WO1994012104A1

WO1994012104A1 - Method and device for effecting aesthesiometries

Info

Publication number: WO1994012104A1
Application number: PCT/ES1993/000091
Authority: WO
Inventors: Carlos Belmonte Martinez; Miguel Angel Pozo Garcia; Chen Xiaojie; Juana Gallar Martinez
Original assignee: Universidad De Alicante
Priority date: 1992-11-20
Filing date: 1993-11-19
Publication date: 1994-06-09
Also published as: AU5466694A

Abstract

The method comprises: (a) applying to the cornea or conjunctiva of the eye, whose sensitivity is to be determined, a flow of gas which contains CO2 and air in variable concentrations, or an acid isotonic solution; and (b) effecting a qualitative or quantitative aesthesiometry of the local irritation produced by the application of the irritating product, based on the determination of the pain threshold and intensity, through oral answers or the use of a logic scale. The device comprises a CO2 bottle (1); an air bottle (2); a gas mixing device (3); a gas flow indicator (4); a CO2 content indicator (5) (as a percentage); a pressure transducer (6); an oscilloscope (7); a valve (8); a pulse generator (9); a lens universal support (10); the numeral (11) representing the cornea of the individual to be examined. Application for the measurement of the corneal and conjunctival sensitivity of the eye.

Description

TITLE OF THE INVENTION

Procedure and its corresponding device to perform stesiometries.

TECHNICAL FIELD OF THE INVENTION The present invention falls within the technical field of the measurement or determination of the sensitivity of the cornea and conjunctiva of the eye and, specifically, refers to a new procedure and its corresponding device for said determination in the that an air stream containing carbon dioxide or an aerosol containing an acid solution is applied.

STATE OF THE PRIOR ART OF THE INVENTION

Although the measurement of corneal sensitivity has great clinical utility, its routine use has been limited by the problems posed by the procedures available to carry it out.

Currently existing stesiometers (Boberg-Ans, Cochet-Bonnet, Draeger, Buerman-McCulley), employ a solid stimulus of physical contact with the cornea, such as a nylon filament or an electromechanical probe that compresses the cornea with force variable. The disadvantages of this procedure include first of all the almost absolute guarantee of an epithelial lesion. In addition, the stimulus is always supraumbral; In the case of nylon, its non-perpendicularity and change in stiffness with moisture make it also not very reproducible. All these stesiometers are based on the mechanical stimulation of the cornea. The present invention broadens and improves the possibilities of the currently available mecha-stesiometers, by resorting to a different type of stimulation, chemistry, which activates the sensory nerve fibers of the cornea by a mechanism different from that of mechanical stimuli and which , because it uses a gas stream to transport the stimulus, it also avoids its direct contact with the cornea. DETAILED DESCRIPTION OF THE INVENTION

There are various tissues, including those of the eye, specialized nerve endings that transform the chemical, mechanical or thermal lesion stimuli into a nervous message that ultimately results in pain sensations. These painful endings can be stimulated by the application of chemical irritants or by the action of acid solutions.

The present invention relates firstly to a new method for determining the degree of sensitivity of the cornea or ocular conjunctiva by applying a stream of air containing carbon dioxide, which locally modifies the pH of the tissue, or by the application "of an aerosol containing an acid solution that exerts this same action. The change in pH acts as a chemical stimulus on the sensory nerve endings of the cornea, exciting them when the acidity reaches a threshold value. Since the change can be adjusted of pH produced by controlling the concentration of C0 ₂ in the applied gas or that of the acid substance in the aerosol, it is possible to quantitatively determine the chemical threshold at different points on the anterior surface of the eye.This method can be used to evaluate the Consequential reductions in corneal sensitivity to metabolic or surgical corneal lesions.

