APPARATUS FOR AND A METHOD OF MEASURING BLOOD PRESSURE OF LABORATORY ANIMALS

Abstract: An apparatus for measuring blood pressure of laboratory animals e.g. rats, comprising respective cages (10) for accomodating the animals that have a bottom (11) which is preheated between 33 and 35` C to intensify circulation of the animals. Respective cuffs are arranged around the tails of the animals pressurized by a common pressure actuator (23). The cuffs comprise optical pulse sensors coupled to respective measuring channels of a measuring and filter unit (30) with steep low-pass characteristics having cut-off frequencies under 10 Hz to eliminate disturbing noise effects. The operation is controlled by an evaluating unit (40). In the method for measuring the blood pressure, the pressure is established and changed simultaneously for each animal located in preheated cages, and in each channel the pressure corresponding to the occurrence of the first sensed beat pulse is stored and regarded as a blood pressure value if an undisturbed pulsation is going on with predetermined conditions after the first beat. The measurements are carried out in a sequence of measuring periods and the corresponding results are evaluated by mathematical statistical technique for each animal. If the results cannot be evaluated, new measuring sequences are started.

Description: APPARATUS FOR AND A METHOD OF MEASURING BLOOD PRESSURE OF -LABORATORY ANIMALS Technical Field The invention relates to the field of laboratory pharmacology, more particularly to a method of and an apparatus for measuring blood pressure of laboratory animals, principally to detect the effects of antihypertensive drugs. Background Art An important step in researching anti- hypertensive drugs is to study the effects of new materials in tests with laboratory animals. These tests have statistical character and they have to be carried out on a large number of animals through a long period of time. For such tests a blood pressure measuring equipment is required, by which the blood pressure of the laboratory animals can be taken in any moment without any damage to the animal during the treatment that can last for several weeks or months. To carry out the measurements fast and pre¬ cisely, using up as few human work as possible and to provide results evaluated statistically form the subject of further requirements. The so-called Heatless method (referred to e.g. in the catalogue of .the Innovators Instru¬ mentation Co. U.S. relating to the "Indirect Blood Pressure Test System for Rats") is known as a 5 non-invasive technique for measuring blood pressure. According to this method, a sensor cuff containing an optical signal source and a sensor is fastened on the tail of a rat located in stocksjN As the ■ < " 1 heat exchange of the rats is low at the employed 0 temperature, the pulsation of the tail-veins is weak. The measured data are recorded in appropriate form by which skilled persons can draw conclusions for the systolic blood pressure. In such individual measurements each rat 5 has to be held down separately to ensure that its tail be at rest during the measurement. The trembling of the tail and other factors, however, make the measurement uncertain and a lot of skill and patience are required to obtain acceptable results. _» 0 Owing to the great number of measurements which are to be carried out, automatic measurements were favourable, however, the automatic measurements have been considered so far as unaccomplishable because of the adverse noises, movements and other 5 disturbing effects associated therewith. Automatic measurements were actually carried out in cases where the laboratory animal had been given sedatives or been anaesthetized previously to eliminate move¬ ments interfering with the measurement. The object 0 of most of the tests, however, is to detect the influence o " f certain drugs on blood pressure, and this influence is dependent also on the sedative or narcotic applied. Object of the Invention The object of the present invention is to provide a method and an apparatus for measuring blood pressure on a plurality .of laboratory animals automatically and simultaneously, that can eliminate the need for using sedatives. Disclosure of the Invention The basic principle of the present in¬ vention lies in the way of suppressing and eliminat- ing the effects interfering with the measurement. The signal-to-noise ratio of the pulse-detection can be increased considerably by rising the temperature of the laboratory animals, e.g; by heating the bottom of their cages (to a temperature range of 33 to 35°C), because it intensifies their circul¬ ation. Such a heating causes about a 1G% consistent increase in blood pressure. According to another aspect of the present invention the pressure is changed simultaneously for all of the laboratory animals by means of a common pressure developer and distributor equipment. The signals of the individual pulse sensors are processed in separate measuring channels and the measuring channels comprise a matching amplifier, a low-pass filter with a cut-off rate of about 80dB/decade and a cut-off frequency of not more than 10 Hz, AC-coupled amplifiers, a comparator and a decoupled coupling unit. The filtered signals of the measuring channel are processed in several measuring phases as follows. When the first measuring signal is sensed, the corresponding pressure is recorded and it is - 4 - * considered as the blood pressure if at least a given number (e.g. 4) of signals is sensed, during each one of subsequent periods with