Most patients presenting for vitreoretinal surgery are elderly and have significant comorbidities.1 Vitreoretinal surgeries often are associated with a high incidence of postoperative pain, most likely as a result of traction on the extraocular muscles and sclera.2 The performance of vitreoretinal surgery solely under local anesthesia (LA) is now preferred by most patients, surgeons, and other staff, and it is associated with the least disturbance to the patient’s normal activity.3 Recent reports suggest that the use of sub-Tenon’s block anesthesia is becoming more widely practiced among anesthesiologists and ophthalmologic surgeons because of to its greater safety and reliability than traditional ophthalmic regional anesthesia techniques.4,5
Dexmedetomidine is a centrally acting, highly selective α-2-adrenoreceptor agonist with both sedative and analgesic properties and is devoid of respiratory depressant effects. Dexmedetomidine has been studied as an additive to local anesthetics in peripheral nerve block, plexus block, and neuraxial anesthesia to shorten the onset and prolong the duration of analgesia.6–9
The aim of this study was to evaluate the motor and sensory block durations as primary end points and the postoperative analgesic effects as a secondary end point after adding dexmedetomidine to levobupivacaine for sub-Tenon’s block anesthesia in patients undergoing vitreoretinal surgery.
As yet, dexmedetomidine is not approved for perineural administration by the US Food and Drug Administration. Because we have no equivalent regulatory agency in Oman, the IRB of the Magrabi Eye & Ear Hospital, Muscat, Oman, was responsible for the review and approval of the study protocol before patient enrollment, taking into consideration the legislative requirements and existing national regulations as well as applicable international norms and standards. The IRB committed the authors to use only a dose of 20 μg dexmedetomidine based on the data from previous studies that safely used dexmedetomidine perineurally (20–100 μg).6–8 Furthermore, they monitored this study throughout all the stages. This study was registered in the European clinical trials database (https://eudract.ema.europa.eu/, EudraCT number: 2014-005648-17) and in the ClinicalTrials.Gov (NCT02327156). Written informed consent was obtained from all the patients.
Sixty ASA physical status I to III adult patients, listed for elective primary retinal detachment surgery using sub-Tenon’s block anesthesia, participated in this prospective, double-blind, randomized study. Satisfactory akinesia and predictable surgical time of <3 hours were inclusion criteria for this study. Exclusion criteria included patients younger than 18 years, patients with a single eye, history of sleep apnea, severe cardiac disease, and drug abuse or any contraindication to LA. This study was performed at the Magrabi Eye & Ear Hospital in Oman between January 2014 and September 2014. All operations were performed by the same surgeon. The patients were randomly divided into 1 of 2 groups depending on the LA solution used: either 4 mL of 0.75% levobupivacaine (Chirocaine, Abbott Laboratories, Elverum, Norway) with 15 IU/mL hyaluronidase in addition to 1 mL of normal saline (group L, n = 30) or 4 mL of 0.75% levobupivacaine with 15 IU/mL hyaluronidase in addition to 20 μg dexmedetomidine (Precedex, 200 μg per 2 mL; Hospira, Lake Forest, IL) diluted with 1 mL of normal saline (group LD, n = 30). The total volume of the local anesthetic solution used was 5 mL, which was prepared at the bedside before the injection and provided in patient-specific, sealed packaging by a member of the staff not involved in the study. Patients admitted to the operating room fasted for 8 hours and were not premedicated. A peripheral IV cannula was inserted, and standard monitoring was applied and recorded heart rate, noninvasive arterial blood pressure, electrocardiogram (5 leads), and peripheral capillary oxygen saturation. Supplemental oxygen was given through nasal cannula at 4 L/min. All blocks were performed by the same surgeon experienced in the technique described by Guise.10 Both the patient and the surgeon were blinded to the solution used.
