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Nonvasive Blood Gas

7 Sensing with Electrodes
7.1 INTRODUCTION
The metabolism of all living cells in the body requires oxygen and an energy
substrate, generally glucose. As the result of oxidative metabolism, heat and CO2
are produced as well as regulated molecular byproducts, and O2 in the blood is
consumed. The lungs are the organ in which the external atmosphere interfaces with
the body’s blood supply; O2 is taken in and CO2 is exhaled. The partial pressure of
oxygen (pO2) in an alveolus is typically 104 mmHg. Venous blood entering a
capillary in the alveous wall has a pO2 of c. 40 mmHg. Thus, an initial pressure
gradient of 104 − 40 = 64 mmHg causes O2 gas to diffuse into the capillary, combine
with hemoglobin in red blood cells (RBCs) and be dissolved in the water in the
blood. The blood exiting the capillary contains c. 104 mmHg pO2. All the oxygenated
alveolar blood mixes with venous blood from the non-oxygenating tissues of the
lungs, bringing the pO2 down to about 95 mmHg. This is the pO2 of arterial blood
pumped to the body from the left ventricle.
In the peripheral systemic capillaries, oxygen diffuses into the interstitial fluid,
which has a pO2 of c. 40 mmHg. Thus, venous blood returned to the heart and lungs
has a pO2 of c. 40 mmHg. The average pO2 in the systemic capillaries is about 70
mmHg (blood enters with a pO2 of 95 and exits with 40 mmHg).
Normally, about 97% of the O2 carried in arterial blood is combined with
hemoglobin molecules inside red blood cells (erythrocytes), and the remainder of
the O2 is dissolved in the plasma. In terms of partial pressures, 92.2 mmHg is carried
as oxyhemoglobin (HbO), and 2.8 mmHg O2 is carried dissolved in arterial blood.
The venous blood sent to the lungs under resting (basal metabolic) conditions has
about 75% HbO, and a pO2 of 40 mmHg. Under conditions of intense exercise, the
venous HbO can drop to as low as 19% saturation; the interstitial fluid (and venous)
pO2 drops to c. 15 mmHg (Guyton, 1991, Ch. 40).
Any disease or condition that interferes with the normal exchange of gases in
the alveoli, the transport of O2 to the systemic capillaries, the return of CO2 to the
lungs, and the exchange of O2 and CO2 in the systemic micro-circulation will give
rise to life-threatening hypoxia or acidosis. Section 7.2 describes noninvasive chem-
ical means of monitoring pO2 in the body. (Note also that Section 15.8 covers pulse
oximetry, a noninvasive optical technique of measuring the percent O2 saturation
(sO2) of hemoglobin in the peripheral circulation.)
Also considered in this chapter is the NI transcutaneous measurement of pCO2
in the peripheral blood, tcpCO2. High blood tcpCO2 is a sign of metabolic acidosis,
which can have several causes, including damaged alveoli in the lungs. (Damaged

173

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174 Noninvasive Instrumentation and Measurement in Medical Diagnosis

alveoli will also give low tcpO2 readings.) Normal blood pH is c. 7.4. If the pH
decreases for any reason, the rate of breathing increases automatically to exhale CO2
at a greater rate, and the kidneys also compensate for elevated acidity in the extra-
cellular fluid by actively excreting hydrogen ions at an increased rate. Thus, another
cause of high pCO2 can be kidney failure, in which the tubular epithelial cells actively
transport H+ ions from their interiors into the collecting tubes for excretion in urine
at a reduced rate. Low blood flow to the kidneys or damaged tubular cells can
decrease this normal mechanism for blood pH regulation. High pCO2 can occur
normally in exercise, but it drops in minutes due to increased breathing effort and
H+ elimination by the kidneys. Acidosis can also result from gluconeogenesis in
diabetes mellitus. Here, low intracellular glucose concentration causes liver cells to
break down fatty acids to acetoacetic acid and acetyl-Co-A. Acetyl-Co-A is used as
an energy source, and acetoacetic acid enters the blood, causing the pH to fall.
Although CO2 is not involved directly, the lower pH causes the ratio of pCO2 to
[HCO3− ] to increase. Loss of intestinal bicarbonate in severe diarrhea can also cause
acidosis, and an elevated pCO2 to [HCO3− ] ratio (Guyton, 1991, Ch. 30).

