CA1163516A - System for demand based administration of insulin - Google Patents
System for demand based administration of insulinInfo
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- CA1163516A CA1163516A CA000367629A CA367629A CA1163516A CA 1163516 A CA1163516 A CA 1163516A CA 000367629 A CA000367629 A CA 000367629A CA 367629 A CA367629 A CA 367629A CA 1163516 A CA1163516 A CA 1163516A
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- insulin
- accordance
- body fluid
- patient
- osmolality
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Abstract
ABSTRACT
A system is disclosed for demand-based administration of insulin which utilizes a change in a physical property of a patient's body fluid as an indicator that a change in the body fluid glucose level has occurred and that an appropriate amount of insulin should be supplied to the patient. Body fluid osmolality or one of its colligative properties are particularly suitable for this purpose. A second sensor for measuring such properties as electrical conductivity may be added to detect changes in osmolality caused by such factors as dehydration.
Insulin can be delivered to the patient from an extracorporeal source by means of a dual lumen catheter. One lumen of the catheter provides a passageway for the insulin dose and the other lumen provides a passageway through which a replaceable sensors can be introduced into or removed from the patient's body. In the alternative, the entire insulin administration system can be implanted into the patient.
A system is disclosed for demand-based administration of insulin which utilizes a change in a physical property of a patient's body fluid as an indicator that a change in the body fluid glucose level has occurred and that an appropriate amount of insulin should be supplied to the patient. Body fluid osmolality or one of its colligative properties are particularly suitable for this purpose. A second sensor for measuring such properties as electrical conductivity may be added to detect changes in osmolality caused by such factors as dehydration.
Insulin can be delivered to the patient from an extracorporeal source by means of a dual lumen catheter. One lumen of the catheter provides a passageway for the insulin dose and the other lumen provides a passageway through which a replaceable sensors can be introduced into or removed from the patient's body. In the alternative, the entire insulin administration system can be implanted into the patient.
Description
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SYST~ FOR D~AND-BASED ADMINISTRATI~ ~F INSULIN
DESCRIPTION
Technical Field This invention relates to means for ascer-taining insulin demand of a patient based uponmeasurable changes of a body fluid physical property and to means for controlled administration vf insulin.
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Background of Invention Diabetes mellitus is a disease characteri~ed by hyperglycemia, polyuria, and wasting. Hypergly-cemia is due to decreased utilization of glucose andalso increased production of glucose.
The discovery of insulin in 1922 has made it possible to control the blood glucose level in !~ diabetic patients, at least partially. This enhanced the well ~eing and survival of diabetic patients;
however, recent studies indicate that long term complications of diabetes such as blindness, heart failure, kidney failure, neuropathy and vascular disease are not completely obviated by insulin therapy. It has been suggested that the foreyoing long term complications are due to one or more o~ the followi~g reasons~ the control of glucose levels by periodic injection of insulin is imperfect and better glucose control is important, (2) the control of metabolic substances other than glucose is important and necessary for the management of the diabetic patient, and (3) the levels of hormones other than insulin also should be adjustedl i.e., the glucagon concentration should be reduced.
To improve the control vf glucose levels, several methods have been suggested. Among such ,}.
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j 3 5 ~ ~3 ~ 2--methods are the "close controll' method whereby a patient is hospitalized with attendant frequent assays of blood sugars and frequent insulin injections (e.g., before each meal). To effect control, the individual or the clinical laboratory has to perform frequent blood sugar analyses on a regular basis.
A further extension of the aforementioned treatment by "close control" is the use of a contin-uous or constant rate infusion of insulin usin~ aninsulin dispenser for infusion of this hormone into the patient. With such a machine, the rate of insulin administration must be predetermined by a physician, and further requires the maintenance of a steady diet and a continued uniform sensitivity of the patient to insulin.
It has been proposed to use a sensor respon-sive to the patient's glucose level'for regulating the rate of insulin adminstration by the aforementioned insulin dispenser. However, all glucose sensors proposed to date have been unstable in vivo when used for time periods in excess of several weeks and thus are not very practical. A
variety of problems have been encountered with such sensors: (1) Sensors that rely on the oxidation of glucose (with glucose oxidase) exhibit stability problems due to the inherent instability or inactivation of such enzymes, (2) sensors relying on the direct oxidation of glucose (by means of electrodes) encounter undesirable polarization phenomena on the electrode surfaces, (3~ the in vivo period of reliability of heretofore known implanted glucose sensors is shortened by fibrous or fibrinous encasement, This is so because all heretofore known glucose sensors are rate dependent. That is, ~ ~;3~6 the glucose concentration in a patient's blood is indicated by the reaction rate of qlucose at the sensor. Glucose in the blood must diffuse to the electrode or to the enzyme present in the sensor.
