Method of direct tissue gas tension measurement and apparatus therefor

A new method of tissue oxygen tension measurement which is suitable for human use utilizes an implanted Silastic tube which is inserted through four to five cm of subcutaneous tissue leaving the ends exposed. With the tube filled, for example, with a saline solution, reference and oxygen electrodes are inserted at the exposed ends and by the use of a polarographic potential the amount of oxygen which permeates through the tube from the tissue into the saline solution may be measured on a continuous real-time basis.

The present invention is directed to a method of direct tissue gas tension 
measurement and apparatus therefor and more specifically to a method 
utilizing a gas permeable tube implanted in the tissue and where gas 
polarography is used for the real-time measurement of the amount of oxygen 
in the human tissue. 
There have been and are several currently available methods to measure 
tissue oxygen in a human patient. A Brantigan U.S. Pat. No. 4,016,863, 
issued Apr. 12, 1977, discloses a tissue gas diffusion catheter device 
which is inserted into the tissue and the fluid therein is allowed to 
become equilibrated with the gas contained in the surrounding body tissue. 
Specifically, oxygen contained in this surrounding body tissue diffuses 
through the Teflon wall of the catheter into the contained fluid. 
Thereafter, the equilibrated or "tonometered" fluid is analyzed by, for 
example, a mass spectrometer or a blood gas analyzing instrument which is 
available in hospital laboratories. Such blood gas instrument may utilize 
an oxygen polarographic technique to analyze the fluid which has been 
placed in the table mounted instrument. 
A variation of this method has been used in patients where a Silastic tube 
is implanted which allows tissue oxygen to equilibrate across the Silastic 
with the fluid that has been introduced into the Silastic tube. This fluid 
is then removed and analyzed at a remote fluid-gas analyzer as discussed 
above. Such technique was found to require prohibitive amounts of skill 
and labor and thus unsuited to routine clinical use. 
In the foregoing Silastic implanted tissue tonometer, as described in the 
Brantigan patent, in one mode of use a water solution is pumped through 
the tubing at a sufficiently slow rate to allow the water to become 
equilibrated with tissue gases. The exiting fluid is then conducted in a 
continuous flow to the inlet of a standard clinical blood gas instrument 
at the bedside, and the gas content analyzed. One difficulty here is the 
"use of the expensive blood gas analyzing instrument" which must be at the 
patient's bedside; in addition, the great time lag and resulting 
inaccuracies produced by the slow moving fluid. Another difficulty is 
occasioned by the need for hydraulic connections, stiff tubes and pumps 
which restrict allowable patient motion. 
Another type of instrument utilizes ultra-thin platinum electrodes to 
develop microelectrode oxygen potentials. These microelectrodes are 
extremely precise. However, since they are directly inserted into the 
tissue, they may be contaminated by tissue proteins which may alter their 
calibration. Also their position in tissue relative to blood vessels 
profoundly affects the measured value. Therefore, a number of readings 
must be taken from different sites and a mean value calculated. 
Microelectrode systems are also difficult to handle and fragile and 
therefore unsuited to routine clinical use. 
One type of "bare" platinum electrode which is inserted into tissue is, for 
example, produced by the Diamond Electro-Tech, Inc. of Ann Arbor, Mich. 
(formerly Transidyne General Corporation) under a type 760 oxygen 
electrode. Here there is a platinum wire encased in a glass, plastic, 
stainless steel sheath. The electrode system is always poisoned by tissue 
proteins, and this method is not acceptable for clinical use. 
Measurement of oxygen percutaneously with a heated skin device has been 
utilized successfully. While this is a non-invasive device which is placed 
on the skin, its success requires that the skin be heated to erythema to 
obtain measurable oxygen concentrations. This causes a major change in 
local perfusion. Furthermore, heating causes changes in skin lipid 
structure and shifts the oxygen-hemoglobin disassociation curves of the 
blood in that of the skin to the right. Serious burns due to its use have 
been reported. 
It is, therefore, an object of the present invention to provide a method 
and apparatus therefor of direct tissue gas tension measurement which has 
a real-time read-out and which is simply inexpensive and accurate and 
lends itself to clinical use as opposed to laboratory use. 
