate in group 1 and group II was 77.06 ± 3.9 and 75.5 ± 3.8 g, respectively. Our study results were comparable to Bekker et al., who found that dexmedetomidine, given at a similar dosage, effectively reduced the increase in SBP during the perioperative phase, without raising the incidence of bradycardia or hypotension.^[17] Hemodynamics changes with the effect of dexmedetomidine can be illustrated by its activation of presynaptic a2-receptors, which strengthens the negative feedback inhibition of noradrenaline release from the peripheral nerve terminal along with its inhibitory effect on central sympathetic outflow due to a2-receptor stimulation in the locus coeruleus of brainstem.^[18] Hogue et al. published that dexmedetomidine maintains baroreflex sensitivity, allowing patients to maintain a normal heart rate response to BP changes. The noted decline in the heart rate is primarily attributed to sympathetic withdrawal rather than enhanced vagal activity.^[19] Dexmedetomidine uniquely provides sedation devoid of respiratory depression, featuring a wide safety margin and an excellent sedative capacity.^[20] It does not heighten the frequency of post-operative complications. Our study was consistent with the systematic review conducted by Salomé et al.^[21] who noted less sedation in the OFA groups than in opioid-based groups in the post-anesthesia care unit. In addition, both groups had a better recovery profile, lower sedation score, and no significant complications.

Perioperative xylocaine infusion reduced significantly postoperative nausea vomiting (PONV). In our study, there was no significant post-operative nausea and vomiting but in group 1, only one case shows PONV as described in Table 7. This is in accordance with the meta-analysis conducted by Vigneault et al.^[22] Perioperatively, ketamine was effective in reducing the incidence of PONV in subanesthetic doses. Numerous studies verified our data showing a noteworthy reduction in PONV with ketamine infusion.^[23,24]

Both ketamine with xylocaine^[25] and dexmedetomidine with xylocaine^[26] show synergistic effect in sedation as well as in analgesia, this was also observed by authors while performing a colon procedure.

Second, the elimination half-life of dexmedetomidine is approximately 2 h,^[27] half-life of xylocaine is 86 min,^[28] whereas, of ketamine is 2.5 h,^[29] and pharmacologically, majority of these drugs are eliminated after 4–6 half-lives when the effects of discontinuation become evident.

Both these properties of synergism and elimination half-life can lead to prolongation of sedation and analgesic duration up to 24 h as observed in our study. While comparing dexmedetomidine and ketamine, we found dexmedetomidine to be more sedative than ketamine up to 12 h, as also observed by Sivakumar et al.^[30]

CONCLUSION

Intraoperative xylocaine and ketamine or dexmedetomidine infusion reduces pain intensity and better hemodynamic stability without any opioid related adverse effects for patients undergoing superficial non-cavitary surgeries under general anesthesia. Consequently, we suggest that any of two group drug combinations can provide as satisfactory adjuncts for multimodal analgesic regimen to lessen postoperative opioid usage. Hence, both groups of drugs can be used as total opioid-free anesthesia/opioid sparing technique. Dexmedetomidine was found better than Ketamine in view of postoperative analgesia. Further studies should be done to particularize the dose and duration of xylocaine, dexmedetomidine, or ketamine in other types of surgeries under general anesthesia. Hence, we conclude that the OFA technique using preincisional and intraoperative intravenous infusion of xylocaine as the foundation with adjuvant like ketamine or dexmedetomidine is effective in providing clinically satisfactory perioperative analgesia to the patients undergoing general anesthesia, especially the surface, non-body cavity surgical procedures. Out of the 2 study drugs, namely ketamine and dexmedetomidine, there does not seem to be any significant difference between them in providing adequate intraoperative analgesia as well as maintaining intraoperative hemodynamic stability. However, postoperatively, dexmedetomidine seems to be better in providing superior analgesia. Both drugs produce time-dependent sedation, which is just adequate to maintain the comfort of the patient, without compromising the safety.