{"id":50358,"date":"2023-09-30T11:08:59","date_gmt":"2023-09-30T11:08:59","guid":{"rendered":"https:\/\/biomedpharmajournal.org\/?p=50358"},"modified":"2023-10-07T09:18:21","modified_gmt":"2023-10-07T09:18:21","slug":"a-comparison-of-the-recovery-profile-of-dexmedetomidine-when-administered-by-different-routes-in-patients-undergoing-laparoscopic-cholecystectomy-a-randomized-controlled-trial","status":"publish","type":"post","link":"https:\/\/biomedpharmajournal.org\/staging\/vol16no3\/a-comparison-of-the-recovery-profile-of-dexmedetomidine-when-administered-by-different-routes-in-patients-undergoing-laparoscopic-cholecystectomy-a-randomized-controlled-trial\/","title":{"rendered":"A Comparison of the Recovery Profile of Dexmedetomidine When Administered by Different Routes in Patients Undergoing Laparoscopic Cholecystectomy\u2013A Randomized Controlled Trial."},"content":{"rendered":"\n

Introduction<\/strong><\/p>\n\n\n\n

Laparoscopic cholecystectomy was introduced to the\nmedical world in October 1989.[1]<\/sup> Decades after its introduction,\nthe demand for this minimally invasive procedure is still on a constant rise,\nand so is the demand for a safe and fast-tracking anesthesia plan. A faster and\nsmoother recovery of patients from anesthesia after a surgical procedure is\ncritical for early discharge. Dexmedetomidine was approved for human use in\n1999. It is a short-acting \u03b12 agonist with analgesic, sedative, and anxiolytic\nproperties[2]<\/sup>, making it the most preferred agent of choice in\nsurgeries requiring minimal hospital stay like laparoscopic cholecystectomy.\nDexmedetomidine is usually administered through an intravenous route. The\nliterature library is flooded with numerous clinical studies on the recovery\nprofile of intravenous dexmedetomidine from general anesthesia[3-7]<\/sup>\nand the postoperative pain relief properties[8-11]<\/sup>. Intravenous dexmedetomidine\nis associated with undesirable side effects like prolonged sedation after\nsurgery and prolonged extubation time from anesthesia.[6] <\/sup>We\nconducted this study to compare the extubation time from anesthesia when\ndexmedetomidine was administered through the conventional intravenous route and\nwhen it was administered through an interfascial transversus abdominus plane\n(TAP) block and rectus sheath (RS) block in patients undergoing laparoscopic\ncholecystectomy surgeries under general anesthesia. <\/p>\n\n\n\n

In this randomized controlled trial, we proposed a null\nhypothesis stating that there would be no significant difference in extubation\ntime from anesthesia between the intervention arm which received\ndexmedetomidine in TAP block with RS block, and the control arm, which received\nintravenous dexmedetomidine.<\/p>\n\n\n\n

The main objective of this study was to analyze the time\ntaken to extubation. The secondary objectives studied were the VAS score for\npostoperative pain at rest. Other parameters measured were a) Time taken to\nopen the eyes after stopping sevoflurane, b) Intraoperative and postoperative\nHemodynamics, c) Modified Aldrete score (MAS) at extubation, d) Time taken to\nattain MAS of ten, and e) Complications associated with dexmedetomidine\nadministration.<\/p>\n\n\n\n

Methods<\/strong><\/p>\n\n\n\n

We included 54 patients aged 18 to 60 years old in this\nstudy. Patients belonging to ASA physical status I and II who were posted for\nlaparoscopic cholecystectomy were included in the study. Patients withheart\nrate (HR) below 50\/min, systolic pressure <100 mm hg, known cardiac, renal,\nor hepatic dysfunction, and known allergy to \u03b12\u2011agonists were excluded from the\nstudy. The institutional ethical committee approved the study (1891\/IEC\/2019),\nand informed written consent was obtained from all the participants. The study\nwas registered in the Clinical Trials Registry – India (CTRI\/2021\/04\/032752).<\/p>\n\n\n\n

Study\ndesign and sample size estimation<\/strong><\/p>\n\n\n\n

This study was\ndesigned as a randomized controlled trial with a parallel-arm design and a 1:1\nallocation ratio done in a tertiary care hospital from April 2021 till the\nsample size was achieved. It is a double-blinded clinical study.<\/p>\n\n\n\n

The sample size for\neach group was calculated using the formula [(Z1-\u03b1\/2 + Z1-\u03b2)2 \u03c32(1+1\/k)] \/ <\/em>(d-\n\u0394)2for a superiority trial with continuous outcomes. The power of\nthe study was 90%, and the two-sided confidence interval was 95%. The sample\nsize required for each group of the parallel arm was 24, and the total sample\nsize for the study was 48. The study was done on 54 patients adjusting for 10%\nanticipated dropout.<\/p>\n\n\n\n