In accordance with the above object, there is provided a method of direct 
tissue gas tension measurement by use of a gas permeable tube implanted in 
such tissue and by gas polarography comprising the steps of implanting a 
predetermined length of the tube through the tissue and leaving a pair of 
exposed ends. Thereafter, reference and gas electrodes are inserted in the 
respective ends of the tube and it is filled with an electrolytic fluid. 
Oxygen permeates from the tissue through the tube into the liquid. A 
polarographic potential is applied between the gas and reference 
electrodes and the electrical signal from the gas electrode is measured. 
An equivalent apparatus is provided.

FIG. 1 shows the apparatus of the present invention as it would be used on 
a human patient. In the subcutaneous tissue 10, is implanted an 
approximately four centimeter length of Silastic tubing 11 which is 
permeable to the oxygen or other gas contained in the tissue. It is 
impermeable to fluids in the tissue and especially fluids containing 
protein which might otherwise contaminate the measuring electrodes. In the 
drawing, the tube is shown at 11a as exiting or coming "out" of the skin; 
11b labeled "in" is the insertion point of the tube. Thus, the tube ends 
11a and 11b of the gas permeable tube are exposed and may have electrodes 
inserted as shown. 
Referring briefly to FIG. 2, this illustrates a spinal needle 12 which has 
fitted within it a mandrel 13 on which is fitted and glued one end of tube 
11. Thus, as is apparent, the outer diameter of the tube is matched to the 
outer diameter of the spinal needle so that insertion of the sharpened end 
12a of this spinal needle through the tissue creates a hole in the tissue 
of the same diameter as the tube. This prevents the unwanted formation of, 
for example, tissue serum which may affect the accuracy of measurement; or 
rather the transfer of a representative sample of the tissue oxygen into 
the electrolytic fluid contained within the tube 11. 
The spinal needle as illustrated in FIG. 2 is bent to maintain the mandrel 
within the needle and to facilitate placement of the needle through skin. 
For implantation, needle 12 is inserted by the medical personnel 
subcutaneously by passing it through the skin into the subcutaneous layer, 
keeping it parallel to the skin for four cm, and passing it out through 
the skin again. The Silastic tubing 11 follows in the needle track as 
illustrated in FIG. 1. The needle and excess tubing are then cut off and 
the tube is secured in place with sutures or sterile tape at its entrance 
and exit from the skin. Thus, tube ends 11a and 11b are left exposed. 
Next, in order to accomplish the polarographic measurement of oxygen from 
the tissue 10, which will now permeate through the tube into a fluid 
electrolyte, which will be placed in tube 10, reference and oxygen 
electrodes are placed in the two exposed ends of the tube. Specifically, 
at end 11a an oxygen sensitive electrode 14 is placed having a coaxial 
wire electrode end 17 shown in dashed outline in FIG. 1 which extends 
approximately one and one-half cm from the point where the tube leaves the 
skin. 
FIG. 3 illustrates the oxygen electrode in greater detail. The 
cross-section of its end, which is cut off at a 90.degree. angle, is 
illustrated in FIG. 4. It includes a platinum wire 18 surrounded by a 
glass sheath 19 and then a plastic sheath 21 and finally a stainless steel 
outer sheath 22. This is in effect a 21 gauge hypodermic needle with the 
tip of the platinum wire 18 being approximately 25 microns. 
The 90.degree. cutoff as opposed to a beveled tip minimizes the possibility 
of puncture of the tube during insertion. 
The electrical connection to the electrode is also illustrated in FIG. 4 
with the center conductor 23 of the coaxial cable 16 being connected to 
the platinum wire and the outer sheath 24 being connected to the stainless 
steel sheath 22. 
The sheathed bare-tipped oxygen electrode 14 is available as model 760 from 
Transidyne General Corporation of Ann Arbor, Mich. which as discussed 
above is now Electro-Tech, Inc. And, as also discussed, it is not suitable 
for clinical use by direct insertion in the tissue because the platinum is 
always poisoned by tissue protein deposited on it. 
