US3364929A

US3364929A - Method for administering muscle relaxant drug

Info

Publication number: US3364929A
Application number: US419949A
Authority: US
Inventors: Walter S Ide; William H Nickerson
Original assignee: Burroughs Wellcome Co USA
Current assignee: SmithKline Beecham Corp
Priority date: 1964-12-21
Filing date: 1964-12-21
Publication date: 1968-01-23
Anticipated expiration: 1985-01-23
Also published as: BE674054A; SE340324B; FR1466608A; DE1539104A1; DE1539104B2; NL6516659A; IL24839A; GB1123365A; CH428965A

Abstract

A portable neuromuscular blockade monitor having application for (i) determining the type and degree of blockade present in a patient, (ii) determining the correct time for administration of muscle-relaxant drug or antagonistic drug, or (iii) determining the amount of muscle-relaxant or antagonist to be administered, comprises a dry battery of greater than zero but up to 12V output, a transistorized oscillator circuit to convert the D.C. energy from the battery into a series of electrical pulses which are of two fixed frequencies, the first being in the range of 1 pulse per second to 1 pulse per 10 seconds and the second being in the range p 25 to 250 pulses per second, a switch means for enabling either of these frequencies to be selected and maintained, a step-up transformer and potential divider on the stepped up voltage side of the transformer and a pair of terminals to take the pulse output from the device via the potential divider.

Description

Jan. 23, 1968 w. 5.105 ETAL 3,364,929

- METHOD FOR ADMINISTERING MUSCLE RELXANT DRUG Filed Dec. 2l, 1964 ,zo ,22 3 lll 5? 45 f2( 58 56X z3 40 Z8 2Q 25 E 5M@ 6&5 N

Z5 75 HM' METER 0R A OSCILLOSCOPE ELE CTR \CQL. SUMUU TwlTcH fTETANus TwITH gb Nowoepommzme BLOCK MH @Us TunTcH g" .36. DEPoLQmzmG BLOCK INVBNTORS HHH l I l I I wlham H .NwKevmm Y BY TwlTcH TETANUSl TwmzH 90M@ (mm Y ATTQRNEY` United States Patent Office 3,364,929 Patented Jan. 23, 1968 3,364,929 METHOD FOR ADMINISTERING MUSCLE RELAXANT DRUG Walter S. Ide, Eastchester, and William H. Nickerson,

Tuckahoe, N.Y., assignors to Burroughs Wellcome &

Co. (U.S.A.) Inc., Tucltahoe, N Y., a corporation of New York Filed Dec. 21, 1954, Ser. No. 419,949 4 Claims. (Cl. 128-172.1)

ABSTRACT OF THE DISCLOSURE A method for administering a muscle relaxant antagonist drug to counteract muscle relaxant drugs which produce both non-depolarizing and depolarizing blocks in patients, comprising the steps of rst applying an electrical stimulus to the ulnar nerve and/ or the nerve motor point muscle junction of a patient at a twitching frequency rate, secondly applying electrical stimulus at a tetanus frequency rate to the same part of the patient, and thirdly reapplying the electrical stimulus at the frequency rate, differentiating between responsiveness of the patient to said stimuli to determine the types of neuromuscular block, and introducing an antagonist into the system of the patient only if the response of the patient is such that a non-depolarizing block exists.

Athe completion of surgery, it is sometimes required that the patient who has been administered a muscle relaxant drug be stimulated by the administration of an antagonist drug to counteract the elfects of the muscle relaxant drug. Commonly used antagonist drugs are physostigmine, eserine and edrophonium.

In some instances instead of the antagonist stimulating the patient a continuation of the relaxation of the patient for prolonged periods has occurred. The prolonged period of relaxation has tended to be greater than that which would ordinarily occur without the administration of the antagonist, It is believed that this continuation of relaxation is related to the type of neuromuscular block existing in the patient.