Statistical\nanalysis<\/strong><\/p>\n\n\n\n

We used the\nKolmogorov-Smirnov test to analyze the normal distribution of the collected\ndata. Graphpad Prism was used to perform the statistical analysis. We used mean\nand standard deviation to express the continuous variables and the unpaired\nt-test to compare the groups. The median with an interquartile range was used\nto express discrete data. We used the Wilcoxon Rank Sum test to compare\nmedians. Categorical variables were reported as percentages, and Pearson’s chi-square\nwas used to determine statistical significance. Wherever the P <\/em>was\nless than 0.05, we considered the difference between groups to be significant.<\/p>\n\n\n\n

Randomization,\nallocation concealment, and blinding methods<\/strong><\/p>\n\n\n\n

The random numbers\nwere created by someone not involved in the intervention, data collecting, or\ndata analysis procedure. The patients were randomly assigned to Group C\n(control group) or T (test group). Allocation concealment was done using a\nsealed envelope method. This envelope was handed over to an anesthesiologist\nnot involved in the study only on the day of surgery. After administering\ngeneral anesthesia to the patients, this anesthesiologist administered\ndexmedetomidine as per the random allocation in the envelope. The patient was\nthen handed over to the principal investigator, who was blinded to the\nrandomization to monitor intraoperatively and record the required parameters\ntill the study period.<\/p>\n\n\n\n

Conduct\nof anesthesia <\/strong><\/p>\n\n\n\n

Anesthesia was\nadministered using fentanyl 2mcg\/kg, propofol 2mg\/kg, and vecuronium 0.1mg\/kg.\nMaintained using O2:N20: Sevoflurane = 1:1:1.5% and vecuronium 0.05mg\/kg\nadministered according to the neuromuscular monitor. <\/p>\n\n\n\n

Immediately after\nintubation, patients in group C received 50 micrograms of dexmedetomidine\ndiluted in 100ml normal saline through the intravenous route over 10 minutes.\nThey were administered TAP block and RS block using ultrasound with 50ml of\n0.3% ropivacaine local anesthetic. Patients in Group T received 100 ml of\nintravenous plain normal saline. They were administered TAP block and RS block\nusing ultrasound, with 50ml of 0.3% ropivacaine local anesthetic mixed with 50\nmcg of dexmedetomidine.<\/p>\n\n\n\n

The block was\nadministered by a blinded anesthesiologist experienced in performing\nultrasound-guided TAP and RS blocks. After strict aseptic precautions, a linear\nultrasound probe (6-13 Hz probe of GE Vivid TM) was positioned in the anterior\naxillary line in the subcostal region. Next, a 20G Quincke’s needle was\ninserted in-plane under an ultrasound probe to place the needle tip between the\nfascial planes of the internal oblique and transverse abdominis muscles. After\nconfirming the needle tip by test injection of one-milliliter saline, fifteen\nmilliliters of the local anesthetic as appropriate for the group allocation was\ninjected on each side. The successful injection was confirmed by creating a\nlens-shaped space between the two muscle planes. Then the same ultrasound probe\nwas placed on one side of the umbilicus, and the rectus muscle was imaged in a\ntransverse orientation. Next, the needle tip was placed in the fascia between\nthe anterior and the posterior rectus sheath. Then, ten milliliters of the\nlocal anesthetic as appropriate for the group allocation were injected on each\nside. The successful injection was confirmed by creating a lens-shaped space\nbetween the two fasciae. <\/p>\n\n\n\n

Any fall in heart\nrate less than 20% from baseline was treated with Inj. Atropine 0.6 mg iv, drop\nin systolic pressure less than 20% from baseline, was treated with Inj.\nEphedrine 6mg iv increased heart rate to more than 20% from baseline and was\ntreated with Inj. Fentanyl 1mcg\/kg and a rise in the systolic pressure of more\nthan 20% from baseline were treated with Inj.Propofol 1mg\/kg bolus. The\nvolatile agent was switched off at the time of placing the last suture by the\nsurgeon.<\/p>\n\n\n\n