predetermined length (e.g. during periods of'l second). The num- ber of the periods can be e.g. six. A measurement series consisting of several measurement periods is accepted only then if a given percentage (e.g. 70-80 per cent) of its periods supplies valuable signals. A signal is valuable, if it lies within a given (e.g. a 10 per cent) variance range of an average value derived from the measure¬ ment series. If this condition is not met, the measure ment series will be repeated a given times, e.g. not more than three times. Brief description of Drawings Fig. 1 shows the schematic block diagram of the apparatus of the present invention; Fig. 2 shows an enlarged sectional elevatio view of the combined clamping and sensor unit of the apparatus of Fig. 1; Fig. 3 is a sectional view taken along line III-III of Fig. 2; Fig. 4 shows the block diagram of the stages associated with a measuring channel; and Fig. 5 is a time diagram of pressure and pulse signals during one measuring series. Best Mode of Carrying Out the Invention Referring to Fig. 1, there is shown the block diagram of an apparatus for measuring blood pressure of rats. This apparatus comprises twelve measuring locations with respective measuring cages 10,...10, 2 arranged like stocks. The measuring cages restrict the free movement of the laboratory ani¬ mals and the tails of the *" laboratory animals extend out from the cages. The measuring cages 10 have a common bottom 11 heated to a temperature of about 34 C for the duration of the measurements by means of a heater 12 and a temperature regulator unit 13. As a result of the heating the blood circulation of the laboratory animal will be intensive, facilitating the measurement. Respective combined clamping and optical sensor units 20,...20,' are fastened on the tail of each laboratory animal. A preferable embodiment of such a unit is shown in Figs. 2 and 3. Respective air conduits 21 and signal lines 22 are connected to each combined clamping and optical sensor unit 20. The air conduits 21 are coupled to a common pressure developer and distributor equipment 23 that receives electric control signals from a prog¬ ram controller and evaluating unit 40. The signal lines 22 are coupled to inputs of a measuring and filter unit 30. The pressure developer and dist¬ ributor equipment 23 comprises a compressor that increases the pressure in the interior of the pressure distributor of the equipment with a given rate in response to a control signal. There is pro¬ vided a narrow opening formed by a needle valve - _. 6 - in the pressure distributing space of the equipment 23 that ensures a pressure drop at a given rate. A pressure transducer 31 is coupled to the distributor space, . and it supplies an electric output signal 5 proportional to the pressure prevailing in the space, and this signal is connected to one of the inputs of the program controller and evaluating unit 40. The raeasuring^and filter unit 30 is controlled by the program controller and evaluating 10 unit 40 preferably comprising a microprocessor. The measured data are recorded by a data recording equipment 50, e.g. by a line printer connected to the program controller and evaluating unit 40. Reference is made now to Figs. 2 and 3, 15 wherein the arrangement of the combined clamping and sensor unit 20 is shown. The tail 14 of the laboratory animal is girdled on a given length by a cuff 24 made of elastic material, e.g. of rubber. Both ends of the cuff 24 connect tightly to two • 20 ends of a rigid carrier ring 25. An air channel 26 is formed inside the carrier ring 25 that connects to a bore tooled in the centre of the carrier ring encircling outwardly the cuff 24. An air duct 27 communicates with the air channel 25 and adapted for 25 receiving the end of the air conduit 21 (see Fig. 1) In the middle of the carrier ring 25 a transverse bore is provided in which a light source 28 and a light sensor 29 are arranged in opposite 30 positions. Reference is made now to Fig. 4 in which the block diagram of a measuring channel of the measuring and filter unit 30 is shown. The light sensor 29 coupled to the input of the measuring and filter unit 30 through the signal line 22 has also been shown in Fig. 4. The measuring channel comprises a capacitor 32 for DC decoupling, a matching ampli¬ fier 23 of low-pass characteristic connected with its input to the capacitor 32, a low-pass filter 34, a pair of amplifiers 35a_rand 35b connected to the output of the filter 34,a capacitor 35c for DC sepa- ration between the amplifiers, a comparator 35 and a coupling unit 37 with DC separation, comprising pre¬ ferably a light emitting diode 37 and a current gene¬ rator.37b controlled by the light of the diode 37. The operation of the blood pressure measur- ing system of the present invention will ' be described with reference to the time diagrams of Fig. 5. Before the beginning of the measurements the laboratory animals are located into the respective measuring cages 10, and the combined clamping and op- tical sensor units 20 are fastened on their tails. The heating is switched on, and in some time thereafter the temperature of the animals takes an elevated constant value. Then the compressor of the pressure developer and distributor equipment 23 is switched on in the moment t Q , and from this moment the pressure in the pressure distributor, as well as in the air channels 26 of each sensor 20 increases exponentially. The pressure transducer 31 converts the increase in pressure to an electric signal, whose curve section defines the period T3 in Fig. 5, the initial rate of increase in pressure is about 3-4000 Pa/sec and the pressure keeps on increasing until it reaches a pre¬ determined maximum value P m„ ax„. The maximum pressure P max ~~ s s et ky t * ~l e prog ram cont roll er and evaluating unit 40 and it can vary between about 1,066 x 10 Pa and 1,4 x 10 Pa, depending on the actual labo¬ ratory circumstances. The typical*- value is 1,33 x 10 Pa.