Al-Azhar Assiut Medical Journal

ORIGINAL ARTICLE
Year
: 2017  |  Volume : 15  |  Issue : 3  |  Page : 127--134

Comparative study of midazolam, dexmedetomidine, and ketamine as an adjuvant to lidocaine in intravenous regional anesthesia for forearm and hand surgeries


Alaa E Mahmoud, Abdelwahab A Saleh, Ali A Mahareak, Ali A Alkumity 
 Department of Anesthesiology and Intensive Care, Faculty of Medicine, Al-Azhar University, Cairo, Egypt

Correspondence Address:
Abdelwahab A Saleh
2 Safwat Street Shubra Elkheima, Alqualubia
Egypt

Abstract

Background Intravenous regional anesthesia (IVRA) is an ideal method of providing anesthesia for minor surgical procedures to the extremities performed on an ambulatory basis. This study aimed to study the effects of adding midazolam, dexmedetomidine, or ketamine as an adjuvant to lidocaine in IVRA during forearm and hand surgeries and examine their benefits and complications. Patients and methods A total of 120 patients were included, aged 40–60 years (American Society of Anesthesiologists physical status I–II), undergoing hand and forearm, from April 2015 to August 2016. Patients were randomly divided into four equal groups. Lidocaine-only group (LL group) received IVRA using 40 ml of lidocaine 0.5% (3 mg/kg). Lidocaine plus midazolam group (LM group) received IVRA using 40 ml of lidocaine 0.5% (3 mg/kg) plus midazolam 50 µg/kg added as an adjuvant. Lidocaine plus dexmedetomidine group (LD group) received IVRA using 40 ml of lidocaine 0.5% (3 mg/kg) plus dexmedetomidine 1 µg/kg added as an adjuvant. Lidocaine plus ketamine group (LK group) received IVRA using 40 ml of lidocaine 0.5% (3 mg/kg) plus ketamine 0.5 mg/kg added as an adjuvant. The time of onset, duration, and quality of analgesia; levels of sensory and motor block; heart rate; mean arterial blood pressure; and visual analog score were recorded. Adverse effects of hematoma, injection pain, skin erythema, sedation, and hallucinations were recorded. Results The onset time of sensory and motor blocks was significantly shorter in the adjuvant groups LM, LD, LK in comparison with the control group LL. The grade of sensory and motor blocks was significantly better in groups LM, LD, and LK in comparison with the LL group. The onset time of tourniquet pain was significantly shorter in the control group LL in comparison with adjuvant groups LM, LD, and LK. There was a significant increase in fentanyl requirements in the control LL group compared with adjuvant LM, LD, and LK groups. The duration of postoperative analgesia was significantly prolonged in adjuvant groups LM, LD, and LK compared with the control LL group. Hematoma, injection pain, cutaneous erythema, and hallucination were reported as postoperative complications. Conclusion The addition of midazolam, dexmedetomidine, or ketamine to lidocaine for IVRA improved the quality of intraoperative and postoperative analgesia with minimal adverse effects and higher patients and surgeon satisfaction.



How to cite this article:
Mahmoud AE, Saleh AA, Mahareak AA, Alkumity AA. Comparative study of midazolam, dexmedetomidine, and ketamine as an adjuvant to lidocaine in intravenous regional anesthesia for forearm and hand surgeries.Al-Azhar Assiut Med J 2017;15:127-134


How to cite this URL:
Mahmoud AE, Saleh AA, Mahareak AA, Alkumity AA. Comparative study of midazolam, dexmedetomidine, and ketamine as an adjuvant to lidocaine in intravenous regional anesthesia for forearm and hand surgeries. Al-Azhar Assiut Med J [serial online] 2017 [cited 2018 Nov 18 ];15:127-134
Available from: http://www.azmj.eg.net/text.asp?2017/15/3/127/226048


Full Text



 Introduction



Intravenous regional anesthesia (IVRA) described by August Bier in 1908 involves intravenous administration of a local anesthetic into a tourniquet-occluded limb. Nowadays, with slight technical modifications, IVRA is an ideal method of providing anesthesia for minor surgical procedures to the extremities performed on an ambulatory basis [1].