When a stream of C0 ₂ is applied to the surface of a mucosa it evokes pain sensations. This seems to be due to the rise in the local concentration of C0 ₂ , which, reacting with water produces carbonic acid (C0 ₃ H ₂ ) which in turn dissociates into bicarbonate ion (C0 ₃ H ^~ ) and H ⁺ lo which produces a local increase in the concentration of H ⁺ (ie the reduction of the pH that acts on the sensory nerve endings, exciting them. According to the above, the procedure of the present invention is characterized in that it comprises the following operations: a) apply at one or more points of the cornea or conjunctiva of the eye, the sensitivity of which is to be determined, a gas stream containing CO ² and air at varying concentrations, or either an isotonic acid solution at variable pHs; and b) carry out a stesiometry of the local stimulation produced by the application of the stimulating substance, based on the determination of the threshold and the intensity of the pain, by means of verbal responses or the use of an analogue scale, the stimulating substance being constituted by C0 ₂ mixtures with air at concentrations ranging from 10% to 95%, or isotonic solutions of a weak acid adjusted to a pH between 3.5 and 7.0.

As examples of weak acid, there may be mentioned acetic acid, citric acid and the like.

The applicant has been able to verify in anesthetized cats that when a stream of a gaseous mixture of air and C0 ₂ is applied at different concentrations on the surface of the cornea, it is produced from a C0 ₂ concentration of 30-50%, an excitation of the sensory nerve endings of the cornea, responsible for detecting harmful stimuli. For this, the electrical activity in said corneal nerve fibers is recorded, checking a discharge of nerve impulses therein, proportional to the change in pH and the concentration of C0 ₂ in the gas mixture. This response is immediate, reaches a maximum at the time of application and persists while maintaining the stimulus.

Similarly, it has been proven in humans, that the concentration that triggered the discharge of nerve impulses in the anesthetized cat, produced an immediate sensation of stinging and pain when applied on the cornea, analogously, the application of acidic or irritating chemical substances on the surface of the cornea, by means of an aerosol that limits its distribution to a restricted area of the cornea, evokes electrical activity in the corneal nerves of the anesthetized cat and burning sensation or pain in humans.

In addition, the present invention also relates to the corresponding device for performing the stesiometries. The device, which is represented in Figure

1 attached, consists essentially of the following elements: two bullets for gases, one of them (1) for C0 ₂ 100% and another (2) for air; a gas mixer (3), provided with a gas flow indicator (4) and an indicator of the% content in C0 ₂ (5), in which the mixing of air and C0 _{2 takes place} in proportions when necessary; a pressure transducer (6); an oscilloscope (7); a valve (8); a pulse generator (9); and a universal lens holder (10). In this way, it is possible to make a fine stream of gas influence the cornea (11) of the individual under study and measure the response that it produces in said cornea.

BRIEF DESCRIPTION OF THE FIGURES Figure 1; It represents the device for performing stesiometries of the present invention. The different references have the following meaning:

(1) 100% C0 ₂ bullet

(2) Air bullet (3) Gas mixer

(4) Gas flow indicator

(5) C0 ₂ % content indicator

(6) Pressure transducer

(7) Oscilloscope (8) Valve (9) Pulse generator

(10) Universal lens holder

(11) Cornea of the individual under analysis.

Figure 2: It is a graph that represents, for different concentrations of C0 ₂ , the discharge of the terminations in the cat's cornea and the magnitude of pain in humans using the VAS scale. Semi-logarithmic representation is included. Figure 3: It is a graphic representation showing the measurement in humans, expressed as repeated mean in successive days, which shows the reproducibility of the method of the invention. Semi-logarithmic representation is also included.

EMBODIMENTS OF THE INVENTION The present invention is further illustrated by the following examples, which should not be considered as limiting its scope.

EXAMPLE 1 In 5 healthy volunteers, under 10 years of age and without any ocular pathology, a graduation goggle with a 0.1 mm tipped silicone tube, located 5 mm from the surface, was placed in its center corneal This tube was connected to a system composed of two gas tanks containing respectively 98% C0 ₂ and air, which are joined in a gas mixer, which allows to obtain predetermined concentrations of C0 ₂ (10 to 90%). The mixer outlet was connected to one of the upper arms of a V-tube, the other being connected to a second air tank. An electronic valve system allowed air or a given mixture of C0 ₂ to be alternately expelled through the lower outlet of the Y-tube. The gas exiting the latter (air or the mixture of C0 ₂ ) was passed through a humidifier and a regulator. pressure and finally connected with the silicone tube located in front of the cornea. Before starting the experiment, a pulse of 1 s duration with 98% C0 ₂ was applied to the cornea and the subject was asked to consider the sensation of pain evoked as maximum. Next, air was sent to the cornea, adjusting the output flow below the mechanical threshold thereof, so that the gas stream was not felt by the subject. From this moment, by means of a pulse generator that governs the electronic valves, pulses of 1 s duration were applied with increasing concentrations of C0 ₂ and with 1 min of interval between pulses, asking the subject to indicate at what time he felt some feeling of irritation in the eye, and when it happened, it was indicating the intensity of the feeling on a scale of 1 to 10, in which 10 corresponded to the feeling of initial pain evoked by C0 ₂ to 98%.

