Hyaluronidase 7.5 IU/mL added to the local anesthetic improves peribulbar block, but smaller concentrations have not been shown to be effective. In this prospective, double-blinded study, 714 consecutive ocular surgery patients were randomized into three groups: no hyaluronidase (n = 241), hyaluronidase 3.75 IU/mL (n = 244), and hyaluronidase 7.5 IU/mL (n = 229). Retrobulbar/peribulbar block was performed with two injections of a 1:1 mixture of bupivacaine 0.75% and lidocaine 2%, 6–8 mL. Patient data were collected on demographics, initial volume of local anesthetic, need for supplementary block, and akinesia of the anesthetized eye. When hyaluronidase was used (3.75 or 7.5 IU/mL), the initial block was sufficient and the anesthetized eye was akinetic significantly more often than in the group without hyaluronidase. The hyaluronidase groups (3.75 and 7.5 IU/mL) did not differ significantly in any respect. We conclude that the addition of hyaluronidase 3.75 or 7.5 IU/mL improved the success of the initial retrobulbar/peribulbar block and akinesia and reduced the need for supplementary block.
Implications: We conclude that the addition of hyaluronidase 3.75 or 7.5 IU/mL improved the success of the initial retrobulbar/peribulbar block and akinesia and reduced the need for supplementary block.
Hyaluronidase has a reversible depolymerizing action on hyaluronic acid, which is a component of connective tissue. Hyaluronidase does not offer any advantage in most regional blocks (1–4), but it improves the quality of regional anesthesia of the eye.
Lewis-Smith (5) studied the effect of hyaluronidase on subcutaneous infiltration blocks with lidocaine, and the results were visualized by using fluorescein. He showed that the onset of anesthesia was hastened, the spread of infiltrate was extended, and the duration of anesthesia was reduced by the presence of hyaluronidase. In peribulbar anesthesia, hyaluronidase 7.7 IU/mL accelerates the absorption of both lidocaine and bupivacaine (6). In the study conducted by Krohn et al. (7), the frequency of complications in cataract surgery was less when hyaluronidase was added to the local anesthetic solution. Adding hyaluronidase 15 IU/mL to a mixture of bupivacaine and lidocaine in retrobulbar anesthesia significantly improved the motor block (8). Similarly, the addition of hyaluronidase 7.5 or 15 IU/mL to etidocaine improved peribulbar block (9).
In our department, hyaluronidase 3.75 IU/mL is used with a 1:1 mixture of bupivacaine 0.75% and lidocaine 2% in retrobulbar/peribulbar blocks for ocular surgery. In the literature, there is no evidence of the effectiveness of 3.75 IU/mL concentration of hyaluronidase. In an earlier study from our department, 7.5 IU/mL was shown to be effective (9), and therefore, we considered it necessary to compare the use of local anesthetic solution with hyaluronidase 3.75 or 7.5 IU/mL, and without hyaluronidase in retrobulbar/peribulbar block.
The ethics committee at Helsinki University Eye Hospital approved the study protocol. Informed consent was obtained from the patients. During 4 mo, 714 consecutive adult patients scheduled for retrobulbar/peribulbar block for elective cataract, glaucoma, or eye muscle surgery were included. Patients who were admitted to the hospital for emergency surgery, corneal transplantation, retinal ablation, or vitreous operations were not included.
Because we were testing patients at our normal clinical practice, the blocks were performed by all doctors working in our department at that time. Approximately half of the blocks (370) were performed by experienced staff members (three anesthesiologists) and the remainder by five trainees in anesthesiology and ophthalmology.
The patients were allocated into three groups according to the concentration of hyaluronidase in the local anesthetic mixture: no hyaluronidase (G0), hyaluronidase 3.75 IU/mL (G3.75), and hyaluronidase 7.5 IU/mL (G7.5). For practical reasons, only one hyaluronidase concentration was used each day, and the concentration was determined by permuted block-restricted randomization. Only the nurse preparing the local anesthetic mixture for that day knew which hyaluronidase concentration was used.
The ocular block was performed as follows. Topical anesthesia was induced by oxybuprocaine (Oftan Obucain® 4 mg/mL; Star, Tampere, Finland). Transconjunctival retrobulbar/peribulbar block was performed as described previously (10)—injection at medial canthus, near perpendicular direction of the frontal plane peribulbarly, with a 12-mm, 30-gauge needle (Microlance®; Becton Dickinson, Orogheda, Ireland). An inferolateral retrobulbar injection was performed by using a 31-mm, 27-gauge needle (PrecisionGlide®; Becton Dickinson, Franklin Lakes, NJ). The local anesthetic was a 1:1 mixture of bupivacaine 0.75% and lidocaine 2%, with epinephrine 5 μg/mL added to the injection at the medial canthus. The volume of the initial block was adjusted according to the lean body weight: 6 mL for patients <70 kg, 7 mL for patients between 70 and 80 kg, and 8 mL for those >80 kg. This initial volume was evenly divided between the peribulbar and retrobulbar injections.
Patient data were collected on sex, age, ophthalmic diagnosis and surgery, axial length of the eye (mm), initial local anesthetic volume (mL), and the need for a supplementary block or general anesthesia. The description of any supplementary regional anesthesia (topical, sub-Tenon, or retrobulbar/peribulbar) was registered. The eye movements were checked 10 min after injecting the local anesthetic solution. Movements of the six extraocular muscles (superior/inferior/lateral/medial rectus and superior/inferior oblique) were scored 0–2 as follows: score 0 = no movement, score 1 = partial movement, and score 2 = full movement of any of those six muscles. Correspondingly, we scored separately levator palpebrae and orbicularis oculi muscle movements (0–2). Consequently, the maximum score of all eye movements was six and the minimum zero.