7.2 TRANSCUTANEOUS O2 SENSING

7.2.1 INTRODUCTION: THE CLARK ELECTRODE
Several methods, given direct contact with a blood sample, can accurately measure
the pO2 of blood. For a description of these invasive instrumental means, see Webster
(1992). In this text, however, we are devoted to examining noninvasive medical
instruments, and there is presently only one effective means of transcutaneously
measuring peripheral tissue blood pO2. This system is based on the electrochemical
Clark electrode, first described in 1956 (Hahn, 1998).
The basic Clark electrode can measure pO2 in gases or liquids. It is an electro-
chemical, polarographic system in which a fixed potential is maintained across the
electrodes through which a dc current flows that is proportional to the concentration
of the rate-limiting reagent, O2, which participates in oxidation/reduction reactions
that take place at the electrode surfaces (oxidation takes place at the anode; reduction
occurs at the cathode). A plastic membrane porous to O2 separates the sample
compartment from the reaction compartment (around the electrodes). The reaction
compartment is filled with an aqueous buffer solution (at about pH 7), containing
chloride ions (which can be from KCl). The O2 that reacts at the electrode surfaces
must diffuse in through the membrane from the sample compartment. Figure 7.1
illustrates a cross section through the basic Clark cell. The anode (+ electrode) is a
AgCl-coated Ag ring or “washer;” the cathode (− electrode) is the small exposed
tip (12 to 25 µm diameter) of an insulated platinum wire. The membrane is typically
25 µm polyethelene or polypropylene. The chemical reactions that occur at the Pt
cathode are reductions (Hahn, 1998):

O 2 + H 2 O + 2e − → HO 2− + OH − 7.1

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Nonvasive Blood Gas Sensing with Electrodes 175

Ib Rb
R2 Rc
VR
R1
(0 V)
(Virtual gnd.)
Vo
Voltage - 0.7 V
reference
OA OA

I O2 + I b I O2 + I b

Clark electrode
Plastic

O-ring

⇑
AgCl anode pO 2 Polypropylene membrane

Pt cathode Buffered electrolyte

FIGURE 7.1 Cross-section and support electronics for a Clark polarographic O2 sensor. The
left-hand op amp and reference source supply the 0.7 V bias voltage for the cell. The right-
hand op amp serves as a current-to-voltage converter. Rb sets dc current Ib to cancel out the
zero-oxygen current of the Clark cell.

HO 2− + H 2 O + 2e − → 3OH − 7.2

HO 2− catalytic
 → 1 2 O 2 + OH −
decomposition
7.3

or, as a net reaction:

O 2 + 2 H 2 O + 4e − direct
 → 4OH − 7.4

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176 Noninvasive Instrumentation and Measurement in Medical Diagnosis

The OH− ions are buffered to maintain neutral pH, and the chloride ions carry charge
to the AgCl anode. Four electrons flow for every diatomic oxygen molecule reacted;
thus, the Clark cell current at a given temperature is given by:

IC = Ib + KC pO2 7.5

By U.S. convention, in metal wires, current flows in the opposite direction to

electrons. The Clark cell is generally operated at a fixed potential of 0.7 volts; its
current is linearly proportional to the pO2 in the measurement compartment. A small
dc background current, Ib, flows at pO2 = 0, which is due to ion drift in the electric
field between the electrodes. The current vs. pO2 graph taken with Vcell = 0.70 V
and pH 6.8 is essentially linear, enabling a two-point calibration of a Clark O2
electrode (at pO2 = 0 and pO2 = 160 mmHg (atmospheric)). The left op amp in
Figure 7.1 acts as a 0.7 V voltage source; the right op amp is a low-dc drift FET-
input type with very low IB that is used as a current-to-voltage converter (transim-
pedance). Its output, after subtracting the background current, Ib, is Vo = KC pO2.
The normal tempco of a Clark cell is 2% per degree Celsius, and the linearity is
better than 1% over the physiological pO2 range (Hahn, 1998).
The response time of a Clark cell to a step change in measured pO2 is largely
governed by the thickness of the membrane, but also depends on O2 and ion diffusion
times in the electrolyte. Typical Clark cell response time (time to reach half the
steady-state value) is on the order of tens of seconds. For a theoretical treatment of
Clark cell response dynamics, see Hahn (1998). Because of the low-pass character-
istic of the Clark cell’s response, it responds to a smoothed, or time-averaged pO2.