Now again, referring to FIG. 1, the other exposed end 11b of tube 11 has a 
reference electrode 26 inserted into it. This is accomplished by use of a 
nylon female hub 27 which is glued onto tube 11 into which is inserted the 
tapered port of a three-way stopcock valve 28. Such stopcock 28 is 
manufactured by Pharmaceal, Inc. of Toa Alta, Puerto Rico under model 
number K75. It is illustrated more fully in U.S. Pat. No. 3,185,179. It is 
a three-way stopcock which has a handle 29 which in normal use provides 
for three different flow paths between its three ports 31, 32 and 33. 
However, the present invention utilizes this stopcock by putting the 
handle 29 in its fourth position which thereby connects all three ports 
together as indicated by the dashed lines. Thus, port 31 is press fitted 
into the nylon bushing 27; in port 32, is placed the reference electrode 
26 which passes through the stopcock, the nylon hub 27 and into the tube 
11. Then onto port 28 is placed a hypodermic syringe 34 containing an 
electrolytic solution such as sodium or potassium chloride which is then 
injected into the tube 11, both to flush it and then fill it, so that gas 
or oxygen from tissue 10 may permeate through the Silastic wall of tube 11 
into the saline solution. A gel might also be used. 
Reference electrode 26 is of the silver/silver chloride type which is 
well-known for use in a polarographic technique. 
After the tube 11 has been implanted, the electrodes are in place, and the 
electrolytic fluid has been placed in tube 11, the gas or oxygen in the 
tissue is allowed to permeate through the tube into the liquid. FIG. 5 
illustrates that with the present invention the time to permeate up to, 
for example, a 90 percent partial pressure value may be as little as 50 
seconds. In practice, for clinical accuracy, two or more minutes would be 
allowed. The curve shows that the permeation of oxygen through the 
Silastic tubing occurs in an asymptotic mode. 
In order to measure the amount of oxygen in the saline liquid in tube 11, 
and therefore in the tissue 10, a polarization voltage or polarographic 
potential must be applied between tbe oxygen and reference electrodes in 
accordance with well-known polarographic technique. In the case of oxygen, 
this voltage is approximately 0.64 volts with the oxygen electrode 14 
being at a negative potential or the cathode potential. This potential 
varies from 0.60 to about 0.74 volts depending on the platinum electrode. 
The signal current from the oxygen electrode is then read by a suitable 
measuring instrument and its magnitude is proportional to the partial 
pressure of oxygen in the tissue 10 which is designated PO.sub.2. 
FIG. 6 illustrates the circuit for applying the polarographic potential of 
0.64 volts between the reference and oxygen electrodes 14 and 26. Tube 11 
is, of course, shown implanted in tissue 10 with the saline solution 
within the tube and the polarographic potential of 0.64 volts applied 
across it. The reference electrode 26 is connected to the coaxial 
connector 37 and the oxygen electrode 14 to the coaxial connector 39. 
With respect to the reference electrode, the central terminal 38 of 
connector 37 is utilized and this in turn is connected to a source of 
polarographic potential 44 via line 43. Line 43 is also connected to the 
outer shield sleeve 42 of coaxial connector 39. 
Coaxial cable 16 of oxygen electrode 14 is plugged into connector 39. Thus, 
the center platinum electrode 18 via line 23 is connected to the center 
electrode 41 which is connected to common through a resistor R3. Thus, 
between this common and reference electrode 26, there is the polarographic 
potential of approximately 0.64 volts. The connection 24 of this potential 
to the oxygen cable 16 is merely for shielding. Since it is connected as 
illustrated in FIG. 4 to the stainless steel sheath 22, there is no 
polarographic action that takes place and this connection, from that 
standpoint, is irrelevant to the process. 
The source of very accurate polarization potential is provided by the 
electrical circuit 44 which has as its most important part a 1.3 volt 
highly accurate mercury battery 46. This is in series with a resistor R6. 
The final potential is provided by the dividing action of series connected 
resistors R4 and R5 which are in parallel with battery 46 and resistor R6. 
The common point of the resistors is also connected to common. A capacitor 
C1 acts as a radio frequency bypass from the line 43. 