Demographic\nvariables like age, sex, weight, and ASA status were collected. Clinical\nvariables like heart rate and mean arterial pressure were recorded from when\nthe patient entered the operating room (0 min) and every 15 minutes after that\ntill four hours (240 mins). Inhalational and intravenous anesthetic drugs were\nadministered, and their total doses used intraoperatively were recorded. The\nprimary outcome variable recorded was the time of extubation (the time taken to\nremove the endotracheal tube from the time of stopping sevoflurane). The\nsecondary outcome variable measured was the VAS score at rest after extubation\nand every 6 hours after that for the first 24 hours and the VAS score at\nmovement at 18 hours after extubation. Other variables collected were the time\nof opening eyes (the time taken to open eyes either spontaneously or on verbal\ncommand from the time of stopping sevoflurane), time taken to achieve a\nmodified Aldrete score of ten (calculated from the time of extubation), and\nModified Aldrete scores at extubation. In addition, any complications that\noccurred during extubation and due to drug effects like bradycardia,\nhypotension, hypertension, tachycardia, and emergence agitation were recorded.<\/p>\n\n\n\n

Results<\/strong><\/p>\n\n\n\n

This randomized controlled study was conducted on 54 patients who underwent laparoscopic cholecystectomy surgery under general anesthesia. Figure 1. shows the details of participant enrollment and the study flow. As seen in table 1, the demographic characteristics and the mean quantity of intraoperative anesthetic drug consumption were comparable between the groups. <\/p>\n\n\n\n\n\n
\"\"<\/td>\n\n

Figure 1: Consort flow chart showing the selection process, the study flow, and data collection.<\/span><\/strong><\/span><\/b><\/p>\n

<\/p>\n

Click here to view Figure<\/a><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

Table 1: The comparison of demographic variables and the total dose of drugs used in the two groups.<\/strong><\/p>\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
\n

