Implantable electrochemical sensor having an external reference electrode

The reference electrode, which is physically removed from the sensing electrode, is functionally connected by means of a Ringer's solution formulation serving as an electrolyte bridge between the reference electrode and the fluid or tissue of the patient under test.

The present invention relates generally to the art of measuring or 
monitoring ion activity in vital fluids and tissues, and is more 
particularly concerned with a novel implantable specific ion sensor 
assembly having special utility in in vivo monitoring applications. 
BACKGROUND OF THE INVENTION 
An electrochemical sensor consists of a paired sensing and reference 
electrode combination. In measuring pH or other ion activity it is 
necessary to use an ion sensing electrode in conjunction with the 
reference electrode which also makes contact with the system on which 
measurements are being made. In certain cases the reference electrode can 
make direct contact with the system which necessitates that the system 
contain a fixed and known concentration of an ion that can enter into 
equilibrium with the reference electrode. More generally, the reference 
electrode is immersed in a solution having a known content of the ion with 
which it equilibrates and contact of this solution with the system being 
measured is made via a suitable "salt bridge." This bridge may consist of 
an extension of the vessel in which contact with the reference electrode 
is made. A specific ion sensor of the latter type is disclosed and claimed 
in U.S. Pat. application Ser. No. 491,772, filed July 24, 1974 (now 
abandoned), and assigned to the assignee hereof. 
SUMMARY OF THE INVENTION 
By virtue of our novel concepts to be described, new and important 
advantages of economy and utility can be obtained. In particular, the 
electrochemical sensor of this invention avoids the necessity for various 
structural components essential to prior devices of this general type and 
yet all the essential functions are retained. In addition, the necessity 
for removing blood or other samples from the patient's body for test 
purposes can be avoided, the reference electrode need not be introduced 
into the patient and it need not be biocompatible. Moreover, these 
advantages can be obtained without incurring any performance or 
reliability penalty and without increasing production cost. 
Our basic concept is to make multiple use of an injectable isotonic 
solution. Thus, a solution of a kind normally introduced intravenously 
serves as an electrolyte in equilibrium with the reference electrodes and 
as an electrolyte bridging between the blood, for example, and the 
reference electrode. The performance of the sensing electrode is not 
impaired since in accordance with this invention the solution is 
introduced into the bloodstream at a location slightly downstream from the 
active tip of the sensing electrode. Similarly, in the case of tissue ion 
activity measurement, a suitable isotonic solution is employed as the 
reference electrode electrolyte and as the bridge but is stationary 
instead of continuously flowing as in the case above because muscle or 
other tissue outside the vascular compartment only slowly absorbs injected 
fluids. Again, though, the active tip of the sensing electrode is disposed 
out of contact with the isotonic solution electrolyte although the 
insulated lead and that electrolyte solution share the catheter lumen. In 
both cases, however, the reference electrode is directly in contact with 
the isotonic solution electrolyte within the catheter or within a conduit 
communicating therewith for delivery of the isotonic solution into the 
catheter lumen continuously or intermittently, as required. 
As indicated above, we have discovered that the essential reference 
electrode function can be adequately performed while isolating the 
reference electrode and its electrolyte from the body fluid or tissue 
being tested. A suitable reference electrode/electrolyte combination is a 
chlorided silver wire, tube or other configuration in contact with a 
saline solution. We have also found that the particular nature or 
composition of the isotonic saline solution is generally not critical to 
the reference electrode function, the various saline or Ringer's solution 
formulations, for example, adequately serving the purpose for proper 
reference electrode function. Still further, for some monitoring and 
measurement purposes not requiring continuous reference electrode 
function, the isotonic solution flow can be controlled and interrupted as 
required for the other purposes without significant penalty to the 
reference electrode function. 