- The measurement starts in the moment t,, 5 when the compressor is switched off and the pressure in the system decreases exponentially at a rate of about 3000 Pa/sec as the air flows out through the needle valve. While the pressure decreases, the pressure in the system will be equal to the blood 10 pressure of one of the laboratory animals say in the point A-, , and in the corresponding moment t« the optical sensor 29 associated with that animal will generate an electric signal train to the input of the measuring channel pulsing synchronously with 15 the beats of the heart of the,animal. In the measuring channel (Fig. 4) the matching amplifier 33 cuts off the high frequency components of the signal coming from the channel because of its low-pass characteristics with a 2.0 cut-off frequency of about 400-500 Hz. The low-pass filter 34 consists of two stages with a resultant cut -off rate of 80 dB/decade and a cut-off frequency of about 8 Hz. This high cut-off steepness permits the effective rejection of high frequency noises. 25 The capacitor 32 decouples the DC components from the measuring channel. This choice of filtering range ensures the transmission of signals derived from the pulsation of the laboratory animals being in the range of about 150-480 pulses/minute. The 30 amplifiers 35a, b in the measuring channel amplify the output of the filter signals and the compara¬ tor 36 generates pulses from these signals (e.g. by null-co paration) which occur in the form of current pulses in the output of the current gene- 35 rator 37b. These pulses can be seen as vertical spikes on the time-scale used in Fig, 5. When the first impulse is received, the program controller and evaluating unit 40 stores the corresponding pressure in that instant t 2 . The unit 40 regards this pressure stored in the moment t 2 as a valuable measuring datum if the following conditions are met. The program cont¬ roller and evaluating unit.40 counts the pulses coming in from the measuring channel during six consecutive seconds from the moment t . If at least four pulses are received in each of the six consecutive seconds, then the pressure value stored in the moment t 2 and illustrated in point A, is considered to be the blood pressure of the animal associated with the concerned measuring channel. The establishment of the above conditions is important for the elimination of noise signals caused by the trembling and other movements like tail-strokes of the laboratory animals. In measurement period 1 shown in Fig. 5 the blood pressure of all laboratory animals is measured in a similar way and the corresponding data are recorded separately for each channel. The other two measurement periods 2 and 3 shown in Fig.5 illustrate two defective measurements. When the first measurement period 1 has ■ been completed in the moment t,, another measure¬ ment period 2 is started, in which the pressure curve has a shape similar to that of the previous measurement period. In the moment t . the optical sensor 29 assigned to this channel senses a pul¬ sation caused e.g. by trembling in the point A that lasts through about a few seconds. The program controller and evaluating unit 40 records the pressure in the moment t.. The normal pulsation of the animal starts at the moment t,_ at the point A 3 , and the signals caused by the trembling and the pulsation, respectively, follow each other conti¬ nuously. Therefore the at least four pulses are received during each of the six consecutive periods of 1 second, and the system records the false pressure value prevailing in the point A 2 as the actual blood pressure of the animal. In the third measurement period 3 the pulsation starts at moment t g associated with point A 4. on the pressure curve. Two-seconds later due to tailstrokes or the like the pulsation ceases for a short period of time, then it starts again in the moment t^. The pressure in the moment t_ is indicated in the point A 5 . The program controller and evaluating unit 40 does not take the recorded pressure in the point A. into account because the conditions have not been met, but it considers the pressure of the point A 5 as the actual blood pressure because the pulsation can be sensed without dis¬ turbances after the moment t_. This measurement is also false, since it considers the false value of the point A-. as a result instead of the correct value of the point A.. It can be seen from the above description that the measurements are carried out separately in the respective channels in consecutive measurement periods cc-mmon to all channels, in which the actual pressures are the same in all channels. Each measurement period has the same duration T, and the periods T-. of pressure increasing are also the same for all channels, while only the periods T 2 of the pulse occurrence are different between the channels. Although the application of measuring channels shown in Fig, 4 resulted in a considerable increase in noise and false signal rejection, the above described examples illustrate that the app- lication of such measuring channels cannot elimin¬ ate in itself the possibility of false measure- ments. For the sake of attaining increased reliability, a