Hemolysis detector

An apparatus and method are disclosed for continuous, on-line monitoring of extracorporeal blood in a blood path. A shell has a blood inlet port, a blood outlet port and two compartments: a blood compartment and a plasma compartment separated by a semi-permeable membrane that allows plasma to pass, but not red blood cells. Blood flows through the blood compartment and transmembrane pressure is applied between the blood and the plasma compartments causing the plasma inside the plasma compartment to be replaced by fresh plasma that is flowing through the blood compartment. Any color change of the plasma in the plasma compartment can be detected.

BACKGROUND OF THE INVENTION 
Handling of the blood outside the body, referred to as extracorporeal, is 
frequently used in medical procedures in treatments such as 
blood-oxygenation, plasmapheresis, leukopheresis, hemopheresis, 
extracorporeal chemotherapy, hyperthermia, hypothermia, bone marrow 
transfusions, blood transfusions processing by heart lung machines during 
surgery and dialysis for patients with kidney failure. In such procedures 
there is always a risk that homolysis, or the breaking of red blood cells, 
may occur. 
As is known to those practicing the art, the breaking of blood cells is 
deleterious not only from the loss of the function of those cells, but 
also by the release into the blood plasma of hemoglobin which is toxic. 
Heretofore, in hemodialysis, hemoperfusion, blood transfusion and other 
extracorporeal blood therapies, whether hemolysis occurred was determined 
by taking blood samples and subjecting them to analysis. This is typically 
done by taking the sample to a laboratory to separate red blood cells from 
plasma and looking for the artifacts of hemolysis, such as hemoglobin, in 
the plasma. 
This approach is not usually satisfactory because of the damage that can be 
done to a patients blood while the test is being performed. It is also 
possible that hemolysis may occur to a significant degree between the time 
in which the tests are performed. 
Currently there is no system available for on-line hemolysis detection. It 
is, therefore, impossible to have continuous, on-line detection of 
hemolysis in a red blood containing components such as packed blood cells, 
buffy coat or whole blood in a blood line. Hemolyzed blood is dangerous to 
the patient due not only loss of blood cells, but more importantly the 
toxic effects of free hemoglobin. 
Detection of hemolysis in plasma is further complicated by the fact that 
the characteristics of plasma, in particular color, vary from individual 
to individual and varies for a single individual over time depending of 
such factors as diet, and other metabolic differences that manifest 
themselves in the blood. 
While the prior art has concerned itself with methods and apparatus for 
separation of blood components, these have not been employed to detect 
hemolysis on a real-time, continuous basis. 
For example, U.S. Pat. No. 3,705,100 to Blatt et al. describes a method and 
apparatus for fractionating blood in order to separate the blood 
components that may be desirable in blood transfusions. Taught is the use 
of centrifugal separation techniques and the use of a filtration membrane 
such as anisotropic and depth filter membranes. This allows the plasma 
component of blood to be used in an emergency while the formed elements of 
the blood such as red blood cells, white blood cells, and platelet are 
returned to the donor so that more frequent bleedings can be taken. 
U.S. Pat. No. 4,191,182 to Popovich, et al. describes a method and 
apparatus for plasmapheresis. Again, the system described employs a 
membrane with the appropriate pore sized to fractionate blood into 
cellular and plasma components. This reference particularly points out 
that flow rates are important to attaining the desired result using the 
specified sheer stresses and pressures on the membrane ultra filter. 
U.S. Pat. No. 4,350,156 to Malchesky, et al. describes a continuous, 
on-line system and apparatus for removing macromolecules from a 
physiological fluid such as blood. Membranes are employed in a blood flow 
path to separate blood plasma, cellular components, and macromolecules 
that are associated with progress of a variety of diseases. Removal of 
these molecules inhibits the progress of certain diseases. 
U.S. Pat. No. 4,374,731 to Brown, et al. describes a method and apparatus 
for performing plasmaphereses while controlling the plasma collection rate 
through a plasmapheresis membrane filter. By regulating the pressure on 
the plasmapheresis membrane filter, the flow of plasma therebetween can be 
controlled. 
The goal of these prior art patents is to separate as much plasma as 
possible from the blood for therapeutic or collection purposes. Therefore, 
these membranes plasmapheresis devices normally have a membrane surface 
area in the range of several thousand square centimeters in a plasma port 
in the plasma compartment through which the plasma can be collected for 
removal or further treatment before it is returned back to the patient. 
It is an object of the present invention to provide an on-line device that 
can continuously detect hemolysis that may be developing in a blood path. 
It is a further object that such device be capable of performing without 
attention or replacement. 