The results obtained allowed to establish that the excitation threshold was in a concentration of C0 ₂ at 50%, being reproducible in the same subject and with a reduced variability among individuals. There is a relationship of direct proportionality between C0 ₂ concentration and intensity of sensation, as well as between it and the duration of the stimulus. EXAMPLE 2

In adult cats anesthetized with sodium pentobarbital, the electrical activity of dissected nerve fibers of the ciliary nerves at the posterior pole of the eye was recorded. unique fibers were identified that innervated the cornea and responded to mechanical, chemical stimulation with 10 mM acetic acid and thermal (<42 ° C), being classified as polydal nociceptors.

A stream of C0 ₂ was applied to the corneal surface at varying concentrations, measuring the variation in the frequency of fiber discharge studied. It could be observed that there was a proportionality relationship between the firing frequency of the fibers and the concentration of C0 ₂ . The temporal course of the response was analogous to that evoked by application of a 10 M acetic acid solution on the cornea, although the intensity of the response to the 10 mM acetic acid solution was approximately 70% lower than in the case of C0 ₂ . These results indicate that the change in local pH produced by C0 ₂ stimulates polymodal nociceptor fibers that mediate the sensation of corneal pain, and that its stimulating action is more effective than that of a topically applied acid solution.

EXAMPLE 3 This example shows another series of experiments performed in accordance with the present invention:

1. Experiments with animals

For electrophysiological experiments in cats, tanks containing mixtures of air and C0 ₂ calibrated at different concentrations (0%, 35%, 50%, 65%, 80% and 98.5% of C0 ₂ ) were used. The gas samples were humidified and transported by a gas impervious tube to a three-way valve. An outlet of the valve ends in a glass tube of lm in diameter whose end was arranged perpendicular to the corneal receiving field of the registered unit by means of a manipulator at a distance of about 0.5 cm. The gas jet pressure was adjusted with a pressure regulator at the tank outlet to a value that did not produce any nerve activity when air stimulation was performed.

2. Experiments in humans

In one part of the studies on human sensations, the same calibrated mixtures of gases used in animal experiments were used (0, 35, 50, 65, 80 and 98.5%). In another group of experiments, it they obtained varying concentrations of C0 ₂ by mixing the contents of two tanks filled with 98.5% C0 ₂ and air. To obtain the desired concentration of C0 ₂ at the gas outlet (10% to 90% of C0 ₂ in 5% increments) a previously calibrated gas mixer with an infrared C0 ₂ detector was used.

The gas mixtures were humidified and conducted through a gas impermeable tube to a three-way solenoid valve controlled by a pulse generator. One of the valve outlets was connected to a 0.5 mm diameter silicone tube and taken to a universal lens holder for graduation tests. The end of this tube was placed in the center of the lens holder by means of a stereoscopic vision lens, placing it perpendicularly to the center of the cornea and at a distance of 8-10 mm from the corneal surface. The second valve outlet deflects the gas away from the eye. Gas flows continuously through this outlet except when the electronic valve momentarily changes the direction of flow to the surface of the cornea, for a pre-established period of time (0.1-10 s) (Figure 1). The gas jet pressure was adjusted by regulating the flow of the gas mixture with a pressure regulator. For the calibration of the gas jet pressure, the tube outlet connected in series to a pressure transducer (Statham P23XL) was placed perpendicularly to the saucer of a precision balance with the nozzle placed at a distance of 10 cm from the saucer. The force exerted by gas flow increases were measured in mg with the balance and correlated with the corresponding voltage outputs given by the transducer. The gas temperature was 242C. 3. Psychophysical Measures

Thirteen healthy volunteers (8 men and 5 women, aged between 23 and 37 years) They participated in this study. None of them wore contact lenses or exhibited any ocular pathology. They were extensively informed of the object of the study as well as were free to interrupt the session at any time. The experimental protocol began with a general description of the experiment.