All measures were assessed by an anesthetist not engaged in the study. Motor block was assessed by evaluation of the akinesia in the 4 quadrants through a 3-point scoring system, where 0 = akinesia, 1 = partial akinesia, and 2 = normal movement, with a maximal score of 8. The motor block was considered successful if the akinesia score was ≤3.11 If inadequate motor blockade was observed 10 minutes after block, supplementary anesthesia (2 mL of levobupivacaine) was injected through the same conjunctival incision. Sensory block was evaluated by the abolition of the corneal reflex to instillation of drops of physiologic solution on the conjunctiva and cornea. The motor block and sensory block durations (minutes) were then evaluated postoperatively every hour when there was no surgical contraindication to removal of the eye cover. The sedation level was assessed by means of the Ramsay sedation scale (Table 1), which was explained to the patients in the preoperative visit, during the surgery, and at 4, 8, 12, 18, and 24 hours postoperatively.12
The patients were kept in the hospital for the first postoperative night because early (initial 6 to 24 hours) postoperative positioning (head-up, face-down, or head-inferior position) is often important in the management of subretinal fluid and to avoid complications related to retinal detachment repair. The degree of postoperative pain was assessed using the Verbal Numeric Rating Scale (VNRS) of pain, where 0 = no pain and 10 = the worst pain imaginable at 1, 2, 3, 4, 6, 8, 12, 18, and 24 hours postoperatively. The patients were given 1 mg/kg diclofenac intramuscularly if the VNRS for pain was >4. Tramadol 100 mg was given IV by infusion over 15 minutes as rescue analgesia medication along with the diclofenac if the patient complained of severe pain (VNRS > 7). Both analgesics were given in a maximum frequency of 6 hours and 3 doses maximally per 24 hours. The total diclofenac consumption (milligrams) and the number of patients (percent) who required tramadol were recorded. Sleep quality on the first postoperative night was assessed in the day after surgery using the Consensus Sleep Diary,13 which is a self-monitor questionnaire to be recorded by the patients on a night-by-night basis. The Consensus Sleep Diary is regarded as the gold standard for subjective sleep assessment. At the end of the questionnaire, the patient rated the quality of sleep to be very good, good, fair, bad, or very bad. The patients were examined on the day after surgery and after 1 week for any clinical signs of nerve damage or perineural inflammation.
A preliminary study was conducted on 10 patients (5 in each group). Sub-Tenon’s block anesthesia using 4 mL of 0.75% levobupivacaine plus 15 IU/mL hyaluronidase resulted in prolongation of the motor block duration from 252 ± 88 minutes in group L to 331 ± 92 minutes in group LD when 20 μg dexmedetomidine was added. On the basis of this study, it was calculated that a total number of 60 patients (30 pairs) would be required to have a 90% power of detecting a 30% prolongation in the motor block duration at a significance level of 0.05. Altman’s nomogram for the calculation of sample size or power was used (Altman DG. Practical Statistics for Medical Research. London: Chapman & Hall, 1991). Data were presented as mean ± SD or number (%). In the intergroup comparison, Pearson χ2 test was used to analyze the nominal categorical data; the ordinal categorical data were compared using the Mann–Whitney U test. Comparison of quantitative/numerical variables between the 2 groups was performed with an independent 2-sample t test. The significance level was set at P < 0.05. Statistical analysis of the results was conducted using the computer program SPSS version 16.0 for Windows (SPSS, Chicago, IL).
Sixty-eight patients were assessed for eligibility for this study. Eight were excluded from enrollment either because of failure to meet the inclusion criteria (n = 5) or because they declined to participate in the study (n = 3). Sixty patients were randomly divided equally into 1 of 2 groups. All patients received the allocated treatment, whereas 1 patient in each group required supplemental injection of local anesthetic. This is a common practice in eye blocks, and they were not dropped or replaced in the study. Afterward, all patients were followed up and analyzed (Fig. 1).
This study demonstrated comparable results concerning age, gender, weight, duration of surgery, and surgery side in the dexmedetomidine group compared with the levobupivacaine group (Table 2). The motor block duration (minutes) was significantly (P = 0.001) longer in the dexmedetomidine group compared with the patients in the levobupivacaine group (Table 2). Similarly, the sensory block duration (minutes) was significantly (P = 0.001) longer in the dexmedetomidine group compared with the patients in the levobupivacaine group (Table 2). Significantly (P < 0.0001) greater Ramsay sedation scale levels in the dexmedetomidine group patients were reported compared with the levobupivacaine group patients 30 minutes after the block and onward until the end of surgery (Fig. 2).
During the postoperative period, patients in the dexmedetomidine group achieved significantly (P < 0.0001) lower values of VNRS compared with those in the levobupivacaine group between the periods from 4 to 12 hours postoperatively (Fig. 3). Consequently, diclofenac consumption (mg) was significantly (P = 0.001) less in the dexmedetomidine group compared with the patients in the levobupivacaine group (Table 2). Furthermore, the percentage of patients who required tramadol rescue medication was significantly (P = 0.039) less in the dexmedetomidine group compared with the levobupivacaine group (Table 2). The patients in the dexmedetomidine group showed significantly (P < 0.0001) higher rates of good sleep quality on the first postoperative night (70%) compared with the patients in the levobupivacaine group (30%; Fig. 4). The clinical examination on the day after surgery and after 1 week disclosed no clinical signs of nerve damage or perineural inflammation.
