【摘要】 目的：在兔模型中利用局部麻醉来研究两种麻醉剂的眼心反射发生率及其预防，同时我们还研究了局部麻醉对角膜愈合的影响。方法：健康的成年新西兰白兔（雌雄皆有）48只，分成两组（A组和B组），分别用氯胺酮（A组，24例）、异丙酚（B组，24例）麻醉。在此双盲研究中，通过用或不用局部麻醉（40g/L 利多卡因, 5g/L盐酸丙美卡因, 5g/L布比卡因）对眼睛的不同干预，记录各组眼心反射发生率。应用每种局部麻醉后，通过对眼睛的临床检查，组织病理学，胶原染色以及投射电子显微等方法对术后1d长达7d角膜毒性和愈合进行评估。结果：在氯胺酮的麻醉下未出现眼心反射，而在异丙酚的麻醉下，心率显著下降（P<0.01）。因此，局部麻醉可以成功地防止眼心反射的发生并且不影响角膜愈合。结论：局部麻醉没有任何局部副作用，可以被推荐用来预防眼心反射。
【关键词】 眼心反射；局部麻醉；角膜愈合；氯胺酮；异丙酚
INTRODUCTION
Oculocardiac reflex (OCR) is a physiological response of the heart to physical stimulation of the eye or the ocular adnexa, characterized by bradycardia or arrhythmia, which sometimes leads to cardiac arrest. It is defined as 10% decreases in heart rate (HR) or occurrence of any arrhythmia induced by traction during the extraocular muscle surgery of recessionresection type or manipulation of extraocular muscles during other eye surgeries. The incidence of OCR has been encountered with strabismus surgery, ranging from 32% to 90%. Transient cardiac arrest could be as frequent as 1 in 2200 corrections of strabismus depending upon the methods used and the criteria of evaluation chosen. The OCR has also been reported in LASIK[1]. It has been observed during eye muscle surgery, repair of detached retina, compression of gasserian ganglion, enucleation of eye, by contact lens[2], and repair of nasal fracture under general anesthesia.
The anesthetic regimen modulates the expression of OCR[35]. Several preventive strategies[6,7] have associated complications[8]. Pediatric ophthalmic surgery is usually performed under general anesthesia. We have studied the incidence of OCR under ketamine and propofol anesthesia, commonly used for pediatric ophthalmic surgery[9,10], in a rabbit eye model and its prevention by using topical anesthetic. Topical anesthetics are recognized as excellent corneal analgesic, but their toxic effect on corneal epithelial cells limits its use during corneal epithelial wound healing. Mechanism of the impairment of corneal reepithelialization with topical anesthetics, however, has not been evaluated[11]. On the other hand several literatures have reported the safety of using local anesthetics topically on the eye[12,13]. We therefore sought to investigate the effect of topical anesthetics on corneal healing.
MATERIALS AND METHODS
Subjects The work was carried with prior permission of Institutional Animal Ethics Committee and abiding by the tenets of Association of Research in Vision and Ophthalmology. The study was conducted on fortyeight clinically healthy adult New Zealand white rabbits of either sex between the age group of 1 year to 1.5 years and weighing between 3kg to 3.5kg. Routine clinical evaluation and preoperative ophthalmic examination of both eyes of all the animals was done prior to the experiment.
Methods The total number of animals were randomly divided into two groups; Group A and B consisting of twentyfour in each group irrespective of age, weight and sex. In this study, all the 24 animals of Group A, received ketamine hydrochloride (Ketmine 50, Themis Medicare Ltd Gujrat India) at the dose of 35mg/kg as general anesthetic, and animals of Group B were administered propofol (10g/L propofol, 10mL, Cleris Life Sciences L.T.D., Ahmedabad) at the dose of 7mg/kg as general anesthetic.