IVRA has multiple advantages, including ease of administration, rapidity of recovery, rapid onset, and controllable extent of anesthesia [2]. On the contrary, IVRA has several disadvantages such as short duration, inadequate muscle relaxation, tourniquet pain, systemic toxicity of local anesthesia, and rapid recovery of the sensory block after deflation of the tourniquet, which causes insufficient postoperative analgesia and demands another mode for postoperative analgesia [3].

In attempt to improve intraoperative and postoperative qualities of the IVRA, several adjuvant can be added, i.e., opioids [4], ketamine [5], muscle relaxant [6], nonsteroidal anti-inflammatory drugs [7], clonidine [8], dexmedetomidine [9], and neostigmine [10].

The current study aimed to compare between midazolam, dexmedetomidine, and ketamine as an adjuvant to lidocaine in IVRA for cases of hand and forearm surgeries with an assessment of tourniquet pain, postoperative pain, analgesic requirements, and occurrence of complications.

 Patients and methods



This prospective randomized controlled study was carried out on 120 patients with American Society of Anesthesiologists (ASA) grades I and II aged between 20 and 60 years admitted to Al-Azhar University hospitals scheduled from April 2015 to August 2016 for elective forearm and hand surgeries lasting for less than 90 min. After approval from the ethical committee, informed and written consents were obtained from all patients in this research.

Patients were randomly assigned into four groups (30 patients each) by randomized table created by computer software program (Acer, Taiwan) using sealed envelopes.

Patients groups

Patients were divided into the following groups:Lidocaine-only (LL) group received IVRA using 40 ml of lidocaine 0.5% (3 mg/kg).Lidocaine plus midazolam (LM) group received IVRA using 40 ml of lidocaine 0.5% (3 mg/kg) plus midazolam 50 µg/kg added as an adjuvant.Lidocaine plus dexmedetomidine (LD) group received IVRA using 40 ml of lidocaine 0.5% (3 mg/kg) plus dexmedetomidine 1 µg/kg added as an adjuvant.Lidocaine plus ketamine (LK) group received IVRA using 40 ml of lidocaine 0.5% (3 mg/kg) plus ketamine 0.5 mg/kg added as an adjuvant.

Inclusion criteria

The inclusion criteria included ASA class I or II patients, of both sexes, aged between 20 and 60 years and underwent forearm and hand surgeries.

Exclusion criteria

Patients with the following conditions were excluded from the study: ASA III or IV patients, age below 20 or above 60 years, allergy to any of the study drugs, sickle cell anemia, peripheral vascular diseases, post-traumatic injuries, uncooperative patients, history of epilepsy, and operations longer than 90 min.

Preoperative assessment

Preoperative evaluation included a detailed history, physical examination, and investigations (complete blood count, kidney function tests, liver function tests, prothrombin time, and international normalized ratio).

Premedication for all groups consisted of intravenous 1 µg/kg fentanyl. The lidocaine was 2% preservative free. Dose 3 mg/kg, and 0.9% NaCl was added to make up a total volume of 40 ml in all groups.

Double pneumatic tourniquet, along with the pressure gauge, should be checked for leaks before the procedure. Esmarch bandage or Rhys–Davies exsanguinator was used for exsanguination.

After application of monitors, with the patient lying in a supine position, a cannula, 20-G size, was placed in the nonoperative hand for crystalloid infusion and emergency drugs. Another cannula of 22-G size was inserted in a dorsal vein of the operative hand.

A double pneumatic tourniquet was then placed around the upper arm of the operative limb, over a pad of cotton. The arm was elevated for 2 min then exsanguinated with an Esmarch bandage. The proximal cuff was inflated to 100 mmHg above the patient’s systolic pressure. Circulatory isolation of the arm was verified by inspection, through the absence of radial pulse and loss of pulse oximetry tracing in the ipsilateral index finger. Then 40 ml of lidocaine 3 mg/kg in the control LL group, lidocaine with midazolam (50 µg/kg) in the LM group, lidocaine with dexmedetomidine (1 µg/kg) in the LD group, and lidocaine with ketamine (0.5 mg/kg) in the LK group was injected slowly within 60 s.