On the basis of these discoveries, it will be understood that the assembly 
of this invention, briefly described, includes an insulated sensing 
electrode with an electrochemically active portion at one end, cannula 
means receiving and enclosing a portion of the insulated length of the 
sensing electrode, and electrolyte delivery means including a conduit 
communicating with the cannula means and an electrolyte source, all in 
combination with a metallic reference electrode positioned in the assembly 
at a location removed from the electrochemically active portion of the 
sensing electrode and exposed to direct contact with electrolyte delivered 
through the conduit into the cannula means. 
As will be described in detail, the reference electrolyte is in liquid form 
and, preferably, the reference electrode is located in the conduit rather 
than in the cannula. Additionally, the cannula is suitably in the form of 
a catheter for insertion into a blood vessel or into muscle tissue or 
other tissue outside the vascular compartment, and the reference electrode 
may take the form of a tube extending lengthwise of the catheter and 
disposed coaxially with the elongated electrode lead. In these various 
design alternatives, it is generally desirable that the insertable 
components be miniaturized so far as possible, but it should be recognized 
that it is a special advantage of this invention that the reference 
electrode may be comparatively large and therefore of simple design. 
In view of the foregoing description, those skilled in the art will further 
understand that the reference electrode half cell of this new sensor is 
itself a new departure from the prior art constituting a novel 
subcombination of the specific ion sensor of this invention. Thus, this 
half cell comprises a tubular body of electrically insulating material 
having an open end for communication with a subject to be tested, an 
elongated silver reference electrode in the tubular body and extending 
therefrom for connection to electrical readout means, and an isotonic 
solution electrolyte in contact with the reference electrode and the open 
end of the tubular body. Preferably, the electrode is of silver and a 
portion thereof within the tubular body is coated with silver chloride. 
Additionally, the electrolyte is a liquid and the tubular body has an 
inlet opening to receive the electrolyte which flows through the tubular 
body in contact with the silver chloride coating and out through the open 
end of the said body.

DETAILED DESCRIPTION OF THE INVENTION 
As illustrated in FIG. 1, in vivo specific ion sensor assembly 10 includes 
a cannula or catheter 11 having a side arm 12 to receive tubular body or 
conduit 13 of suitable electrically insulating material through which 
isotonic solution electrolyte 14 can be introduced into lumen 15 of the 
catheter. Leading end 16 of the catheter is open and disposed in blood 
vessel 17 for discharge of electrolyte 14 continuously or intermittently 
into bloodstream 18 at a point slightly downstream from active tip 20 of 
sensing electrode 21 which is suitably the same in construction and mode 
of operation as that disclosed and claimed in copending patent application 
Ser. No. 491,772 referred to above. Insulated lead 23 of sensing electrode 
21 extends through lumen 15 and through cap 25 fluid-tightly closing the 
other end of catheter 11. Conduit 13 communicates with isotonic solution 
electrolyte reservoir 27 and at a point between the reservoir and catheter 
11, reference electrode 29 in the form of a silver wire bearing a silver 
chloride coating is disposed in the conduit, lead 30 of the electrode 
extending through cap 31 fluid-tightly sealing the reference electrode 
access opening in the conduit. Shielded cables 33 and 34 connect leads 23 
and 30 of the sensing and reference electrodes, respectively to pH meter 
38. 
In operation of the FIG. 1 assembly, flow of electrolyte through conduit 13 
is regulated by three-way stop cock 35 and valve 36 disposed downstream 
and upstream, respectively, from reference electrode 29, and by pump 37 of 
the venoclysis set. Thus, as indicated above, readings may be taken 
continuously or intermittently and meter 38 may be coupled to a recorder 
if desired. It will be understood that during periods of such use the 
isotonic solution serves as an electrolyte bridge between bloodstream 18 
and reference electrode 29 and also in establishing the reference 
electrode/electrolyte couple. Stop cock 35 is open at such times and the 
electrolyte is therefore in contact with both the bloodstream and 
reference electrode 29. 