Variable<\/strong><\/p>\n<\/td>\n

\n

Group C<\/strong><\/p>\n

(Mean \u00b1 SD)<\/p>\n<\/td>\n

\n

Group T<\/strong><\/p>\n

(Mean \u00b1 SD)<\/p>\n<\/td>\n

\n

P value<\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

Age in years<\/p>\n<\/td>\n

\n

42.1 \u00b1 7.95<\/p>\n<\/td>\n

\n

43.3 \u00b1 8.40<\/p>\n<\/td>\n

\n

0.59<\/p>\n<\/td>\n<\/tr>\n

\n

Gender<\/p>\n<\/td>\n

\n

Male (n)<\/p>\n<\/td>\n

\n

11<\/p>\n<\/td>\n

\n

9<\/p>\n<\/td>\n

\n

0.67<\/p>\n<\/td>\n<\/tr>\n

\n

Female (n)<\/p>\n<\/td>\n

\n

16<\/p>\n<\/td>\n

\n

18<\/p>\n<\/td>\n<\/tr>\n

\n

Weight in kg<\/p>\n<\/td>\n

\n

59.74 \u00b1 4.36<\/p>\n<\/td>\n

\n

59.19 \u00b1 3.83<\/p>\n<\/td>\n

\n

0.62<\/p>\n<\/td>\n<\/tr>\n

\n

ASA<\/p>\n<\/td>\n

\n

I (n)<\/p>\n<\/td>\n

\n

10<\/p>\n<\/td>\n

\n

17<\/p>\n<\/td>\n

\n

0.64<\/p>\n<\/td>\n<\/tr>\n

\n

II (n)<\/p>\n<\/td>\n

\n

17<\/p>\n<\/td>\n

\n

10<\/p>\n<\/td>\n<\/tr>\n

\n

Duration of surgery in minutes<\/p>\n<\/td>\n

\n

99.74 \u00b1 10.90<\/p>\n<\/td>\n

\n

102 \u00b1 11.98<\/p>\n<\/td>\n

\n

0.47<\/p>\n<\/td>\n<\/tr>\n

\n

Fentanyl in microgram<\/p>\n<\/td>\n

\n

119 \u00b1 8.29<\/p>\n<\/td>\n

\n

117 \u00b1 7.12<\/p>\n<\/td>\n

\n

0.35<\/p>\n<\/td>\n<\/tr>\n

\n

Propofol in milligram<\/p>\n<\/td>\n

\n

116 \u00b1 16.9<\/p>\n<\/td>\n

\n

120 \u00b1 10.6<\/p>\n<\/td>\n

\n

0.30<\/p>\n<\/td>\n<\/tr>\n

\n

Vecuronium in milligram<\/p>\n<\/td>\n

\n

7.81 \u00b1 0.74<\/p>\n<\/td>\n

\n

7.65 \u00b1 0.94<\/p>\n<\/td>\n

\n

0.49<\/p>\n<\/td>\n<\/tr>\n

\n

Sevoflurane in milliliter<\/p>\n<\/td>\n

\n

15 \u00b1 1.64<\/p>\n<\/td>\n

\n

15.3 \u00b1 1.8<\/p>\n<\/td>\n

\n

0.52<\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

The extubation time after anesthesia and the other parameters for endpoints of recovery from anesthesia was significantly lower in group T (P<\/em> 0.0001) and are shown in Table 2. The resting VAS in group C at six hours, 12 hours, and 18 hours postoperative was significantly higher than in group T at the same time points. [group C = 4(3.5-5.5), 40 (31.5-44), and 51 (48.5-57.5), respectively, vs. group T = 2(1.5-3), 17(13.5-20.5), and 25(19-29.5) respectively]. These differences had a P <\/em>value of 0.0001. The movement VAS at 18 hours in group C [ 68(63-71)] was also significantly higher than in group T [ 55(47.5-61)]. Figure 2 represents the box plots of the postoperative VAS for pain.<\/p>\n\n\n\n

Table 2: The comparison of the variables of the recovery profile between the two groups.<\/strong><\/p>\n\n\n\n\n\n\n\n\n\n
\n

Variable<\/strong><\/p>\n<\/td>\n

\n

Group C<\/strong><\/p>\n

(Mean \u00b1 SD)<\/p>\n<\/td>\n

\n

Group T<\/strong><\/p>\n

(Mean \u00b1 SD)<\/p>\n<\/td>\n

\n

P value<\/strong><\/p>\n<\/td>\n

\n

95% CI<\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

Time to extubation<\/p>\n<\/td>\n

\n

10.87 \u00b1 1.71<\/p>\n<\/td>\n

\n

4.37 \u00b1 0.25<\/p>\n<\/td>\n

\n

0.0001<\/p>\n<\/td>\n

\n

5.83 to 7.17<\/p>\n<\/td>\n<\/tr>\n

\n

Time to eye opening<\/p>\n<\/td>\n

\n

8.81 \u00b1 1.01<\/p>\n<\/td>\n

\n

3.33 \u00b1 0.22<\/p>\n<\/td>\n

\n

0.0001<\/p>\n<\/td>\n

\n

5.08 to 5.88<\/p>\n<\/td>\n<\/tr>\n

\n

MAS at extubation *<\/p>\n<\/td>\n

\n

7 (6-7)<\/p>\n<\/td>\n

\n

8 (8-9)<\/p>\n<\/td>\n

\n

0.0001<\/p>\n<\/td>\n

\n<\/td>\n<\/tr>\n
\n

Time to attain MAS 10<\/p>\n<\/td>\n

\n

5.03 \u00b1 0.6<\/p>\n<\/td>\n

\n

3.37 \u00b1 0.49<\/p>\n<\/td>\n

\n

0.0001<\/p>\n<\/td>\n

\n

1.36 to 1.96<\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

* Expressed as Median (IQR)<\/p>\n\n\n\n
\"\"<\/td>\n\n

Figure 2: Chart showing the box-whisker plots comparing median VAS scores in the post-operative period between Group C and Group T.<\/span><\/strong><\/p>\n

<\/p>\n

Click here to view Figure<\/a><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

Figure 3 and figure 4 show the variability of the mean arterial pressure (MAP) and heart rate (HR) variability. The MAP and HR in the control group were much lower than in the test group till 45 minutes after administering dexmedetomidine. This was statistically significant. <\/p>\n\n\n\n\n\n
\"\"<\/td>\n\n

Figure 3: Chart showing the comparison of MAP means in the intraoperative period between Group C and Group T.<\/span><\/strong><\/p>\n

<\/p>\n

Click here to view Figure<\/a><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n\n
\"\"<\/td>\n\n

Figure 4: Chart showing the comparison of heart rate means in the intraoperative period between Group C and Group T.<\/span><\/strong><\/p>\n

<\/p>\n

Click here to view Figure<\/a><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

There was an 18.5% incidence of bradycardia in the control arm. No participant had bradycardia in the test arm. The incidence of emergence agitation was 11.11%, and postoperative nausea and vomiting (3.7%) in group T and no cases in group C. We did not encounter any other complications.<\/p>\n\n\n\n

Discussion<\/strong><\/p>\n\n\n\n

In our study, when\ndexmedetomidine was administered in the abdominal wall plane blocks the\nrecovery endpoints from anesthesia like the time to extubation, eye-opening\ntime after stopping the volatile agent, and the time taken to attain a modified\nAldrete score of 10 were all significantly lesser than when dexmedetomidine was\nadministered through intravenous route. This finding is similar to a study\nconducted by Ye Q et al. [12] <\/sup>in laparoscopic cholecystectomy and\nalso similar to studies conducted by Xue Y et al. [13]<\/sup> and Qin et\nal. [14]<\/sup> in laparoscopic gynecological surgeries. <\/p>\n\n\n\n