sequence of measurements is carried out comprising a predetermined number _k of measur¬ ing periods taken on a number _n of laboratory animals, in which j can be varied between about 5 and 20 and it is preferably 16, The data obtained from the respective channels are evaluated by channels as follows: at the end of the _k measuring periods in valuable pressure data will be available in each channel. If m <_ c • k ( k being between about 0,7 and 0.8), the sequence is conditionally accepted as good , and the evaluation process can be started. If the above condition is not met, a further sequence is started. New sequences are started maximum three times, and if the above condition is still not met, an error indication is generated. If the value obtained for rn has satisfied the preset condition, an examination will be carried out on the " sequence of the valuable blood pressure values on the basis of mathematical statistics. It will be examined whether the elements of the sequence fall within a given range of deviation of an expectable mean value with a certainty of a predetermined confidence level. For carrying out this examination, the elements falling out of that range will not be considered and it will be de- ter ined whether the number of the remaining ele¬ ments is higher than a further predetermined value (or than ), If this condition is met* the mean value of such remaining elements will be consider¬ ed as the blood pressure of the animal examined by that channel. If this condition is not met, new measurement sequences will be started maximum three times. In each sequence of- measurements the evaluation is carried out separately for each channel, and the sequence is repeated, if at least one of the channels request such repetition. For the sake of sparing superfluous evaluations, in case of repeated measurements the evaluation is restricted to the concerned channels only, By means of the above described technique blood pressure measurements have been carried out with an accuracy better than about Z% in case of rats, and apart from the treatment of hypotensive agents no other treatment was applied.

Claims: Claims 1. Apparatus for measuring blood pressure of laboratory animals, comprising individual measur¬ ing cages adapted to accomodate respective ones of the laboratory animals, combined clamping and optical sensor units fastened respectively on the tails of the laboratory animals, measuring channels for pro¬ cessing output signals of-^ ' the optical sensors, and a program controller and evaluating unit, c h a ¬ r a c t e r i z e d in that said measuring cages (10,,,.10, 2 ) comprise a bottom (11), a heater (12) for heating the bottom (11), a temperature regulator unit (13) coupled to the heater (12) for adjusting the temperature thereof to a predetermined value, the apparatus further comprising a pressure developer and distributor equipment (23), air conduits (21) coupl¬ ing the combined clamping and optical sensor units (2θ) to said equipment (23) and a pressure trans¬ ducer (31) coupled to a common distributor space of said equipment (23) and having an output connected to an input of the program controller and evaluating unit (4θ) for supplying a pressure signal. 2. The apparatus as claimed in claim 1, in which each measuring channel comprises in series a decoupling capacitor (32), a matching amplifier (33) of low-pass characteristic, a low-pass filter (34) with high cut-off rate and a cut-off frequency under 10 Hz, an amplifier (35) connected to the output of the filter (34), a comparator (36) and a coupling unit (37) with DC isolation connected to the output of the comparator. 3. The apparatus as claimed in claim 1, in which the air space of the pressure developer and distributor equipment (23) communicates through an opening of a needle valve with the free space. 4. A method for simultaneous measure- ment of blood pressures of laboratory animals, comp¬ rising the steps of accomodating the laboratory animals in respective cages, measuring .their blood pressures by means of sensors fastened on their tails, in which the i m p r o v e m e n t lies in the steps of heating the bottom level of the cages to a temperature between 33 and 35 C during the measurements, increasing and decreasing the air pressure in said sensors simultaneously ' and repeatedly in a number of consecutive measuring periods, detecting the pulse signals of every la¬ boratory animal through a measuring channel having a low-pass characteristics with a cut-off frequency of not more than 10 Hz, recording the pressure value in each period when the first pulse signal is detected and regarding this value as " the blood pressure of the laboratory animal if at least a predetermined number of pulse signals being detect¬ ed within respective ones of consecutive time sections of given length following the detection of the first pulse. 5. The method as claimed in claim 4, further comprising the steps of accomplishing a confidence test on the blood pressure data obtained in a sequence of consecutive measuring periods and examining, whether at least a predetermined portion of said data being within a predetermined variance range and if that is the case the mean value of pressure data within said variance range being re¬ garded as the blood pressure, and if not, said sequence is repeated not more than a predetermined number of times.

Inventors: DANITZ B, GLOFAK P, KISS M
Applicants: DANITZ B, GLOFAK P, KISS M, VILLAMOS IPARI KUTATO INTEZET, VILLAMOSIPARI KUTATO INTEZET
Application year: 1980
Main classification: A61B5
IPC codes: A61B5