The specific ion sensor assembly of FIG. 2 likewise includes a catheter 40 
having a side arm 41 to receive a tubular body or conduit 42 of suitable 
electrically insulating material through which gelled electrolyte 43 can 
be introduced into the catheter to fill lumen 45 thereof. The catheter 
also has an open end 47 disposed in muscle tissue as indicated at 48. 
Active tip 50 of the sensing electrode extends through the open end 47 of 
the catheter into muscle tissue 48 while the lead 52 of the electrode 
extends the length of catheter lumen 45 and through cap 54, fluid-tightly 
closing the opposite end of the catheter. 
Reference electrode 56 in the form of a chlorided silver tube likewise 
extends through cap 54 and through a portion of the length of lumen 45 of 
the catheter in which it is coaxially disposed around lead 52 of the 
reference electrode. Electrode 56, however, terminates within the catheter 
at some distance removed from tip 50 and does not directly contact tissue 
48. 
Electric cables 59 and 60, preferably of the shielded type described in the 
reference of FIG. 1, connect the sensing and reference electrodes, 
respectively, to pH meter 62. 
The specific ion sensor assembly of FIG. 2 operates generally as described 
in reference to FIG. 1, the basic difference being that a gelled or 
stationary electrolyte is used instead of a flowing electrolyte isotonic 
solution. This is because of the physical difference between the 
bloodstream and muscle tissue, particularly in respect to absorption rate. 
The development of vacancies or bubbles within the catheter 40 can lead to 
erroneous pH readings. Accordingly, a syringe 70 is provided for 
maintaining a void-free condition within lumen 45. 
If desired, one may in accordance with this invention use two separate 
catheters and separate the sensing electrode from the reference electrode 
in that manner without impairing the operation of either one. Catheters of 
generally the FIG. 2 type would be specially suited for this purpose and 
would find use in applications involving muscle tissue and the like rather 
than in the vascular compartment, where multiple openings are not 
desirable. 
While the illustrated apparatus has been described with particular 
reference to hydrogen ion activity measurement or monitoring operations, 
those skilled in the art will understand that this invention is equally 
applicable to the monitoring or measurement of other ions in the blood or 
in muscle tissue or in other fluids or tissues of the body. In other 
words, the basic new principles of design and mode of operation of the 
sensors of this invention apply as well to other specific ion in vivo 
sensing systems and devices incorporating the sensing electrode and 
reference electrode combination. 
The following are illustrative, but not limiting, examples of the practice 
of our present invention: 
EXAMPLE I 
An in vivo blood pH sensor assembly like that illustrated in FIG. 1 was 
used in tests on a dog. The pH-sensing electrode was a polymer membrane pH 
sensor as described and claimed in U.S. Pat. No. 3,743,588 assigned to the 
assignee hereof. This sensor was inserted through a cannula implanted in 
the left carotid artery, the cannula being continuously flushed with 
lactated Ringer's solution (130 mEq sodium ion, 4 mEq potassium ion, 3 mEq 
chloride ion, 28 mEq lactate ion) supplied under pressure from the 
venocylsis set shown in FIG. 1. The flow rate of the electrolyte was 
approximately 1 milliliter per minute. The reference electrode in this 
instance was a chlorided silver wire sealed into one end of a small 
diameter plastic tube which was filled with a solution of 4N potassium 
chloride that was gelled with two weight percent Agar-Agar. The potassium 
chloride electrolyte furnished the chloride ion concentration to establish 
the electrochemical potential of the silver/silver chloride couple, and it 
also served as an intermediate electrolyte bridge between the chlorided 
silver wire and the lactated Ringer's solution with which it was in 
contact at the opposite end of the plastic tube. The electrodes were 
connected as described above to the pH meter (Instrumentation Laboratories 
Model 245), the output being displayed on a recorder (Hewlett-Packard 
Model 7100B). Electrical pick-up noise was reduced to less than 1 
millivolt by effective shielding of the cables. The potential difference 
between the pH-sensing electrode and the reference electrode was 
precalibrated in vitro in buffers thermostated at 37.degree. C. before 
implantation in the animal, and this pH calibration was used throughout 
the in vivo test. The in vivo test lasted approximately 51/2 hours, during 
which time arterial pH, as measured by the in vivo sensor, was 
continuously displayed. To monitor the accuracy of these data, blood 
samples were withdrawn from the site of the pH sensor, through the 
three-way stopcock attached to the exterior end of the cannula, and their 
pH independently determined in vitro using a blood gas and pH analyzer 
(Radiometer Model 27GM). Eight such samples were taken at intervals of 
approximately 45 minutes during the 51/2 hour test, and the difference 
between the in vitro measurement and the in vivo sensor reading at the 
time of sampling were compared. In three instances this difference was 
+0.03 pH units, in one instance +0.01 pH units, and in four instances 
there was no difference. On the average, then, in this test the in vivo 
sensor indicated a blood pH higher by 0.01 pH unit than that indicated by 
the in vitro method, with a root mean square difference of 0.02 pH units. 