7.2.2 THE TRANSCUTANEOUS TCPO2 SENSOR

The transcutaneous tcpO2 sensor uses a Clark cell that is internally heated and
temperature regulated to operate at a temperature of 40˚ to 45˚ C, ± 0.1˚ when on
the skin. The elevated temperature of the Clark cell membrane is necessary to cause
vasodilation and reddening of the skin under the sensor. A thin layer of an isotonic
aqueous contact gel is placed between the skin and the heated sensor’s membrane
to facilitate outward diffusion of O2 from the skin through the membrane. The sensor
has built-in thermistors to monitor the Clark cell’s electrolyte temperature and the
skin temperature under the membrane. The thermistor outputs are used to control
the power supplied to a heater coil surrounding the cell.
Initially, transcutaneous operation of the heated Clark cell was found to be
effective in babies and small children because of their thinner skin. Unfortunately,
because of the delicate skin of infants, prolonged application of a heated sensor can
cause second-degree (blister) burns, unless the sensor is moved every hour or so.
There is a time × temperature product that must be observed to avoid skin damage.
The heated Clark sensor must be given a two-point calibration at its chosen operating
temperature before use.
Heated transcutaneous pO2 sensor systems (the TCM instrument series), made
by Radiometer Copenhagen, are sold worldwide. They are used for such applications

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Nonvasive Blood Gas Sensing with Electrodes 177

as monitoring neonatal pO2 to sense apnea, respiratory distress, etc. They are now
also used in adults for applications in hyperbaric medicine, vascular surgery, wound
care, and in reconstructive plastic surgery to monitor angiogenesis.

7.3 TRANSCUTANEOUS CO2 SENSING

7.3.1 INTRODUCTION: THE STOW-SEVERINGHAUS ELECTRODE
The basis for transcutaneous pCO2 sensing is the Stow-Severinghaus (S-S) electrode,
developed in 1957–1958 (Hahn, 1998). At the heart, literally, of an S-S electrode is
the glass pH electrode half cell, as shown in Figure 7.2. The half-cell EMF of the
glass pH electrode is really two half-cell potentials in series: an EMF is developed
across the special tip glass envelope that is proportional to the pH, and the EMF of
the internal, AgCl coupling electrode immersed in the 0.1 N HCl internal filling
solution. In general,

E GL = E GL
0
+ (2.3026 RT F ) [ pH] 7.6

Where pH is defined as − log10(aH+) ≅ − log10([H+]), R is the gas constant = 8.3147

joule/(mole ˚K), T is the Kelvin temperature, F is the Faraday number = 96,496,
and 2.3026 comes from converting natural logs to log10. At 25˚ C, (2.3026 RT/F) =
0.059156 V.
Interestingly, the pH of the 5 to 20 mM bicarbonate solution surrounding the
glass pH electrode is proportional to the negative logarithm of the partial pressure
of the CO2 in the external solution over the range of 10 to 90 mmHg (Webster, 1992,
Ch. 10]. First, CO2 must diffuse from the external test solution into the bicarbonate
solution through the Teflon membrane, where the following equilibria occur:

CO2 + H2O ⇐⇒ H2CO3 ⇐⇒ H+ + HCO3− 7.7A

HCO3− ⇐⇒ H+ + CO3− 7.7B

NaHCO3 ⇐⇒ Na+ + HCO3− 7.7C

Adding the equations, we find:

xs Solid Constant
CO 2 + H 2 O + NaHCO 3 ⇐⇒ 2 H + + CO 3= + HCO 3− + N a + 7.8

Note that the constant, a, relating the equivalent concentration of CO2 gas dissolved
in blood to the partial pressure is found from:

a=
[CO ]
2
7.9
pCO 2

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178 Noninvasive Instrumentation and Measurement in Medical Diagnosis

+
Vo

Cap

Fill hole

AgAgCl electrodes

Glass pH electrode
Solution of sodium
bicarbonate and NaCl
0.1 N HCl

pH-sensitive glass

O-ring

CO2
20µm Teflon membrane

FIGURE 7.2 A Stow-Severinghaus electrode to sense pCO2. A glass pH electrode responds

to the pH of the inner solution, which is shown to be a function of log10 (pCO2) in Equation
7.14.