At the end of surgery, cyclic deflation technique was used to deflate tourniquet. At least 30 min was passed after tourniquet inflation before starting to deflate the tourniquet. Sensory recovery time (times from deflation of tourniquet to the time of complete disappearance of sensory block in all dermatomes supplied by the blocked nerves) was recorded. Motor recovery time (time from deflation of tourniquet to the time of initiation of motor movement in fingers and wrist), the duration of surgery, duration of a tourniquet use, and the total intraoperative fentanyl consumption were recorded.

At the end of surgery, the anesthesiologist and surgeon who were blinded to the study medication were asked about the quality of the operative condition. The anesthesiologist graded the quality of the operative condition according to a four-point numeric scale: 4=excellent, no complaint from the patient; 3=good, a minor complaint from the patient with no need for supplemental analgesics; 2=moderate, a complaint that required a supplemental analgesic; and 1=unsuccessful, general anesthesia was given. The surgeon graded the quality of the operative field according to a four-point numeric scale: 4=perfect, 3=acceptable, 2=poor, and 1=unsuccessful. Pain was assessed after the release of the tourniquet and recorded by anesthesiology resident who was blinded to the study medications at the following times 5 min (T0), 30 min (T1), 1 h (T2), 2 h (T3), 4 h (T4), 6 h (T5), 12 h (T6), and 24 h (T7) after deflation of the tourniquet. Mean arterial blood pressure (MAP) and heart rate (HR) were noted at the same times.

After the end of surgery, patients were transferred to the postanesthesia care unit for 2 h. In the first 8 h, postoperative analgesia in the form of pethidine 30 mg intravenously and paracetamol 1 g intravenously if the visual analog score (VAS) was greater than or equal to 4 were administered. The time for first analgesia (time from tourniquet release till the time of first patient request of analgesic) and the total consumption of pethidine and paracetamol were recorded. Intraoperative or postoperative complications (nausea, vomiting, tachycardia, bradycardia, hypotension, tinnitus, dizziness, diplopia, and hallucinations) were recorded.

Statistical analysis

Calculation of the sample size was depended on the prolongation of the duration of postoperative analgesia. A total of 26 patients in each group were needed to detect a difference at the 5% significance level and give the trial 80% power. We factored a 10% dropout rate, and 30 patients were enrolled in each group. Statistical analysis was conducted using the SPSS (version 20; SPSS Inc., Chicago, Illinois, USA). Quantitative data were described as mean±SD and were analyzed using one-way analysis of variance with post-hoc Tukey honest significant difference test. Categorical data were analyzed by χ2 test. P value less than 0.05 was considered statistically significant.

 Results



The study was carried out on 120 patients randomly assigned into four groups, with 30 patients each. The demographic data (age, sex, height, and weight) were comparable among the studied groups as well as ASA, types, and duration of surgery ([Table 1]).{Table 1}

There was a statistically significant high Ramsay sedation scale (RSS) score in adjuvant groups LM, LD, and LK compared with LL group at 10, 15, 20, 30, 40, and end of the operation (P<0.05). There was a statistically significant low RSS score in the adjuvant group LD compared with the groups LL, LM, and LK over all operation time (P<0.05) [Figure 1].{Figure 1}

Onset time of sensory block was significantly shorter in the adjuvant groups LM, LD, and LK in comparison with control group LL (P≤0.001). Within the adjuvant groups, onset time of sensory block was significantly shorter in the LM group than in LD and LK groups and significantly shorter in the LK group than in LD group.

Offset time of sensory block was significantly shorter in the control group LL in comparison with adjuvant groups (P≤0.001). The grade of sensory block was significantly better in adjuvant groups LM, LD, and LK in comparison with control LL group (P≤0.01).

Onset time of motor block was significantly shorter in the adjuvant groups LM, LD, and LK in comparison with control group LL (P≤0.001). Within the adjuvant groups, time of onset of motor block was significantly shorter in LM group than in LD and LK groups (P≤0.01).

Offset time of motor block was significantly shorter in the control group LL in comparison with adjuvant groups LM, LD, and LK (P≤0.01). The grade of motor block was significantly better in groups LD and LK in comparison with LL and LM groups (P≤0.001).

The onset time of tourniquet pain was significantly shorter in the control group LL in comparison with adjuvant groups LM, LD, and LK (P≤0.001).