The polarographic signal on a line 47 from terminal 41 is connected to the 
inverting terminal of an operational amplifier 48 through the series 
resistors R8 and R9. The non-inverting input, via a resistor R10, is 
connected to a zero adjust potentiometer R1 to provide for adjustment of 
or regulation of the zero level of the final signal measurement apparatus 
which, as will be discussed later, is an ammeter 56. Zero adjust 
potentiometer R1 is in series with R7 and is supplied a very accurate zero 
adjustment voltage from the same battery 46 as is used to provide the 
polarographic potential. 
Another bypass capacitor C2 connects the inverting and non-inverting 
terminals of operational amplifier 48. Power is supplied the operational 
amplifier by batteries 51 and 52, which are both nine volts, to provide 
respective positive and negative polarities as indicated. Capacitor C3 
provides for 60 cycle rolloff, and is connected between the output and 
back to the inverting input of the amplifier 48. The gain of the amplifier 
is controlled by feedback resistors R11 and R12 which in conjunction with 
switch 53, which is connected to a potentiometer R2 and then to the output 
line 54, provides for a variation of ranges of the amplifier. In practice, 
this range with respect to ammeter 56 is equivalent to zero to 150 mm of 
mercury (the partial pressure of the oxygen being measured) or zero to 300 
mm of mercury. Output 54 of operational amplifier 48 is connected to 
ammeter 56 through resistor R4. The ammeter is also bypassed for high 
frequencies by a capacitor C4. The following values of the various 
resistor and capacitors have been used. The capacitor values are in 
microfarads: 
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R1 10 K R8 10 M C1 0.33 
R2 100 K R9 1 M C2 0.01 
R3 22 M R10 1 M C3 0.0047 
R4 7.5 K R11 100 M C4 10 
R5 8.2 K R12 50 M 
R6 100 R13 2.2 K 
R7 10 K R14 4 K 
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The operational amplifier 48 is the type AD (Analog Device) 515. 
Because of the very sensitive nature of the oxygen probe 14 and the 
measurement being conducted, in most cases a calibration must be conducted 
before the actual measurement on the patient. Sometimes it may be wise to 
verify results by again calibrating after use. And, at times, it has been 
found in practice that the system can be used for several days on a 
patient without need for recalibration. 
In any case, with the oxygen electrode of the present invention and the use 
of the specific polarizing potential for oxygen, it has been found that 
there is a linear relationship between the output current I read by 
ammeter 56 and the PO.sub.2 (the partial pressure of the oxygen in the 
saline in tube 11 and thus the tissue). This linear relationship is 
illustrated in FIG. 7. Thus, only two calibration points, zero and max, 
are necessary. 
For use in calibration, FIG. 8 shows a water bath 55 in which is inserted 
the actual Silastic tube 11 which is to be implanted in the patient or an 
equivalent tube. This is not critical. And, as also illustrated in FIG. 1, 
inserted in one end is the reference electrode 26 along with the saline 
solution hypodermic 34 and in the other the oxygen electrode 14. A 
thermometer 57 indicates when the body temperature of 37.degree. C. is 
reached. For the zero level measurement, nitrogen is passed through the 
infusion tube 58, time is allowed for the nitrogen to permeate through the 
Silastic tube 11 into the saline in tube 11, and referring briefly to FIG. 
6, the ammeter 56 is set to zero by use of zero adjust potentiometer R1. 
Alternatively, rather than use nitrogen, the reference electrode may be 
merely disconnected. However, although some dark current may result from 
this, in most cases it may be a second order error and thus of no 
consequence. 
For the maximum level, air into the infusion tube 58 is allowed to permeate 
through the tube 11 and then the maximum level signal is read by ammeter 
56. And this adjusted by potentiometer R2 to, if desired, 150 mm of 
mercury or 300 mm of mercury. 
The apparatus and method of the present invention has actually been used on 
several human patients. An example of such use is shown in FIG. 9. Here 
tissue PO.sub.2 was first measured in an immediate post-operative period 
(that is, after the patient had surgery) where the patient was breathing 
air. When stability was reached, the subject started to breathe 80 percent 
oxygen indicated at zero minutes. A continuous recording was made. A 
typical response to oxygen on the operative day is shown by the top curve 
with circles. Three post-operative days later is indicated by the lower 
curve with dots. It indicates on the operative day that there is much 
greater response to oxygen than at a later time. The FIG. 9 also 
illustrates that with the present invention that a real-time reading of 
the actual tissue oxygen partial pressure is provided, thus indicating the 
actual state of the patient. Referring again to FIG. 5, it has been found 
that there are many patients with roughly a 50 second response time to a 
90 percent level to a step change in PO.sub.2 ; and in general, it has 
been found that a 95 percent response occurs within 60 to 120 seconds. 