For reliable sensor signal output, a constant mass transfer resistance of glucose to the sensing element must be maintained. Progressive fibrous or fibrinous encasement of the sensing element continuously alters such resistance and requires frequent recali~ration of the sensor~
Accordingly, there exists a pressing need for a reliable means for administering insulin to a diabetic patient utilizing a stable implantable sensor.
SummarY of the Invention It has now been discovered that the glucose level and insulin need of a patient can be reliably ascertained by measuring at substantially equilibrium conditions certain changes that have occurred in a physical property, i.e., a property not involving in its manifQstation a chemical change, of a body fluid of the patient. The requisite amount of insulin for diabetes management dispensed in response to a signal generated by such measurement. Determination of body fluid osmolality i5 particularly suitable for this purpose. Typical body fluids whose physical proper-ties can be monitored for this purpose are blood, peritoneal fluid, subcutaneous fluid, or the like.
According to the present invention, a system foe administration of insulin responsive to a ;~ patient's insulin requirement includes an insulin dispenser adapted for infusion of insulin into the ; patient, a transducer means responsive to a physical property of a body fluid of the patient and generat ing a signal having a magnitude which is a function " 5 ~35~
of the aforementioned physical property of the body fluid, and preferably a function of or proportional to osmolality of the body fluid; and a dispenser control mean~ operably associated with the transducer means and with the insulin dispenser to receive the signal and to dispense insulin in response to the magnitude of the received signal. The insulin dispenser can be adapted for implantation, for ion-tophoresis, or for subcutaneous or transcutaneous infusion, as desired. Where the insulin dispenser is externa~ to the patient's body, insulin delivery to the patient is effected via a cannula or by percuta-neous catherization using a catheter made of a bio-compatible material. Preferably the catheter also is provided with a barrier against infection.
In some cases it may be desirable to be able to measure the concentration of other blood constit-uents such as sodium or potassium levels. The concentration of such electrolytes can be determined by implanting a secondary transducer which can be designed to measure the conductivity or ion concen-tration of the blood fluid.
A preferred transducer means for the purpose of the present invention is an implantable blood or tissue fluid osmolality sensor or detector, e.g., an implantable osmometer that generates an electrical, mechanical or telemetry signal which, in turn, controls the operation of t'ne in~ulin dispenser.
Another embodiment would have a primary transducer sensing osmolality and one or more secondary trans-ducers sensing electrolytic conductivity or ion ; concentration. A preferred insulin dispenser is a portable unit that can be worn by the patient or implanted in the patient, and includes an insulin reservoir, a pump means, and a switch means respon-sive to the signal or signals from one or more . ~ i 6 sensors or detectors and controlling the delivery of insulin.
In another preferred embodiment, an implanted sensor is used in conjunction with a dual channel catheter and has a shape enabling the sensor or sensors to be either (a) removed and replaced or (b) removed, cleaned of fibrinous or other material, and replaced through a channel in the catheter other than the channel carrying insulin to the patient.
Insulin from the reservoir can be delivered to the patient intraperitoneally, intravenously, or - subcutaneously, or by any other convenient means as desired.
Brief DescriPtion of the Drawinqs In the drawings, FIGURE 1 is graphical correlation of blood glucose level and blood osmolality in normal and dia~etic mammals;
: FIGURE 2 is a graphical representation of the effect of endogenous insulin on various mammalian blood parameters;
FIGURE 2A is a graphical comparison of measured and calculated osmolality derived from the data shown in FIGURE 2.
;~ 25 FIGURE 3 is a gxaphical representation of the correlation of osmolality to glucose, Na, and K, ~ in a typical normal mammal;
. FIGURE 4 is a block diagram showing a system : for controlled administration of insulin that embodies the present invention;
~ FIGURE 5 is a schematic representationl partly in section, of a vapor pressure osmometer;
; FIGURE 6 indicates the thermocouple tempera-ture curve ~or the osmometer shown in FIGURE 5;
FIGURE 7 is a schematic representation of an implantable oncotic pressure osmometer;
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FIGURE 8 is a schematic representation, partly in section, of a freezing point os~ometer;
FIGURE 9 is a schematic representation, partly in section, of a boiling point osmometer;
FIGURE 10 is a schematic YieW of one embod-iment of the present insulin infusion system includ-ing a supply reservoir, a micropump controlled by a microprocessor, and a dual channel catheter assembly for delivering insulin to the patient and providin~
signals to the microprocessor representing glucose levels in the patient;
FIGURE 11 is an enlar~ed cross-section of the catheter shown in FIGURE 10;
FIGURE 12 is an enlarged view of an exem-plary replaceable sensor partly broken away to show interior detail;
FIGU~E 13 is an enlarged, exploded fragmen-tary section of the proximal end of sensor tube of the catheter and the replaceable cap therefori FIGURE 14 is a cross-section taken generally along plane 14-14 of FIGURE 11 showing the catheter sensor channel and insulin channel;
FIGURE 15 is similar to FIGURE 11, and is : shown here to include a secondary sensor;
FIGURE 16 shows the addition of a semiper-meable membrane to encase the sensors;
FIGURE 17 is an enlarged view of a conduc-tivity sensor partly broken away to show interior detail;
FIGURE 18 is an enlarged view of a ion concentration sensor partly broken away to show interior detail; and FIGURE 19 is a block diagram showing a : system for controlled administration of insulin using two sensors in the body.