This study demonstrated that the use of dexmedetomidine as an adjuvant to levobupivacaine in patients undergoing vitreoretinal surgery under sub-Tenon’s block anesthesia extended the motor and sensory block durations and delivered more effective postoperative analgesia, as shown by lower diclofenac consumption and fewer patients requiring tramadol as a rescue analgesia medication. However, the patients who received dexmedetomidine achieved greater levels of sedation throughout the surgery period and postoperatively for 12 hours.
Similar results had been described in previous studies.6–9 However, most of these studies were designed for different clinical applications. In a study by Esmaoglu et al.,8 the authors reported similar effects when they added 100 μg of dexmedetomidine to levobupivacaine for axillary block. The authors found an increased motor and sensory block durations of 3.6 hours, which also extended the postoperative analgesia period. Similarly, Rancourt et al.7 demonstrated that the addition of 1 μg/kg dexmedetomidine to ropivacaine for posterior tibial nerve block resulted in prolonged duration of sensory blockade with similar onset time. Agarwal et al.14 found that when 100 μg of dexmedetomidine was added to bupivacaine for supraclavicular brachial plexus block, the duration of sensory and motor blocks and the duration of postoperative analgesia were all significantly prolonged and associated with higher sedation levels. Furthermore, Marhofer et al.6 studied 36 volunteers who received ultrasound-guided ulnar nerve block using 0.75% ropivacaine with or without 20 μg of dexmedetomidine and reported a profound prolongation of sensory and motor block durations by 60% in the patients who received dexmedetomidine. Comparable results were found in earlier studies investigating the effect of adding dexmedetomidine to the LA in neuraxial blocks.9,15 These outcomes alone might support dexmedetomidine as a potential adjuvant to the LA in vitreoretinal surgeries.
The mechanism by which α2-adrenergic receptor agonists produce analgesia and sedation is not fully clear, but it is likely to be multifactorial. Oda et al.16 reported that α2 agonists produce peripheral analgesia by reducing the release of norepinephrine and causing α2 receptor–independent inhibitory effects on nerve fiber action potentials, whereas α2 agonists produce central analgesia and sedation by inhibition of substance P release in the nociceptive pathway at the level of the dorsal root neuron and by activation of α2 adrenoceptors in the locus coeruleus. Various studies in animals have been conducted to investigate the mechanism by which dexmedetomidine enhances the sensory and motor block and produces sedation. Brummett et al.17 demonstrated that the use of high-dose dexmedetomidine as an adjuvant to ropivacaine for sciatic nerve block in rats caused an approximately 75% increase in the duration of bupivacaine anesthesia and analgesia. Also, they found that the peripheral analgesic effects of dexmedetomidine were not reversed by α2-adrenoceptor antagonists (idazoxan), whereas it was reversed by pretreatment with an Ih current agonist (forskolin). Brummett et al.18, in another experimental animal study, reported that the sciatic nerve histopathology performed at 24 hours and 14 days showed normal axons and myelin.
Our study revealed no clinical signs of nerve damage or perineural inflammation with the addition of 20 μg dexmedetomidine to levobupivacaine for sub-Tenon’s block anesthesia in vitreoretinal surgery. However, this cannot absolutely assure the safety of the perineural use of dexmedetomidine, because there were some limitations to this study that included the low number of patients and the small dose of dexmedetomidine used. However, the results of this study are promising for further studies aimed at evaluating the safety of perineural dexmedetomidine in eye blocks.
In conclusion, we found that the addition of 20 μg of dexmedetomidine to levobupivacaine for Sub-Tenon’s block anesthesia in vitreoretinal surgery, compared with the use of levobupivacaine alone, extended motor and sensory block durations and provided more effective postoperative analgesia with improvement in the sleep quality on the first postoperative night for these patients.
Name: Ashraf M. Ghali, MD.
Contribution: This author helped design the study, acquire the data, analyze the data, interpret the data, and write the article.
Attestation: Ashraf M. Ghali has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is responsible for maintaining the study records (archival author).
Name: Amir M. Shabana, MD.
Contribution: This author helped prepare the manuscript, analyze the data, and interpret the data.
Attestation: Amir M. Shabana has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: Ashraf M. El Btarny, MD.
Contribution: This author helped design the study, acquire the data, analyze the data, interpret the data, and write the article.
Attestation: Ashraf M. El Btarny has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
This manuscript was handled by: Terese T. Horlocker, MD.
We thank Dr. Mahmoud M. Ibrahim, Assistant Professor of Educational Psychology (statistical education), Sultan Qaboos University, Oman, for his statistical assistance.
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© 2015 International Anesthesia Research Society
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