It is another object of the invention to provide a device that does not 
require careful manual calibration, adjustment or interpretation to 
distinguish between variabilities in normal blood plasma among people or 
between an individual's blood at different times. 
Another object of the present invention is to provide a device that is 
simple and sufficiently inexpensive that the portion of the device in 
contact with the patient's blood is disposable so that contamination 
between patients is eliminated. 
SUMMARY OF THE INVENTION 
The above objects are realized by a device comprising a shell having a 
blood inlet port receiving blood, a blood outlet port for returning blood 
to the blood path and two compartments, a blood compartment and a plasma 
compartment separated by a semi-permeable membrane. The semi-permeable 
membrane allows plasma to pass, but not red blood cells. The blood inlet 
and outlet ports located in the blood compartment allows a passage of at 
least a representative of portion of the blood flowing through the main 
blood path to go through the blood compartment of the shell. An elastic 
air sac is contiguous with plasma compartment in order to periodically 
apply a transmembrane pressure. The plasma compartment has an optical 
window formed along a portion of the shell through which the plasma 
optical characteristics can be evaluated by the transmission or 
reflection. The semi-permeable membrane allows plasma to permeate, but not 
red blood cells. In application, blood flows through the blood compartment 
and transmembrane pressure is generated between the blood and the plasma 
compartments by periodically squeezing and releasing the elastic air sac. 
Because of the alternating change in high and low pressure sides between 
the blood and plasma compartments the plasma inside the plasma compartment 
is always replaced by fresh plasma that is flowing as part of the blood 
through the blood compartment. After an initial optical measurement is 
made, for instance using a light source and photo detector with the 
appropriate filters, any color change in the plasma can be detected and 
presented either as a numerical value or by tripping an alarm at a 
predetermined set point.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT 
Referring now to FIG. 1 shown is an outer shell 10 of the blood-containing 
device which is preferably made from one or more clear polymers. 
Acceptable polymers are those such as acrylic, polystyrene or 
polyvinylchloride. The main criteria for such a housing is that it be 
fairly rigid, inert when exposed to blood and be substantially 
transmissive of light at least one frequency. 
This shell 10 is divided into a blood compartment 12 having an inlet port 
14 and outlet port 16. The inlet port 14 receives a flow of blood from an 
extracorporeal blood path or blood path so that the blood flows into the 
blood compartment 12 then exits the compartment through outlet port 16 to 
rejoin the blood flowing through the blood path or blood path. 
Dividing the blood compartment 12 from a plasma compartment 18 is membrane 
20. The membrane is of the microporous type having a pore size 
distribution and arranged such that it allows only plasma to permeate the 
membrane and remain impenetrable to any cellular elements. The pore 
distribution should typically be within 0.1 to 2.0 microns. An example of 
a membrane having acceptable perimeters and characteristics is Thermopore 
800, manufactured by Gelman Sciences of Ann Arbor, Mich. 
Because cellular components of the blood cannot penetrate membrane 20, only 
the plasma component of the blood including that of lysed cells will be 
found in plasma compartment 18. Included in the plasma component of the 
blood are the remnants of red blood cells that have been lysed or 
undergone hemolysis. Included in these remnants of red blood cells is 
hemoglobin which gives blood its characteristic red color from oxygenated 
iron. 
Contiguous with plasma compartment 18 is air sac 22 which is connected to 
the plasma compartment 18 by air sac neck 24. The elastic air sac 22 is 
preferably made of elastic material such as silicone rubber, polyurethane, 
PVC or other elastomers. 
The purpose of the elastic air sac is to allow a differential pressure to 
be applied to contents of plasma compartment 18 exerting differential 
pressure across membrane 20. The reason for applying this pressure 
difference will be explained below. 
Also contiguous with plasma compartment 18 is light path chamber 26. 
Referring now to FIG. 2, the device of FIG. 1 is shown in a top plan view 
along with associated apparatus. Continuing the description of the light 
path chamber 26, it is shown with the associated light source 28 and optic 
sensor 30. As can be readily determined from the figure, light for instance 
in the green region with a wavelength of 500 to 700 nm, from light source 
28 passes through a quantity of plasma contained in light path chamber 26 
where upon a certain amount of light is absorbed before detection by optic 
sensor 30. 
Also shown is elastic air sac 22 as described in the previous figure along 
with means for compressing and relaxing the elastic sac. Plunger 32 
applies force on the elastic air sac 22 against a fixed member 34. This is 
done by applying power to plunger 32 to compress air sac 22 then 
terminating the power to the plunger to relax the force on the elastic air 
sac. 
Referring now to FIG. 3, the device of FIG. 1 with outer shell 10 in FIG. 2 
is shown in a cross-section through line 3--3. 