In the first test, the mechanical threshold was determined using air pulses of 3 seconds duration at different pressures starting from 1.11 mg to 6.25 mg at intervals of 0.25 mg performing ascending and descending series. All pressure pulses were applied in duplicate with intervals between stimuli of 1 minute. Five minutes after the determination of the mechanical threshold, the chiosensitivity to C0 ₂ was explored. Mixtures of C0 ₂ contained in separate containers in 8 individuals were used. Pulses of 3 seconds duration and increasing concentrations (0, 35, 50, 65, 80 and 98.5%) were sequentially applied at the cornea at 1 minute intervals with the gas flow adjusted 0.5 mg below of the ecological threshold. After a period of time of 5 minutes the experiment was repeated but with mixtures of C0 ₂ concentration in decreasing order. In another group of 5 participants, series of stimulations were carried out using pulses of varying concentration of C0 ₂ (between 10% and 90% of C0 ₂ at 5% intervals) applied at random.

Pain measurement was performed using an electronic version of the Visual Analog Scale (VAS) (Antón et al., 1992) and a Verbal Description Scale (VDS) (Price, 1988). The individuals sat comfortably in a chair in front of a panel with a series of 20 LEDs. The participant could indicate the intensity of the sensation by adjusting with a potentiometer the number of diodes lit. The LEDs were numbered and their color varied gradually from green to red. The individual also indicated the sensation using descrip- verbal tores. Minimum sensation ("noticeable but not irritating"), corresponding to LEDs 1 to 5; Painful threshold and rising sensation, ("irritating but tolerable"), were represented by LEDs 6 through 10, "painful" corresponding to LEDs 11 to 15 and "very painful" with LEDs 16 and older. The highest part of the scale corresponded to the tolerance level. At the end of the experiment, participants were urged to describe the sensation experienced using their own words. Involuntary flickers usually occurred when painful and very painful intensities were reached.

In a group of three individuals, the corneal temperature was measured at the place where the gas stream affected by placing a microwave (Sensotek IT-23, 0.003 inches in diameter) on the corneal surface previously anesthetized with tetracaine. The corneal surface temperature was measured with a digital thermometer (Sensotek BAT-12) throughout the experimental protocol, with no temperature variations exceeding O.lδC.

Claims

1.- Procedure to perform the measurement of corneal and conjunctival sensitivity in the eye (qualitative and quantitative stesiometry) based on the stimulation of the sensory endings of the cornea or conjunctiva and the measurement of the pain threshold caused by chemical stimulation of the cornea or conjunctiva to applying a stream of C0 ₂ or air containing the stimulating substance enables its application restricted to a limited area of corneal or conjunctival surface the; whose procedure is characterized in that it comprises the following operations: a) apply at one or more specific points of the cornea or conjunctiva of the eye, whose sensitivity is to be determined, a gas stream containing C0 ₂ and air in varying concentrations, or a isotonic acid solution at variable pHs; and b) carry out a qualitative or quantitative stesiometry of the local irritation produced by the application of the irritant product based on the determination of the threshold and intensity of pain, by means of verbal responses or the use of an analog scale.

2. Method according to claim 1, characterized in that an isotonic acid solution is applied by means of an aerosol containing an inert gas and said solution.

3. Method according to claim 2, wherein the acid included in the acid isotonic solution is selected from the group consisting of: acetic acid, citric acid or any other weak acid.

4.- Device for performing stesiometries, characterized in that it comprises the following elements: (1) 100% C0 ₂ bullet; (2) air bullet; (3) gas mixer; (4) gas flow indicator; (5) C0 ₂ % content indicator; (6) pressure transducer; (7) oscilloscope; (8) valve; (9) pulse generator and (10) universal lens holder.