In View of the foregoing, a new and improved apparatus for determining the correct time to administer muscle `antagonist drugs was required. Additionally, a new and improved method was required in order to administer antagonists to produce a stimulation of the patient instead of prolonging the relaxation of the patient. Accordingly, it is an object of this invention to provide a new and improved apparatus for providing electrical stimuli4 to differentiate between depolarizing and nondepolarizing neuromuscular blocks due to the action of certain muscle relaxant drugs.-

Another object of this `invention is to provide a new and improved method of administering antagonist drugs. It is a further object of this invention to provide a new and improved method of determining when to introduce muscle relaxant drugs and the administration of such drugs.

It is'an additional object of this invention to provide a new and improved and simplified monitoring apparatus for stimulating the patient and to determine the type of neuromuscular block exhibited by the patient.

Other objects of the invention will in part be obvious and will in part appear hereinafter.

The invention accordingly comprises the several steps and the relation of one or more of such steps with respect to each of the others, and the apparatus embodying features of construction, combinations of elements and arrangements of parts which are adapted to eect such steps, all as exemplified in the following detailed disclosure, and the scope of the invention will be indicated in the claims.

For a fuller understanding of the nature and objects of the invention, reference should be had to the following detailed description taken in conjunction with the accompanying drawings, in which FIG. 1 illustrates schematically a transistorized, neuromuscular block monitoring device;

FIG. 2 is an isometric representation of a splint for mounting on a patient to detect response of a patient to electrical stimuli;

FIG. 3a is a graph illustrating the sequential electrical stimuli applied to the patient in accordance with this invention;

FIG. 3b is a graph showing the resultant response of a patient to the electrical stimuli as a result of a non-depolarizing block affecting the nerves of the patient; and

FIG 3c is a graph illustrating a depolarizing block of a patient in response to electrical stimuli.

Referring now to FIGS. l and 2, a monitor oscillator or pulse generator is shown at 20 for generating an electrical stimuli in accordance with this invention. The pulse generator Z0 includes a relaxation oscillator circuit having an NPN transistor 21 with an emitter electrode 22, a base electrode 23 and a collector electrode 24 and a PNP transistor 25 with an emitter electrode 26, a base electrode 27 and a collector electrode 28. The collector 24 of transistor 21 is coupled to the base 27 of transistor 25. Connected between the base electrode 23 of transistor 21 and collector electrode of transistor 25 is a capacitor 30. Coupled intermediate the base 23 of transistor 21 and capacitor 30 is a variable resistance network for varying the frequency of the oscillator. The resistance network includes a switch 31 and two

resistors

33 and 34, Switch 31 can be connected to either of

resistors

33 and 34 to control the frequency of the oscillator. A source of direct current energy 34, such as a battery, is coupled at its positive terminal to emitter 26 of transistor 25 and to the other end of

resistors

33 and 34. A switch 36 is provided in the line to place the DC energy source 35 in the circuit, One end of the switch is coupled to the emitter 22 and the other end of the switch is coupled to the battery 35. A voltage step-up transformer is generally shown at 37. Transformer has its primary winding 38 between the collector 28 of transistor 25 and emitter 22 of transistor 21.

A resistor 40 coupled in series with capacitor 30 and a capacitor 41 connected across winding 38 are preferably included to decrease extraneous voltages in the circuit. The secondary winding 39 of transformer 37 is coupled across a resistor 4S and a gas tube 46. The'resistor 45 and gas tube 46 are in parallel with a variable resistor 47. The gas tube 46 indicates when the device 20 is providing a signal of a predetermined voltage level. Coupled across variable resistor 47 is a first electrode 50 and a second electrode 51 connected through a resistor 49. The electrodes may be surface-type electrodes which are suitable for applying an electrical stimuli to the arm 52 of a patient. But, preferably, needle-type electrodes are utilized which may be of the standard 25 gage metal needle type.