The numbers of patients who need additional fentanyl requirements were significantly more in control group LL than in the adjuvant groups LM, LD, and LK (P≤0.001). There was significant increase in fentanyl requirements in control LL group compared with adjuvant LM, LD, and LK groups (P≤0.001).

Duration of postoperative analgesia was significantly prolonged in adjuvant groups compared with control group (P≤0.01). Within the adjuvant groups, there was significant increase in duration of postoperative analgesia in LD and LK groups compared with LM group (P≤0.01). The duration of postoperative analgesia significantly prolonged in LD group compared with LK group (P≤0.05).

There was a statistically significant low VAS score regarding postoperative pain in adjuvant groups LM, LD, and LK compared with control group LL at 1, 2, 4, and 6 h (P<0.001). There was a statistically significant decrease in VAS scores in LD, LK groups compared with LL and LM groups at 12 h postoperative (P<0.05). There was no statistically significant decrease in VAS scores in LM group compared with LL group at 12 h postoperative (P>0.05). There were no significant differences between all groups regarding postoperative VAS changes at 24 h (P>0.05) [Figure 2].{Figure 2}

There was a significant increase in postoperative pethidine requirements in LL and LM groups compared with LD and LK groups (P≤0.01).

There was significant increase in patient and surgeon satisfaction in adjuvant groups LM, LD, and LK compared with control LL group (P≤0.01).

Postoperative complications and changes in MAP, HR, and arterial oxygen saturation were comparable among the four groups ([Table 2] and [Figure 3],[Figure 4],[Figure 5]).{Table 2}{Figure 3}{Figure 4}{Figure 5}

 Discussion



In the present study, the onset time of sensory and motor blocks was significantly shorter in the adjuvant groups LM, LD, and LK in comparison with control group LL. Within the adjuvant groups, onset time of sensory and motor block was significantly shorter in LM group than in LD and LK groups and significantly shorter in the LK than LD group. However, the offset time of sensory and motor block was significantly shorter in the control group LL in comparison with adjuvant groups LN, LD, and LK. Within the adjuvant groups, time of offset of sensory block was significantly shorter in LM and LD group than in LK groups. No significant difference was observed between LM and LD groups. The grade of sensory and motor blocks was significantly better in groups LD and LK in comparison with LL and LM groups (P≤0.05).

These results agreed with a study done by Honarmand et al. [11] which reported that the addition of midazolam to lidocaine shortened the onset of the sensory and motor block delayed recovery of sensory and motor block. Midazolam, a benzodiazepine derivate, has analgesic effects mediated by γ-amino butyric acid. Midazolam reduced A-δ and C-fiber evoked activity. γ-Amino butyric acid receptors have also been found in peripheral nerves. The role of A-δ fibers and unmyelinated C-fiber may be considered being involved in tourniquet pain [12]. The pneumatic tourniquet causes ischemia, which distorts nerve penetration by oxidative stress and affects blood–nerve barrier [13]. Benzodiazepine tends to suppress afferent evoked excitation in the substantia gelatinosa and motor horn leading to an antinociceptive effect [14].

Yoshitomi and Kohjitani [15] reported that the addition of dexmedetomidine to lidocaine shortened the onset of the sensory and motor block, delayed the recovery of sensory and motor block, and improved grade of the block. Dexmedetomidine exerts its analgesic effect, as it is a selective α2-adrenoceptor agonist. However, Kleinschmidt et al. [16] demonstrated that there were no significant differences between the groups concerning the onset and recovery characteristics of sensory and motor blockade on the addition of the clonidine 2 μg/kg to prilocaine 0.75% for IVRA.

Viscomi et al. [5] reported that the addition of ketamine to lidocaine shortened the onset of the sensory and motor block, delayed recovery of sensory and motor block, and improved grade of the block. Ketamine exerts a noncompetitive blockade of N-methyl-d-aspartate receptors. N-methyl-d-aspartate receptor antagonists had been implicated in perioperative pain management. Ketamine also has local anesthetic qualities, which has been studied as a sole agent for IVRA, but patients experience transient disorientation and hallucinations after tourniquet release.