~ . , ~3!i ~ ( Descrip~ion of Preferred_Embodiments While the major effect of insulin in the mammalian body is the lowering of the blood sugar concentrationl ;nsulin can affect t'ne concentration of a number of other body substances including potassium, phosphates, hydrogen, ketone bodies such as ~-hydroxybutyrate and aceto acetate, fatty acid levels, sodium, and glycerol. In the diabetic state, the presence of many unidentified compounds is also noted, which compounds are not normal constituents of the body but which are believed to be metabolized by the body after insulin infusion. In the brain such ~idiogenic osmols" can accumulate to levels of up to 40 milliosmols; and can cause cerebral edema or coma during treatment of diabetic ketoacidosis.
Osmolality is defined as the sum of the concentration of all solutes in a solution. Its ~ units are "osmoles" or total moles of solute per ! kilogram of solvent. In the blood, the concentration of all chemical body substances is reflected by blood osmolality whether such substances can be chemically identified or not. It has been found that in the diabetic state, the effects of insulin infusion are reflected by a measurable change in blood osmolality and in osmolality of other body fluids. Moreover, it has been found that the detectable change in blood osmolality following exogenous and/or endogenous introduction of insulin has a greater abs~lute value than would be expected from the change in ~he blood glucose concentration. Changes in other substances such as fatty acids, glycerol, or "idiogenic osmols"
are dissernible by measurement of osmolality, even i, such substances are not measured directly. Since the level of such substances is affected by the insulin level, variations in body insulin demand can be `
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readily detected and accommodated so as to maintain blood os~olality within a desired range.
There may be some cases where it may be desirable to measure more than just the osmolality level. An increase in osmolality can someti~es be caused by severe physical exertion, dehydration or ingesting large amounts of certain electrolytes, e.g.
table salt. While osmolality shows a good correlation with glucose levels, this correlation can sometimes be affected by these causes. Since a severely reduced level of water intake results in diminished water supply in both the intercellular and extracellular fluids, there is a resultant increase in the concentration of all metabolic substances. Such an increase can be detected by an increase in conduc-tivity or ion concentration since the majority of extracellular osmoles are electrolytes. As the osmolality increases due to dehydration or ingestion of salt, the concentration of electrolytes increases raising the electrolytic conductivity and ion concentration. No large increase in electrolytic conductivity or ion concentration is caused by an increase in glucose or other substances controlled by insulin. By measuring the increase in conductivity or ion concentration in conjunction with the osmolality, e.g., ~y two separate sensing means, it is possible to ~Iscreen out" increases in osmolality not caused by increases in glucose and thus avoid an injection of insulin when it may be inappropriate. The outputs from the separate sensors may be subtracted from one another or otherwise processed, for example by using a microprocessor device so as to arrive at a control signal for dispensing insulin to the patient.
FIGURE 1 graphically illustrates the relationship between blood glucose concentration and S t ~
g blood osmolality in normal and in diabetic animals during loss of diabetic control over a time period of one day. Dogs were the experimental animals, and alloxan was used to induce diabetes. Intravenous glucose infusion was used to increase blood glucose levels. Insulin was omitted in the diabetic animal for 24 hours so as to induce loss of diabetic control.
The data points were collected over a one day period and marked changes in osmolality occurred after the infusion of glucose. The slope of the early part of blood osmolality increase is relatively steep and thus provides a sensitive indication that an insulin infusion is needed.
In FIGURE 1, it is seen that in a normal animal osmolality shows a weak relationship to blood glucose during the intravenous glucose infusion.