a for blood is c. 0.03 (mmol/liter)/mmHg pCO2. At chemical equilibrium we have:

{ } [ ] [CO ][HCO ][Na ]

K a( pCO 2 ) = H +
2 =
3
−
3
+
7.10

K is the equilibrium constant for reaction 7.8. Also, from Equation 7.7B at equilib-
rium:

K′ =
[H ][CO ] → [CO ] = K ′ [HCO ] [H ]
+ =
3 = − +
7.11
[HCO ]−
3
3 3

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Nonvasive Blood Gas Sensing with Electrodes 179

Substituting Equation 7.11 into Equation 7.10, we can write:

[ ][
Ka( pCO 2 ) = H + HCO 3− ] [Na ] K ′
2 +
7.12

Taking the logarithm10 of terms in Equation 7.12, and noting that pH is defined by
pH ≡ −log10[H+],

[ ] [
log(Ka ) + log( pCO 2 ) = − pH + 2 log CO 3= + log Na + + log(K ′)] 7.13

or

[
pH = − log( pCO 2 ) − log(Ka K ′) + 2 log HCO 3− + log Na +] [ ] 7.14

which is of the form

pH = − log(pCO2) + A 7.15

because Ka/K′, [HCO3− ] and [Na+] are constant. Thus a Stow-Severinghaus pCO2
meter computes the pCO2 by exponentiating (pH − A), sic:

pCO2 = B10(−k(pH − A)) 7.16

The constants B and k are for display scaling.

Because the pH electrode and the chemical dissociation reactions involved are
all temperature sensitive, any application of the Stow-Severinghaus pCO2 sensor in
vivo, in vitro (with blood), or transcutaneously requires precise temperature regula-
tion to maintain calibration.

7.3.2 TRANSCUTANEOUS TCPCO2 SENSING

The tcpCO2 sensor can be combined with a tcpO2 sensor in the same housing. Such
units are described by Hahn (1998) and Webster (1992) and Radiometer Copenhagen
offers their model TCM™/3, combined tcpCO2 and tcpO2 monitor. The combined
sensor can use the same 0.1 N bicarbonate buffer used in the Stow-Severinghaus pCO2
sensor with the addition of NaCl for the Clark cell electrolyte. Figure 7.3 illustrates
the author’s version of a combined tcpO2 + tcpCO2 sensor. Note that it uses a common
electrolyte and membrane. The entire cell is heated and thermostatically regulated (not
shown in figure). The elevated (c. 44˚ C) temperature causes vasodilation under the
sensor and increases upward diffusion of O2 and CO2 through the stratum corneum
of the skin to the sensor’s membrane. The electrometer amplifier used to amplify the
pH electrode voltage has an ultra-low bias current (in 10s of fA), and super-high input
resistance (c. 1014 Ω). Thus, its bias current will be c. 10−14 A, which is negligible
compared with the 10−8 A Clark cell current. OA-2 thus can serve as a virtual ground

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180 Noninvasive Instrumentation and Measurement in Medical Diagnosis

Electrometer
amplifier

VCO2

VR
- 0.7 V
(Virtual
OA1 ground)

(0 V)
VO2
(Voltage source) OA2
IO2 + Ib IO2 + Ib
(Current to
voltage converter)

0.1N HCl Glass pH electrode

O-ring

Electrolyte

Membrane Pt cathode

AgCl anode (O2)

and ref. (CO2)

FIGURE 7.3 A proposed combined pO2 and pCO2 electrode. OA2 outputs a voltage propor-
tional to pO2, and the electrometer amplifier outputs a voltage VCO2 ∝ −log10 (pCO2) + A.

for both the Clark cell and the Severinghaus electrode; its voltage output depends only
on the Clark cell current.