Power analysis on preliminary data from the pilot study showed that the sample size should be 209 using α 0.05 and power of 0.99. Consequently, approximately 300 patients should be a sufficient number to investigate whether hyaluronidase 3.75 IU/mL is as effective in retrobulbar/peribulbar anesthesia as is hyaluronidase 7.5 IU/mL. To achieve a sufficient safety margin, we decided to double the number of patients to 700.
The hypotheses that hyaluronidase 3.75 IU/mL would not improve the block and that hyaluronidase 3.75 and 7.5 IU/mL do not differ was tested by using the Mann-Whitney ranked sum test with Bonferroni correction. The hypothesis that the three study groups would achieve equally effective blocks was tested by using Kruskal-Wallis one-way analysis on ranks. The need for supplementary blocks and success rates of each of the three eye movement scores as well as failure rates of the sum scores were compared among the three study groups with χ2 analysis. Parametric quantitative variables are expressed as means ± sd (ranges), and nonparametric variables are expressed as medians ± 95% confidence intervals. P values <0.05 are considered statistically significant.
The patients’ distribution, demographic data, and the spectrum of diagnoses did not differ significantly among the study groups (Table 1). Phacoemulsification with ultrasound and implantation of the lens to the posterior chamber was performed in 95% of the cataract patients. No operation had to be canceled because of a problem with the regional anesthetic block, and none of the study patients needed general anesthesia.
The initial block was adequate significantly more often in the groups with hyaluronidase. G3.75 and G7.5 did not differ in this respect (Table 2). With α = 0.01, the initial block in G3.75 was successful more often than in G0 with a power of 0.999. Eye movement scores are itemized in Table 3. The addition of hyaluronidase significantly improved the success of the motor block, and the two doses of hyaluronidase did not differ significantly. Extraocular, levator palpebrae, and orbicularis oculi muscle movement scores yielded similar results in both hyaluronidase groups. All eye movements were abolished significantly more often in the hyaluronidase groups (48%) than in G0 (27%) (P < 0.001). The sum of all eye movement scores gave maximum value (=6) significantly more often in G0 (13%) than in the hyaluronidase groups (2%) (P < 0.001).
Results of studies on hyaluronidase in ocular blocks have been controversial. Published studies cover concentrations from an ineffective concentration of 0.75 IU/mL (11) to an effective one of 300 IU/mL (12). The efficacy of hyaluronidase for the retrobulbar and peribulbar blocks should be discussed separately. Retrobulbar blocks are consistently improved by using hyaluronidase in concentrations from 7.5 to 60 IU/mL (11,13,14). In most studies, the quality of peribulbar blocks was equal with or without hyaluronidase in concentrations from 25 to 150 IU/mL (15–18). However, Dempsey et al. (12) found an improvement in the quality of peribulbar block by using either 50 or 300 IU/mL of hyaluronidase compared with hyaluronidase-free local anesthetic solution, and the same was reported by Sarvela and Nikki (9) by using 7.5 or 15 IU/mL of hyaluronidase. In the present study, the addition of hyaluronidase 3.75 or 7.5 IU/mL was equally effective and significantly improved the success of the retrobulbar/peribulbar block. No variable of this study indicated that increasing the concentration of hyaluronidase to 7.5 IU/mL would offer any further advantage compared with 3.75 IU/mL.
Our clinical impression was that it is often possible to achieve adequate analgesia and motor block without hyaluronidase. Therefore, we believed that the addition of just a small amount of hyaluronidase (3.75 IU/mL) would probably have no effect. To avoid the possibility of testing only an ineffective concentration (3.75 IU/mL) against no hyaluronidase, we included the G7.5 as the effective control (9).
A successful inferolateral retrobulbar injection results in motor block of all extraocular muscles, and consequently the globe is fixed at the primary gaze. The retrobulbar inferolateral injection offers a greater technical challenge than the peribulbar medial injection. Because hyaluronidase hastens and improves the spread of local anesthetic (5), it allows for some inaccuracy in the retrobulbar injection, and despite this, an acceptable block of extraocular and levator palpebrae muscles will be achieved.
The superior branch of the oculomotor nerve divides before entering through the superior orbital fissure into the orbital cavity (19), and that is why the levator palpebrae muscle may be difficult to anesthetize by an inferolateral retrobulbar injection. Motor block of the levator palpebrae muscle is not crucial for cataract surgery with the modern techniques. However, postoperative function of the levator palpebrae muscle and paresis of the orbiculars oculi muscle is a harmful combination because it may result in corneal abrasions. To avoid this, the eye must be covered overnight if long-acting local anesthetics are used.
The orbicularis oculi muscle is anesthetized by the medial canthal peribulbar injection. Motor block of the orbicularis oculi muscle is essential to achieve appropriate conditions for intraocular operations with large wounds, such as are incurred in corneal transplantation. Our results indicate that the efficacy of the peribulbar medial injection is better when either of the hyaluronidase concentrations is added to the local anesthetic mixture. This finding is similar to the results from the use of larger concentrations of hyaluronidase (9,12) and confirms that there does not appear to be a clear dose/response relationship between hyaluronidase dose and quality of peribulbar block.
In conclusion, this study of 714 patients shows that the addition of hyaluronidase 3.75 IU/mL improves the diffusion of local anesthetics resulting in an adequate retrobulbar/peribulbar block significantly more often, and that increasing the concentration of hyaluronidase to 7.5 IU/mL does not offer any further advantage over 3.75 IU/mL. Supplementary blocks were needed significantly more often when the local anesthetic solution was hyaluronidase-free.
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