The electrodes are placed on the arm or the legs of a patient in a well -known manner such that the ulnar nerve and/or the nerve motor point muscle function is stimulated by the signal provided from the oscillator 20. The oscillator operates as follows: upon closure of switch 36 and the connection of switch 31 to one of

resistors

33 and 34, the circuit 20 will begin to oscillate. Assume, for example, that switch 31 is coupled to resistor 34. The value of resistor 34 is selected such that the relaxation oscillator 2t)v will oscillate at a frequency somewhat above zero impulses per second rbut below 30 impulses per second. This is commonly termed as the frequency which will produce twitching of a digital member of a limb of a patient, as for example, a finger or a toe. This will henceforth be defined as the twitching frequency. The exact impulse frequency range to produce twitching will vary with the patient, and therefore af requency of 20 impulses per second is preferred. With switch 31 coupled to the resistor 34, a voltage will be applied to transistor base 23 in such a direction as to cause transistor 21 to turn on. The turning on of transistor 21 causes transistor to turn on. This causes a current to ow within the primary 3S of the transformer 37.

Transistors

21 and 25 will continue to conduct as long as the transformer 37 is unsaturated. After a period of time, transformer 37 becomes saturated and a voltage across secondary 39 rapidly reverses according to Lcnzes law. This causes a potential to be applied to base 23 of transistor 21 of such a polarity as to turn off transistor 21. This, in turn, turns off transistor 25. Capacitor which charged in the reverse direction to cut olf transistor 23 due to the saturation of inductor 37 then gradually discharges until the potential at the base electrode 23 of transistor 21 once again becomes of the proper polarity to turn on transistor 21 to restart the cycle.

The resultant output wave form of the oscillator is shown across

electrodes

50 and 51. It is to be noted that the topmost portion of the turn on cycle is slightly clipped due to the presence of gas tube 46. This gas tube ckering indicates to the observer that the impulse generating device 20 is operating. Assume now that the switch 31 is coupled to resistor 33. Resistor 33 is selected such that the impulse frequency rate will be in the order of between -120 impulses per second. In the preferred embodiment, 50 impulses per second was chosen. This range of frequencies is generally referred to as the tetanus frequency rate. The tetanus frequency reaction is observed by noticing the involuntary closing of a linger or a toe of a patient. The exact values for the frequency rate for both tetanus and twitching is generally a function of the patient and it is, therefore, to be understood that the ranges described are only illustrative and are not limiting.

Although it is to be understood that many modifications may be made to the above circuit, the following circuit values may be utilized to provide an impulse generating device suitable for generating both tetanus and twitching frequency impulses.

Transistor 21 2N335.

Transistor 25 2Nl66.

Capacitor 30 2O microfarads.

Resistor 33 5.1K ohms.

Resistor 34 330K ohms.

Battery 35 3 volts. Transformer 37 Voltage step-up of approximately 30. Resistor 40 100 ohms.

Capacitor 41 l5 microfarads.

Gas tube 46 NESlH.

The device 20 is capable of providing approximately a 90 R.M.S. output signal across

electrodes

50 and 51 when used with a 3-volt battery as the energy source for the circuit. This circuit is particularly usable during the administration of an anesthesia and during operations because it is explosion-proof due to the low value of currents and voltages utilized. To detect the response to the electrical stimuli provided across the

electrodes

50 and 51, a digital member such as a finger 53 of arm 52 may be observed. This may be accomplished without the use of any auxiliary detecting and monitoring devices shown in FIG. l. By applying a twitching frequency signal to the

electrodes

50 and 51, the twitching signal will produce a periodic contraction of the finger 53. The application of a tetanus signal will draw the finger closed. Thus, the twitching and tetanus signals may be observed by watching the motion of the finger or the toes of a patient.

The use of this information will be described at a later time in this specification in accordance with the method of this invention.

Although the reaction of the patient to the application of tetanus and Ytwitching muscle electrical stimuli mayl be obsterved without the use of electrical equipment, it is preferred that some type of electrical monitoring device be utilized to better assist in the recognition of the patients response.

By the use'of a splint, generally shown at 55, which is suitable for mounting on thumb 53, a device for indicating and displaying the response of the patient may be provided. The splint 55 comprises

resilient lat portions

55 and 57 having a bend 58 therebetween. Positioned at one end of resilient member 57 is ring 61 suitable for surrounding the tip portion of patients thumb 53.