The accuracy of the in vivo measurements was also verified after the test 
by repeating the in vitro calibration or the potential difference between 
the pH-sensing electrode and the reference electrode in buffers 
thermostated at 37.degree. C. The calibration was found to have changed by 
+0.02 pH units during the course of the 51/2 hour test. The two methods of 
judging the accuracy of the in vivo pH measurements were thus in 
reasonable agreement, and the accuracy found by either method was 
satisfactory. 
EXAMPLE II 
An in vivo muscle pH assembly like that illustrated in FIG. 2 was used in 
tests on a dog. A catheter was first implanted percutaneously into muscle 
tissue on the outer aspect of the upper thigh, then the assembly 
consisting of the pH-sensing electrode and the silver--silver chloride 
reference electrode inserted as shown into this catheter. The tip of the 
pH-sensing electrode extended into the muscle tissue approximately 1 
centimeter beyond the end of the catheter. An electrolyte solution of 
isotonic 0.15 molar NaCl gelled by the addition of 3 weight percent 
methylcellulose (Dow 90 HG Premium Grade Methocel) was then injected by 
syringe into the side arm of the catheter, filling its volume of 
approximately 0.4 milliliters and making contact with the muscle tissue at 
the tip of the catheter. The syringe was then removed and the side arm 
closed with a fluid-tight cap (not shown). The electrodes were connected 
as in Example I to a pH meter and recorder to yield a continuous record 
over the 3-hour test. The potential difference between the pH-sensing 
electrode and the silver--silver chloride electrode was precalibrated in 
vitro at 37.degree. C. in buffers containing 150 mEq chloride ion. In the 
case of muscle pH monitoring, unlike that for blood pH monitoring, there 
is no alternative, in vitro method for quantitatively determining the 
accuracy of the pH values indicated by the in vivo sensor. Therefore, only 
a repeat of the calibration procedure at the termination of the in vivo 
test could be used; it was found that the calibration had changed by -0.01 
pH units during the 2-hour test. Furthermore, the muscle pH data obtained 
during the test appeared to be reasonable as compared to the experience 
obtained by other investigators, in that muscle pH was generally about 0.1 
pH unit lower than arterial blood pH under most conditions, an increase or 
decrease in one paralleling that in the other. An exception was when 
peripheral vasoconstriction was induced by a severe hemorrhagic shock, in 
which case muscle pH fell rapidly to a value about 1 pH unit below 
arterial pH. 
Modifications contemplated in the devices of this invention include 
thermostating of the reference electrode so that variations in temperature 
will not affect its potential. This would only be desirable if a very high 
degree of pH accuracy is required. Secondly, as stated in Example II, 
instead of having the reference electrode in direct contact with flowing 
electrolyte solution as shown in FIG. 1, an intermediate salt bridge such 
as saturated potassium chloride might be provided. The advantage would be 
that the reference electrode potential would then be independent of the 
precise composition of the flowing electrolyte and it would be unnecessary 
to recalibrate the sensor output if flowing electrolyte of different 
composition were used at some stage of the test.