7.4 SUMMARY
There are several reliable chemical gas sensors that work well when immersed in
blood, in vitro or in vivo, but only two, as we have seen above, have been adapted
to reliable approved nonvasive percutaneous operation.
A wide variety of other sensors work well to sense pO2 and pCO2 in the gas
phase. O2 has been sensed by using the fact that it is weakly paramagnetic, i.e., O2
gas molecules are attracted by a magnetic field, and thus can be separated from N2,
Ar and CO2 in air. Oxygen’s magnetic susceptibility is the basis for several com-
mercial gaseous oxygen meters: The thermomagnetic O2 “bridge,” the Hartmann &
Braun Magnos 7G, the differential pressure “bridge,” the Siemens Oxymat 5M, the
Datex OM-101 differential pressure fast-response O2 sensor, and the Servomex 1111

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Nonvasive Blood Gas Sensing with Electrodes 181

Faraday balance type O2 sensor (Moseley et al., 1991). O2 also can be the rate-
limiting reactant in a fuel cell so output voltage is proportional to pO2, or in a
polarographic chemical reaction (e.g., the Clark cell). The speed of sound in O2 at
a given pressure and temperature is different from other gases, and this property has
been used to sense the pO2 in air (Hong and Northrop, 1991). The fact that O2
absorbs light at 760 nm is the basis for another optical pO2 sensor using the airpath
absorption of light at 760 nm and at another wavelength where O2 does not absorb,
and Beer’s law.
A major means of sensing atmospheric (and respiratory gas) pCO2 makes use
of the IR absorption of the CO2 molecule. Again, two wavelengths are used, one
where CO2 absorbs (e.g., at 4.2 µm) and the other where it doesn’t (e.g., at 3.5 µm).
Water vapor interferes in some CO2 IR absorption bands, so CO2 sensing in respi-
ratory gases requires the gas input to the IR cell to be dried; the drying can be done
chemically, or by heating the gas.
Fiber optic (FO) optical sensors have been used to sense pH through the use of
a pH-sensitive indicator dye, such a phenol red bound to the surface of 5–10 µm
diameter polyacrylamide microspheres mixed with 1 µm diameter polystyrene
microspheres for light scattering. The dye and microspheres are enclosed in a small
plastic tube permeable only to H+ ions. One end of the microtube is sealed; the other
is joined to two optical fibers (input and output). Phenol red in aqueous solution has
an isobestic wavelength at c. 480 nm (wavelength where reflectance is independent
of pH). The wavelength at which maximum change in reflectance vs. pH occurs is
c. 560 nm. By using these two wavelengths to illuminate the indicator dye and
computing the difference in reflected intensities over their sum, pH from 6.1 to 7.6
can be measured (Wolfbeis, 1991). This type of sensor is called an optrode. Note
that, if this sensor is surrounded by a bicarbonate solution that is separated from the
skin by a CO2-permeable membrane, this pH sensor should be usable to measure
tcpCO2. Other indicator dyes have also been used in similar pH optrode sensors.
These include, but are not limited to: sulfo-phenolphthalein, bromthymol blue, and
bromphenol blue (Wolfbeis, 1991).
Another optrode strategy to measure pH (and possibly pCO2) makes use of light-
induced fluorescence, which is pH-sensitive. In one system, immobilized 8-hydroxy-
1,3,6-pyrenetrisulfonate (HPTS) is excited by pulses of 455 nm light. The fluores-
cence response at 520 nm becomes stronger as the pH goes from 5 to 8. HPTS also
has a fluorescence isobestic excitation wavelength at 435 nm. The response here is
also at 520 nm, but its intensity does not change with pH. The 99% response time
of the HPTS sensor was about 1.7 minutes (to a step change of pH; 6 → 8 → 6,
etc.), and its accuracy was c. ± 0.1 pH unit. Other fluorescent pH indicators have
also been used: aminofluorescein and 7-hydroxycoumarin-3-carboxylic acid (HCC)
(Wolfbeis, 1991). Again, an H+ permeable membrane serves to isolate the immobi-
lized fluorescent chemical. This type of sensor, too, has the potential for measuring
tcpCO2.
It is possible that certain solid-state pH sensors can be adapted to tcpCO2
operation. It is known that silicon oxynitride is pH-sensitive over a large pH range
when used as a coating for the gate of a chemically sensitive field-effect transistor

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182 Noninvasive Instrumentation and Measurement in Medical Diagnosis

(CHEMFET) (Kelly et al., 1991). A heated membrane would still be required over
the skin, but the analyte gas would diffuse into a low-volume bicarbonate solution-
filled measurement compartment with which the coated gate of the CHEMFET was
in contact.

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