Regarding RSS, there were statistically significant low RSS scores in adjuvant groups LM, LD, and LK compared with control LL group at 5, 10, and 15 min (P<0.05). There were statistically significant high RSS scores in adjuvant LD and LK groups compared with LL and LN groups at 10, 15, 20, 30, 40, and end of the operation (P<0.05). There were statistically significant low RSS scores in adjuvant LD group compared with LL, LM, and LK groups all over the operation time (P<0.05). These results were similar to those found by the study by Kumar et al. [2].

Memis et al. [9] reported that the addition of dexmedetomidine to lidocaine not only improves RSS in IVRA through improving the quality of block in terms of onset, offset, and VAS score but also exerts transient postoperative sedative effect owing to systemic effect, which depends on the amount of drug reaching systemic circulation.

Gorgias et al. [17] reported that the addition of ketamine to lidocaine improved RSS in IVRA through improving the quality of block in terms of onset, offset, and VAS score.

The onset time of tourniquet pain was significantly shorter in the control group LL in comparison with adjuvant groups LM, LD, and LK (P≤0.001). Within the adjuvant groups, onset time of tourniquet pain was significantly shorter in the LM group than in LD and LK groups (P≤0.01). There was no significant difference between LD and LK groups (P≥0.05).

Ozturk et al. [18] reported that the addition of dexmedetomidine to lidocaine delayed onset time of tourniquet pain in IVRA through improving the quality of block in terms of onset and offset. However, Kleinschmidt et al. [16] demonstrated that there were no significant differences between the groups concerning the onset time of tourniquet pain on the addition of clonidine 2 μg/kg to prilocaine 0.75% for IVRA. Dexmedetomidine is approximately eight times more selective toward the α2-adrenoceptors than clonidine. Hegazy et al. [19] found that the addition of ketamine to lidocaine delayed onset time of tourniquet pain in IVRA through improving the quality of block in terms of onset and offset.

In the current study, there were statistically significant low VAS scores of incisional and tourniquet pain in adjuvant groups LM, LD, and LK compared with control group LL at 10, 15, 20, 30, 40 min, and the end of the operation (P<0.001). At the same time, there was a significant statistical decrease in VAS scores in LD and LK groups compared with LN group at 40 min and at the end of the operation (P<0.05). Moreover, there were no significant differences between LD and LK groups regarding intraoperative VAS changes (P>0.05). These results were in accordance with the Gentili et al. [8], Gorgias et al. [17], and Sen et al. (2006). They reported that the addition of ketamine to lidocaine improved VAS of incisional and tourniquet pain in IVRA through improving the quality of block in terms of onset, offset, and grade of the block.

Regarding rescue of intraoperative analgesia, there was a significant increase in fentanyl requirements in control LL group compared with adjuvant LM, LD, and LK groups (P≤0.001). Within the adjuvant groups, fentanyl requirements were significantly more in group LN than in LD and LK groups (P≤0.01). There was no significant difference between LD and LK regarding intraoperative fentanyl requirements (P≥0.05).

These results matched with the study done by Yoshitomi and Kohjitani [15] who reported that the addition of dexmedetomidine to lidocaine reduced intraoperative fentanyl consumption in IVRA through improving the quality of block and reducing tourniquet pain. Meanwhile, the study done by Hegazy et al. [19] agreed with this study regarding addition of ketamine to lidocaine reduced intraoperative fentanyl consumption in IVRA through improving the quality of block and reducing tourniquet pain.

The duration of postoperative analgesia was significantly prolonged in adjuvant groups LM, LD, and LK compared with control LL group (P≤0.01). These results were in agreement with the studies by Honarmand et al. [11], Yoshitomi and Kohjitani [15], and Hegazy et al. [19]. On the contrary, Kleinschmidt et al. [16] reported that the addition of clonidine 2 μg/kg to IVRA with prilocaine 0.5% did not provide a significant improvement in postoperative pain.