After induction of anesthesia, ECG was recorded using continuouscardiac monitor (Excello+REC Multiparamonitor BPL Limited India) (Figure1A) immediately in both the groups. In Group B, ECG recorded 3 minutes after induction of anesthesia was considered basal heart rate for this group. All ocular manipulations were performed in surgical stage of anesthesia. The depth of anesthesia was assessed by head shaking in response to ear pinching and pedal reflex. At the surgical stage of anesthesia the entire study for OCR was studied in two phases. In initial phase all procedures to incite OCR were done without the use of topical anesthesia. A gap of five minutes was allowed after each type of ocular manipulation i.e. traction on extraocular muscle, application of digital pressure on various sites on the eye ball and superficial keratectomy. This was to register the effect of each type manipulation on the heart rate. A gap of five minutes was allowed to abolish the effect of the previous manipulation. Surgical manipulations were done by applying traction on medial rectus, superior rectus; lateral rectus (Figure 1B). A conjunctival forcep was used to hold the extraocular muscle which was easily identified through the thin conjunctiva in the rabbit eye. Each muscle was held and traction was applied. Any change in heart rate was registered, OCR was incited by applying digital pressure on the eyeball, and the index finger was used to apply pressure on the eye ball on all superior, inferior medial and lateral positions. Uniform corneal defects were created using a 6.5mm trephine (Figure 1C), followed by mechanical superficial keratectomy using No.11 blade (Figure1D). ECG was recorded continuously during the ocular manipulations. A 10% reduction in heart rate was considered positive for oculocardiac reflex.
Figure 1 Continuous monitoring and recording of ECG in rabbits A: Normal; B: Applying traction on extraocular muscle; C: Creating corneal defects using a 6.5 mm trephine;D: Superficial keratectomy（略）
In the second phase still maintaining the surgical level of anesthesia, the rabbits of each group were divided into four subgroups, with six animals in each subgroup. The animals were given rest for few minutes following surgical manipulation of the first phase till the heart rate came back to normal baseline as observed by continuous cardiac monitoring. Similar surgical manipulation by the same surgeon was repeated in each subgroup after using 2 drops either of the topical anesthetics instilled on the cornea, lignocaine 40g/L (Xylocaine 40g/L topical, Astra Zeneca LTD., Bangalore), bupivacaine 5g/L (Sensorcaine 5g/L 20mL, Astra Zeneca LTD., Bangalore), proparacaine 5g/L (Carecain 5g/L, Ajanta Pharma India LTD Bangalore) while in the fourth subgroup no topical anesthetic was administered and used as control.
Extent of corneal injury (wound), on the treated eyes of all 48 animals, was examined on 1st postoperative day. After one day of experiment, 6 rabbits from each subgroup (subgroups of different topical anesthesia and control) were randomly selected and euthanized with overdose of thiopental sodium (Thiosol 500mg,Neon Laboratories, Mumbai) and corneal tissues were collected in glutaraldehyde for transmission electron microscopy (TEM) (Techni g2 Biotwin Fet Holland, Philips).
Fluorescein dye test was performed on 6 rabbits from each subgroup following surgery for recording the course of clinical healing. Postoperative intraocular changes were monitored by slit lamp biomicroscopy and ophthalmoscopy. After 7 days the animals were euthanized by the same procedure, corneal tissues were collected in 40g/L formalin for histopathology and the corneal tissue sections were stained with hematoxylin eosin and sirius red following standard procedure.
Postoperative medication comprised of analgesic Inj meloxicam (Melonex, Intas Pharmaceuticals, Ahmedabad, India) after recovery from anesthesia and topical instillation of eye drops Ciprofloxacin (Ciplox, Cipla India) and Flurbiprofen (Flur, Allergan India), twice a day till euthanasia. Postoperative treatment comprised of topical instillation of ciplox eye drops and flubiprofen eye drops. A temporary tarsorraphy was done in all rabbits for 24 hours.
Figure 2 Corneal healing as detected by flourecein dye test A:Day 1 untreated;B: Day 4 untreated; C:Day 1 with lignocaine;D: Day 4 with lignocaine;E:Day 1 with proparacaine; F: Day 4 with proparacaine; G:Day 1 with bupivacain;H: Day 4 with bupivacain （略）
Figure 3 Histopathology of rabbit treated with topical anesthetics A: Proparacain; B: Lignocain; C: Bupivacain; D: Control（略）
Figure 4 Ultrastructure of rabbit cornea treated with topical anesthetics A:Normal;B: Bupivacaine; C: Lignocain;D: Proparacain; N: Nucleus; M: Mitochondria; E: Endoplasmic reticulum;J: Cellular junction（略）
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