The scientists and clinicians from
four countries brought together in this project have devised a prototype
instrument for continuous and rapid monitoring of the blood chemistry
of patients in intensive care.
The instrument employs a microdialysis 'mini-shunt' to extract molecules
of interest from the bloodstream, a miniaturised flow system to handle
very small volumes of fluid, new biosensors to measure small amounts
of glucose and lactate, and a computer system to process and display
the results in real time.
Although the instrument has been successfully tested on animals, further
development depends on the team finding a suitable industrial partner.
Other applications could be found wherever rapid and continuous chemical
monitoring is required.
Continuous monitoring of patients in intensive
care is now routine. Vital signs such as heart rate, blood pressure,
body temperature and urinary output may all be measured continuously
using physical sensors, with the information immediately available
to doctors. However, it is not yet possible to monitor the blood
chemistry of a patient in a similar way.
That may change if a prototype monitoring system developed under
the EU's Standards, Measurements and Testing Programme comes to
fruition. Scientists and clinicians from Dublin, Berlin, Vienna
and Basel have collaborated on a new method of continuously measuring
the amounts of two important blood chemicals - glucose and lactate.
Two critical chemicals
Glucose, or blood sugar, is the means by which energy from food
is made available within the body. Energy is released when the glucose
combines with oxygen to produce carbon dioxide and water. Where
the supply of oxygen is restricted, however, a chemical called lactate
starts to accumulate in the blood.
A raised level of lactate is regarded as a sign that some part of
the body is being deprived of oxygen, a condition known as tissue
hypoxia. Continuous monitoring of lactate would give early warning
of impending trouble, especially in cases of bacterial infection
and shock, which are major causes of death in intensive care patients.
Likewise, patients suffering from diabetes, who lack the means to
control their blood sugar, would benefit from having their glucose
levels monitored continuously when they are in diabetic coma and
during surgery for other conditions.
Although much research has been carried out in this area, the system
developed under this project is believed to be unique in being able
to simultaneously monitor blood glucose and lactate rapidly and
accurately, using several innovative technologies.
Biosensors and Microdialysis
At the heart of the instrument is a biosensor, a device that detects
the presence of specific molecules by their interaction with an
enzyme placed onto an electrode. As the enzyme breaks down the molecules
a small electric current is produced - the greater the concentration
of molecules, the greater the current.
By an appropriate choice of enzyme, biosensors can be made sensitive
to a variety of molecules including, in this case, glucose or lactate.
The biosensors used in this system were designed jointly by the
research teams at the Max Delbrück Centre for Molecular Medicine
in Berlin and the Technical University of Vienna.
However, human blood is a rich cocktail of many complex molecules,
and the sensors would be contaminated if they were directly exposed
to it. Accordingly, researchers at St Vincent's Hospital in Dublin
employed a technique known as microdialysis to take a sample of
glucose and lactate from the blood.
A catheter, inserted into the patient's central vein, often already
in place for other purposes in intensive-care patients, diverts
a small flow of blood around a circuit and back to the body. In
one section of the circuit the blood flows through a 'mini-shunt'.
This consists of an outer tube, in which the blood flows, surrounding
a thin hollow fibre containing a fluid flowing in the opposite direction.
The fibre is porous to small molecules such as glucose and lactate
but holds back large molecules such as proteins. As the blood flows
over the fibre, glucose and lactate molecules pass through into
the collecting fluid inside.
Rates of fluid flow through the fibre, however, are extremely slow,
about 3 microlitres per minute. The instrumentation required to
handle this fluid must be correspondingly small if the system is
to produce measurements quickly.
The answer, devised at the CIBA laboratories in Basel, was to use
a 'microflow stack' of 22-mm square silicon wafers, looking somewhat
like a squat office block. The sample fluid comes in at the top
of the stack and then trickles down through holes and channels etched
into the wafers until it reaches the biosensors in the 'basement'.
It then passes back up through the stack and is finally collected
for disposal. The stack allows calibration solutions to be directed
to the sensors and also permits other chemicals to be mixed with
the sample fluid where required.
The sensors themselves, and the fluid cell containing them, are
formed directly on to a printed circuit board by thin-film technology.
Channels in the board conduct the fluid from the base of the stack
to the cell. In future versions of the instrument the sample fluid
could then be passed to a number of other sensors for further measurements
to be made. The combined flow volume of the stack and cell is only
The entire system is controlled by a laptop computer running software
designed at Dublin City University. The package has two main components:
a microdialysis control program which controls the rates of flow,
valve settings, system calibration, data acquisition and processing;
and a viewing program for inspecting and displaying data. Graphical
and numerical displays are presented to the user in a Windows-based
virtual instrument panel.
Although the prototype has not yet been tried out on human patients,
tests on anaesthetised dogs have been promising. Continuous measurements
of glucose and lactate compared well with those made by intermittent
blood sampling and measurement using conventional instruments. The
system is sensitive to normal blood levels of the chemicals as well
as the raised levels found during illness. Because of the low volume
of fluid in the system, changes of glucose and lactate in the body
can be detected and displayed within five minutes of their occurrence.
However, there are a number of problems to be solved before the
prototype can be transformed into a marketable instrument. Some
of these are technical, such as further miniaturisation, long-term
stability, and the prevention of blood clotting in the mini-shunt.
But the greatest problem, now that the research project has been
completed, is the need for further funding. Medical devices have
to meet strict European safety standards and the development work
to ensure safety and quality assurance can be very expensive. The
participants hope to find an industrial partner willing to provide
the necessary backing to see the project through to completion.
Further applications are possible wherever rapid and continuous
chemical monitoring is required, such as in the biotechnology industry,
industrial process control and environmental monitoring.