Attached to the other member 56 of splint 55 are

clamps

62 and 63. These clamps are shaped like rings, but have cut out portions for permitting the clamps to extend over the upper portion of patients thumb 53 above the joint. To record the bending of the splint 55, a suitable strain gage 70 is mounted thereon in a position to record the pressure produced by the thumb against the splint. A strain gage, such as the type SR-4 available from Baldwin-Lima Hamilton Corp., Waltham, Massachusetts, may be used. Other types of strain or stress transducers such as strain sensitive diodes and transistors may also be utilized as well as piezo electric devices. Strain gage 70 is connected to a suitable circuit comprising resistor 72 and battery 73 for providing a current through the strain gage. The variations of the current flow through the strain gage due to a change in resistance of the strain gage because of flexing of thumb 53, can then be monitored on a meter such as a voltage meter or an oscilloscope 75. Further, other display devices may be utilized, for example, electrical type brush recorders.

Referring now to FIGS. 3a, 3b and 3c for a description of the method according to this invention, assume that the patient has been injected with a syringe carry,

ing muscle relaxant drugs such as succinylcholine, or dimethyl tubocurare. Further assume that an anesthesiologist deems it necessary to introduce a muscle antagonistic drug to counteract the effects of the muscle relaxant drug. To determine the proper time to inject the muscle relaxant antagonist is, for example, by the use of a syringe 80 as shown in FIG. l, the neuromuscular block monitoring device 20, is turned on and set to provide electrical stimuli at a twitching frequency. The electrical stimuli is applied at the ulnar nerve at the wrist, elbow or at a motor junction point. It is preferable to use needle electrodes which may be inserted into the arm of the patient, rather than surface electrodes which tend to cause slight damage tothe skin due to irritation of the electrodes after long periods of time as, for example, four hours. FIG. 3a shows the application of the electrical stimuli at a twitching frequency of about twenty impulses per second, although variations may exist due to the particular patient. The response of the patient is shown in FIGS. 3b and 3c and may be observed on the oscilloscope 75. The spikes in FIGS. 3b and 3c indicate that the patient has reacted to the stimuli such as to produce a twitching of the digital member. This can also be observe-d by watching the digital member itself. lAfter a period of time as, for example, 20 seconds monitor oscillating device 20 is then set to provide electrical stimuli at a tetanus frequency. In the preferred embodiment, the monitor is set to provide 50 impulses per seconduwh'ich is shown in FIG. 3a. The application of electrical im'- pulses at tetanus frequency produces a clamping response of the patients hand or toes such that the hand or toes tend to close during the application of the tetanus stimuli. This may be observed by noticing the square wave representation in FIGS. 3b and 3c or, again, by watching the digital member.

In the preferred method, the tetanus is held for approximately two to three seconds although many variations may be possible depending on the response of the patient. To determine the nature of the neuromuscular block, the monitor is switched to provide electrical stimuli at the twitching frequency once again. FIG. 3b shows the response of the patients digit-al members to the re-application of the twitch frequency when there exists a non-depolarizing neuromuscular block within the patient. This figure further shows what is generally termed post-tetanic facilitation and which is represented by a sudden increase in the amplitude of the switch response. This has been determined to vbe the response by the patient to a twitch frequency after ythe application of a tetanus frequency electrical stimuli when there exists a nondepolarizing block within the patient. In FIG. 3c there is shown the response of the patient to the twitch electrical frequency stimuli when there exists a depolarizing neuromuscular block within the patient. In this figure it may be seen that there is no post-tetanic facilitation which is indicative of a depolarizing neuromuscular block.

In accordance with this invention, it has been determined that a muscle antagonist drug should be introduced into the patient only when there exists a nondepolarizing block such as shown by the post-tetanic facilitation of FIG. 3b. The introduction of an antagonist drug when there is a depolarizing block such as shown in FIG. 3c potentiates the depolarizing block rather than counteracting the muscle relaxant drug. If the drug is administered when there is a depolarizing block, the patient generally requires a longer period of time to overcome the relaxant drug then would normally -be required if the neuromuscular block were permitted `to switch from a depolarizing to the non-depolarizing neuromuscular block by itself. This will generally occur after a predetermined time interval h-as elapsed to permit the muscle relaxant 4drum to lose at least some of its potency. It should be understood that a sensor strapped to an arm or leg of the patient could also be utilized although a sensor strapped to a digit-al member is preferred.