One significant and primary advantage of the present invention is that the 
measurement of tissue oxygen tension, especially on a real-time basis, is 
a particularly good index of tissue perfusion since it reflects more than 
just blood supply. Rather, it measures the adequacy of blood supply to 
meet tissue oxygen needs. As discussed above, there are a variety of 
techniques available for tissue oxygen measurement. None so far have been 
suited to routine clinical use. The present invention has devised a new 
method of subcutaneous oxygen tension measurement which is sufficiently 
robust (that is, hardy, fast and in real-time), simple, inexpensive and 
accurate to justify clinical use. The subcutaneous tissue is ideal as a 
site for measurement since it is readily accessible and contains a 
vascular bed which is physiologically the first sacrificed when 
circulatory homeostasis is threatened and the last to be reopened when it 
is restored. 
One of the other advantages of the method of the present invention is the 
fact that for each day after implantation, for example, in a human 
patient, there is a definable normal and a definable response to the 
addition of a specified amount of oxygen to the lungs and hence arterial 
blood. 
First, with respect to the definable normal, it is believed that the 
insertion of the tubing does cause some damage to the tissue. It has been 
found that within the first 24 hours of insertion of such tube the 
response to oxygen may be in the range of from 55-65 (PTO.sub.2), and then 
on the second day 48-55; on the third day 40-48; on the fourth day 35-45; 
and thereafter, for the fifth and subsequent days, it is in the same 35-45 
range. This is partially illustrated, of course, in FIG. 9 which shows the 
first day with a curve in circles and three days later with a curve in 
dots. Thus, in actual use, the readings of the first day would have the 
largest correction factor applied to them for normalization and thereafter 
the correction factor would be progressively reduced until the fourth day. 
Since these readings are somewhat relative, the important factor is that 
they are reproducible and definable. This is important from a clinical 
standpoint in that from one patient to the next a reading on a certain day 
can thus be normalized so that the data can be applied equally to several 
different patients. 
Another factor as illustrated in FIG. 9 is that on successive days as 
illustrated between the top and bottom curve the transient response upon 
application of oxygen becomes more rapid as time goes on. For example, in 
the top curve, there is a time lapse of approximately 20 minutes until a 
steady state level is reached and in the bottom curve it is approximately 
12 to 15 minutes. This definable transient response is also useful for 
clinical purposes since it indicates when a measurement has reached a 
steady state condition. 
Post-operative monitoring has already been described. Another typical use 
might be measuring the tension of the anesthetic gases during surgery. 
Many other uses suggest themselves. 
The present method has several advantages over other techniques for 
measuring tissue oxygen. It provides a single integrated mean or average 
of the extracellular fluid oxygen tension. In other words, the Silastic 
tubing in the patient's tissue integrates all the various oxygen tensions 
impinging on its outer surface to provide an average or integrated mean of 
the amount of oxygen in that tissue. This is opposed to inserting a single 
ultra-fine platinum microelectrode in the tissue which gives a very 
localized value. Furthermore, the platinum electrode, which is necessarily 
used in this polarographic technique, is protected from protein 
"poisoning". Thus, there is no worry about the build-up of membrane on the 
electrode or the shift of values after a short period of use. Thus, the 
data is amenable to statistical analysis and is highly proportional to 
regional blood supply and microvascular perfusion. 
From the ease of clinical use standpoint, the new method has several 
advantages. The catheter or Silastic tube is shorter and less traumatic to 
insert. And the tissue oxygen tension can be measured rapidly and 
continuously for long periods. There is little flushing of saline through 
the tubing and artifacts consequent on the amount of partial pressure of 
oxygen in the saline itself are avoided. The Silastic material has been 
found to cause minimal discomfort and little tissue reaction. This allows 
the tube to be removed easily and painlessly after periods as long as two 
weeks or more. Thus, the present invention readily lends itself to 
clinical use.