Studies have\nconcluded that the sedative effect of dexmedetomidine is through the central\nagonistic action on alpha 2A pre-synaptic receptors in locus ceruleus and that\nit is concentration-dependent.[16] <\/sup>This could explain the early\nrecovery profile of patients from general anesthesia in the interfascial\ndexmedetomidine group, possibly due to the differences in dexmedetomidine\nplasma concentration.<\/p>\n\n\n\n

 The secondary\noutcome measure was postoperative pain. When dexmedetomidine was administered\nin the interfascial plane blocks, it significantly prolonged the duration of\npostoperative analgesia. Qin et al. [14]<\/sup> and Xue Y et al. [13]<\/sup>\nconcluded in their studies that when dexmedetomidine was added to the TAP\nblock, the patients had lower pain scores till 24 hours in the postoperative\nperiod. This correlates well with the results of our study. The analgesic\naction of dexmedetomidine is from both central actions on pre-synaptic alpha2A\nreceptor agonistic action and peripheral action on inhibiting A-delta and C\nnerve fibers. [2,15]<\/sup> The analgesic effect when administered in the\ninterfascial plan could be explained through the peripheral action mechanism\nmentioned previously or due to the local perineural action when co-administered\nwith ropivacaine as suggested in a study by Keplinger et al. [16]<\/sup><\/p>\n\n\n\n

The hemodynamic\nanalysis revealed that the fall in heart rate and blood pressure was immediate\nand more in the intravenous group. In the interfacial dexmedetomidine group,\nthe heart rate and blood pressure were maintained steadily throughout the\nintraoperative and postoperative periods until four hours of observation\nwithout any drastic fluctuations. Xu L et al. [17]<\/sup> had administered\n1mcg\/kg dexmedetomidine as an adjuvant to ropivacaine in TAP and RS block in\nopen lower abdominal surgeries and has shown that the heart rate and mean\narterial pressure had a 10% fall from baseline at the time of incision. This\ndifference in results could be attributed to the cumulative effects of other\nanesthetic agents used in their study. The transversus abdominis plane and\nrectus sheath plane are interfacial planes that contain collagenous, fibrous\nconnective tissues and are relatively less vascular. Studies have been\nconducted on the systemic levels of ropivacaine administered in these planes\nand concluded that systemic absorption was slow.[18] <\/sup>This can also\nbe assumed for the pharmacokinetics of interfascial plane dexmedetomidine,\nwhich explains the steady state of the hemodynamic response in the test arm.<\/p>\n\n\n\n

The side effects we\nencountered in our study in the block group were agitation at emergence\n(11.11%) and postoperative nausea and vomiting (3.7%). This result is supported\nby the study conducted by Xue Y et al. [13]<\/sup> <\/p>\n\n\n\n

The available dose\nregimens and pharmacokinetic models of dexmedetomidine are based on the\nintravenous route of administration. Interfascial plane blocks have been\ngaining popularity recently owing to their various advantages and patient\ncomfort. Hence, further studies on the pharmacokinetics of dexmedetomidine in\nan interfascial plane are warranted for formulating precise dosing regimens.\nCombining dexmedetomidine with local anesthetics in the anterior abdominal wall\nblocks the patients undergoing laparoscopic cholecystectomy benefits in two\nways. They have a smoother and faster emergence from general anesthesia and\nprolonged postoperative pain relief. <\/p>\n\n\n\n

This study has a few\nlimitations. First, there is no definite method to confirm the correct\nadministration of TAP and RS blocks except the expertise of an\nanesthesiologist. Hence its reproducibility by other untrained\nanesthesiologists to produce the same results is not guaranteed. The second\nlimitation is that the study participants were followed only up to twenty-four\nhours postoperatively, as the scope of this study was to analyze the recovery\nendpoints from general anesthesia and postoperative pain. Hence, we have no\ndata on the length of hospital stay, which might have been valuable to include\nthis intervention in ERAS protocols.<\/p>\n\n\n\n

Conclusion<\/strong><\/p>\n\n\n\n

When dexmedetomidine\nis administered through the interfascial plan for laparoscopic cholecystectomy\nsurgery, the recovery profile from general anesthesia is improved, and\npostoperative pain is effectively relieved. <\/p>\n\n\n\n

Conflict of Interest<\/strong><\/p>\n\n\n\n

There is no conflict of interest.<\/p>\n\n\n\n

Funding Source<\/strong><\/p>\n\n\n\n

There are no funding sources.<\/p>\n\n\n\n

Reference<\/strong><\/p>\n\n\n\n

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