It will thus be seen that the objects set forth above, among those made 4apparent from the preceding description, are eiiciently attained and, since certain changes may be made in the above article without departing from the scope of the invention, it is intended that all matter contained in the above description or shown in the accompanying drawings shall be interpreted as illustrative and not in a limiting sense.

It is also to be understood that the following claims are intended to cover all of the generic and specific features of the invention hereindescribed, and all statements of the scope of the invention which, as a matter of language, might be said to fall therebetween.

What we claim is:

1. A method for administering a muscle relaxant antagonist drug to counteract muscle relaxant drugs which produce both non-depolarizing and depolarizing blocks in patients, comprising the steps of first applying an electrical stimulus to the ulnar nerve and/ or the nerve motor point muscle junction of a patient at a switching frequency rate, secondly applying electrical stimulus lat a tetanus frequency rate to the same part of the patient, point muscle junction of a patient at a twitching frequency rate, differentiating between responsiveness of the patient to said stimuli to determine the types of neuromuscular block, and introducing an antagonist into the system of the patient only if the response of the patient is such that a non-depolarizing block exists.

2. A method for the intravenous administration of antagonistic drugs to counteract the effects of drugs producing muscle relaxation, comprising the steps of sequentially applying a low amperage electrical stimuli of two different frequencies to a muscle motor point and/or the ulnar nerve of a patient to produce -a muscle stimulus, and administering the antagonistic drugs only when the response of the patient to the electrical stimuli is such that a non-depolarizing neuromuscular block exists within the patient.

3. A method for Vthe intravenous administration of antagonistic drugs to counteract the effects of muscle relaxant drugs producing 'both depolarizing and nondepolarizing neuromuscular blocks in patients, comprising the steps of sequentially applying an electrical stimulus at both twitching and tetanus frequencies to a muscle motor point and/ or the ulnar nerve of a patient to produce a muscle stimulus, Vand administering antagonistic drugs only when the response of the patient to the electrical stimuli is such that a non-depolarizing neuromuscular block exists.

4. A method for administering muscle relaxation antagonistic drugs to counteract the effects of muscle relaxant drugs which produce both non-depolarizing and depolarizing neuromuscular blocks in patients, comprising the steps of first applying an electrical stimulus at a twitching frequency to the ulnar nerve and/ or the muscle motor point of a, patient, then applying an electrical stimulus at a tetanus frequency to the ulnar nerve and/or the muscle motor point of a patient and then reapplying an electrical stimulus at a twitching frequency to the ulnar nerve and/or the muscle motor point of a patient, and administering antagonistic drugs only when the response of the patient is such that a depol-arizing neuromuscular `block will not be potentiated.

References Cited UNITED STATES PATENTS 2,493,155 1/1950 McMillan 128-172.1 2,808,826 10/1957 Reiner et al 12S-2.1 2,830,578 4/1958 De Groff 12S- 24.5 2,840,069 6/ 1958 Squire et al. 12S-2 3,200,814 8/1965 Taylor et al. 12S-2 3,207,151 9/ 1965 Takagi 12S-2.1 3,258,007 6/1966 Karpovich et a1. 12S-2 3,292,620 12/ 1966 Mahler 12S-172.1 2,979,055 4/ 1961 De Beer et al 12S-214 RICHARD A. GAUDET, Primary Examiner. SIMON BRODER, Examiner,

Disclaimer 3,364,929. Walter S. lele, Eastchesber, and William H. Nickerson, Tuckahoe, N.Y. METHOD FOR ADMIN ISTERING MUSCLE RELAXANT DRUG. Patent dated J an. 23, 1968. Disclaimer filed Apr. 20, 197 8, by the assignee, Burroughs Wellcome 00. Hereby enters this disclaimer to all claims of said patent.

[Oficial Gazette June 13, 1.978.]