In addition to blood compartment 12, plasma compartment 18 and light path 
chamber 26, also shown are membrane support ribs 36. These support ribs 
hold membrane 20 in place between the blood compartment and plasma 
compartment and support the membrane, preventing it from shifting as the 
transmembrane pressure fluctuates such that the membrane does not 
excessively bow and tear. 
In application, the device 10 is connected to any portion of a blood path 
or blood path. The elastic air sac 22 is compressed by the plunger 32 or 
by other means to expel air in the plasma compartment into the blood 
compartment. After the blood path is primed with priming solution, such as 
normal saline or Ringer solution, the pressure on the elastic air sac is 
relaxed creating negative pressure inside the plasma compartment and 
drawing the priming liquid across the membrane into the plasma 
compartment. 
As patient treatment commences and blood replaces the priming solution, the 
elastic air sac is compressed by plunger 32 and periodically released. This 
compression/relaxing action for example, every 2 minutes, periodically 
replaces the liquid inside the plasma compartment with new plasma from the 
blood compartment. 
Light transmittance in the green region at 500-700 nm, (or alternately 
reflectance) through the light path chamber 26 is measured by the optic 
sensor such as photocell 30. 
An initial reading is taken to determine the nonhemolyzed transmission of 
the patient's blood plasma. During patient treatment if any hemolysis 
develops, hemoglobin in the plasma appears in the plasma compartment and 
changes the light transmission or reflectance through the light path 
chamber 26. 
Hemolysis can be detected in the line immediately and the appropriate 
action taken to protect the patient. 
As alternate embodiments, the elastic air sac could be replaced by a 
disposable syringe and plunger activator. Other possible embodiments 
employ the use of flexible polycarbonate, acrylic, PVC, or TPX as the 
material for making the shell 10. In such a design transmembrane pressure 
is generated by squeezing the shell 10, itself rather than utilizing a 
separate elastic air sac. 
An apparatus incorporating the present invention was constructed and tested 
as follows: 
The outer shell was made of transparent acrylic housing and Thermopore 800 
by Gelman Sciences was used as the membrane separating the blood 
compartment from the plasma compartment. 
For this particular test device, a small PVC tubing with a slide clamp was 
attached to the plasma compartment side of the outer shell and contiguous 
with that compartment. This was done in order to be able to expel the air 
inside the plasma compartment during initial priming. 
After the device was primed with normal saline, bovine blood was pumped 
through the blood compartment. While pumping the blood through the device, 
distilled water was injected into the incoming blood line to burst blood 
cells. After about three minutes, red color plasma appeared in the plasma 
compartment, indicative of hemolysis. When the test was repeated and the 
device was squeezed between two fingers to generate transmembrane pressure 
between the blood and plasma compartments, a reddish color appeared in the 
plasma compartment almost immediately. 
A similarly successful device was made incorporating a hydrophobic membrane 
in place of the PVC tubing for venting air from the plasma compartment. 
This alternate embodiment also contained a perforated membrane support 
used to support and protect the membrane and incorporated on the blood 
compartment side of the membrane. 
An alternate embodiment of the present invention is constructed using 
hollow fiber, microporous membranes instead of a flat sheet membrane. 
Referring to FIG. 4, a hemolysis detector constructed according to this 
embodiment is shown in cross section. As with the other embodiments, there 
is an outer shell 38, having a blood inlet port 40 and a blood outlet port 
42, a blood compartment 44 and a plasma compartment 46. In contrast to the 
flat membrane of the previous embodiment, however, here are used a 
plurality of hollow fiber, microporous membranes 48 identical to those 
used in blood cell/plasma separation and known to those practicing in the 
art. The hollow fibers number approximately 20 to 30 and serve to separate 
the blood compartment, bounded by the outer surface of the hollow fibers, 
from the plasma compartment, bounded by the inner surface of the hollow 
fibers. In addition to the boundary formed by the hollow fibers, there is 
an additional barrier between the compartments and its support means for 
the fibers, such as potting compound, 49. 
The remainder of the device is identical in function and similar in 
construction to the first embodiment, having an elastic air sac 50 and 
plunger 52 to apply force on the air sac 50 against fixed member 54. 
In this embodiment, the air sac neck and light path chamber, are combined 
in a single element 56. The transmembrane pressure supplied by the 
squeezing of the elastic air sac, transverses the path 56 longitudinally 
while the light generated by light source 58 traverses the pathway 56 
before being received by the optical sensor 60. 
Although the construction of this embodiment is similar and the operation 
is identical, the embodiment using hollow fiber microporous membranes has 
the advantage of a larger membrane area in a similarly-sized device. This 
results in a device which is more efficient in the exchange of plasma 
across the membrane than an equal-sized device using a flat sheet.