Postoperative pethidine requirements were significantly higher in LL and LM groups compared with LD and LK groups (P≤0.01). These results agreed with the study done by Honarmand et al. [11] who reported that the addition of midazolam to lidocaine decreased requirements of postoperative analgesia requirements in IVRA. Moreover, Yoshitomi and Kohjitani [15] reported that the addition of dexmedetomidine to lidocaine decreased requirements of postoperative analgesics in IVRA by increasing duration of postoperative analgesia. At the same time, Hegazy et al. [19] reported that the addition of ketamine to lidocaine decreased requirements of postoperative analgesics in IVRA by increasing duration of postoperative analgesia.

Regarding satisfaction, there was a significant increase in patient and surgeon satisfaction in adjuvant groups LM, LD, and LK compared with control LL group owing to lack of block in the control group (P≤0.01). These results matched with the study done by Honarmand et al. [11], who reported that the addition of midazolam to lidocaine, and Gorgias et al. [17], who reported that the addition of dexmedetomidine or ketamine to lidocaine in IVRA improved patient and surgeon satisfaction through improving quality of block in terms of onset, offset, and tourniquet pain.

In the present study, the addition of ketamine to lidocaine for IVRA did not affect MAP, HR, and SPO2, either intraoperatively or postoperatively. Meanwhile, these results agreed with a study done by Viscomi et al. [5] who did not report any significant changes regarding HR, MAP, and peripheral oxygen saturation on the addition of ketamine to lidocaine for IVRA. Moreover, Esmaoglu et al. [20] reported no significant hemodynamic changes either on the addition of dexmedetomidine 1 μg/kg to lidocaine 0.5% for IVRA. This can be owing to the fact that the tourniquet was not deflated before 30 min, and the tourniquet deflation was performed by the cyclic deflation technique at the end of surgery. Moreover, intravenous ketamine causes a transient increase in the blood pressure over 3–5 min, which then returns to normal level, 10–20 min after injection.

In the present study, two patients from LL and LM groups had small-sized hematoma after removal of the cannula inserted for injection of drugs used in IVRA, which resolved by slight compression at the insertion site. Moreover, pain on injection occurred in two patients in LL and LD groups and one patient in LM group, which resolved by slowing rate of injection. Cutaneous erythema and blanching of the skin after proximal tourniquet inflation and before local anesthetic injection occurred in four patients in LL, LM, and LD groups, which resolved by tourniquet release, and then proper exsanguination of the limb to avoid venous congestion. These results mismatched with a study done by Gorgias et al. [17], Honarmand et al. [11], and Hegazy et al. [19] who revealed no adverse effects occurred during IVRA.In the current study, four patients in LD group complained of sedation after the release of the tourniquet. This result agreed with the study done by Reuben et al. [21] who reported transient sedation on the addition of 150 μg clonidine to lidocaine 0.5% for IVRA in patients undergoing ambulatory hand surgery. Meanwhile, Memis et al. [9] did not report significant postoperative sedation, hypotension, or bradycardia on the addition of dexmedetomidine 1 μg/kg to lidocaine 0.5% for IVRA. These differences in results may be because of the different drugs and doses used in the studies, although with the same pharmacological properties. Hallucination occurred in five patients after tourniquet release in LK group, which was resolved by administration of intravenous 0.1 mg/kg midazolam. There were no other signs of central nervous system toxicity such as circumoral numbness, blurring of vision, and seizure, either intraoperatively or postoperatively, in all groups. These results agreed with a study done by Kaul et al. [22] who noticed the occurrence of postoperative hallucination with ketamine when used as an adjuvant to lignocaine in IVRA in dose more than 0.1 mg/kg owing to a significant dose reached systemic circulation after tourniquet release. On the contrary, these results disagreed with the study by Viscomi et al. [5], as they did not report any neurological adverse effects during IVRA using dexmedetomidine or ketamine as an adjuvant to lidocaine. This may be because of the local metabolism of drugs in an isolated limb, proper use of tourniquet did not allow the significant dose of drugs to reach systemic circulation, and the dose and the concentration of drugs used in the study [23].

 Conclusion



The addition of midazolam, dexmedetomidine, or ketamine to lidocaine for IVRA improved the quality of intraoperative and postoperative analgesia with minimal adverse effects. Despite midazolam fastening the onset time for sensory and motor block, dexmedetomidine and ketamine were superior in delaying the onset of tourniquet pain, prolonging the duration of postoperative analgesia, and resulting in higher patients and surgeon satisfaction.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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