Other solutes must be appearing or disappearing, to cause osmolar changes in the blood as opposed to glucose. In a diabetic animal, on the other hand, osmolality levels were already high, before glucose addition, and increased further in proportion to glucose levels between 200 and 400 mg~. The slope of increase is approximately 20 mOsm/kg per 200 mg%
change in glucose concentration, approximately twice that predicted by the molecular weight of glucose alone. Accordingly, there are other solutes in the serum that contribute to this increase.
~ he time course of these osmolality ch ang es is depicted in FIGURES 2 and 2A where various blood chemistries are depicted for one of the n~rmal dogs.
Samples were collected and insulin levels determined as set forth in the Example hereinbelow. Appropriate response of insulin to a glucose load is exhibited.
It is seen that sodium, potassium, blood urea nitro-gen (BUN) and protein change little during a ~ ~3~
glucose load, but that osmolality shifts dramatically,first increasing, then decreasing. The swings in osmolali~y are believed to be due to changes in "unmeasured" or `'idiogenic" osmoles; these osmoles are indicated by the "osmol gap" calculated by subtracting out the effects of urea, Na, anionsl and glucose from total osmolality. The osmolality changes are due to glucose and to other molecules, as yet unidentified.
A decrease in osmolality to a level below normal is due in part to these unidentified molecules. In a normal animal, after a glucose level increase, the pancreas functions to return osmolality to normal.
A sensor directly or indirectly responsive to osmolality changes in the body at a substantially equilibrium condition can be utilized to control the infusion of insulin and to minimize the adverse effects of diabetes. Such a sensor is sensitive to the degree of elevation of a number of important molecules besides glucose and a signal generated by the sensor controls insulin infusion, with resultant hypo-osmolality of the body stopping further dispens-ing of insulin. For implantation in a patient the sensor means should be compact and of relatively light weight, and preferably of a shape enabling removal through a catheter or cannula. As shown in FIGURES 1 and 3, osmolality is correlated with glucose, there-fore control of osmolality also controls glucose.
FIGURE 4 schematically illustrates a closed loop system for an effective diabetes control utiliz-ing blood, osmolality for example, as tlle indicator ofinsulin demand. Osmolality of other body fluids is also suitable for this purpose. Transducer ll, such as an os~olality sensor, is introduced or implanted into pati~nt 10 in any convenient manner, e.g., within i35 ~6 patient's vascular space, subcutaneously, or intraperitoneally, so as to be in contact with a body fluid such as blood, ~ubcutaneous fluid, peritoneal fluid, or the like. This transducer means can also be applied to body surfaces, e.g., mucosal membranes, so as to be in contact with extracellular fluid, if desired. In any case, the magnitude of the signal generated by the transducer is a function of the osmolality of the body fluid in contact therewith and is utilized to control insulin infusion from reservoir 13 via a catheter, cannula, or similar means utilizing a control unit that receives the transducer signal by electrical or mechanical means, by telemetry, or in any other convenient manner as will be discussed in detail hereinbelow. Thus, a reliable indication of the patient's insulin demand is obtained and the demand can be satisfied by infusion of the desired amount of insulin with attendant control of a variety of metabolic sustances including glucose.
Osmolality alone or in conjunction with electrolytic conductivity or ion concentration may be measured in a variety of body fluids. There is rapid equilibrium between the intracell~lar, vascular, and interstitial components with respect to osmolality, electrolytic conductivity and ion concentration. The interstitial components are those fluids which are outside of cells and outside of the vasculature, and include peritoneal, subcutaneous, salivary, spinal fluids, and the like. A sensor for osmolality as well ; 30 as for conductivity and ion concentration can be placed in contact with any of these.
The measurement of osmolality may be per-formed in several ways. There are four "colligative properties" of solutions, which change in proportion ; 35 to osmolality: 1) vapor pressure, 2) oncotic 3 ~ 6 pressure, 3) freezing point, and 4) boiling point. In each instance, the property measured is a function of the water concentration of the sample; water concentratio~ decreases as solute concentration increases. Accordingly, preferably transducer 11 utiliæes one or more of the aforementioned colliga-tive properties to generate an output signal.
One of the most common methods of measure-ment of osmolality uses vapor pressure, defined as the pressure which water vapor exerts leaving the surface of a fluid. In a closed chamber, this pressure reaches equilibrium with the pressure of vapor in the gas above the fluid, and this pressure is proportional to the concentration of water in the vapor. This concentration of water may be measured conveniently by observation of the "dew point."
A typical instrument for this purpose is the Wescor Vapor Pressure Osmometer. An implantable osmometer 14 utilizing the same principle is schemat-ically depicted in FIGURE 5. In this particularosmometer, a body fluid permeable membrane 15, together with housing 16 define chamber 17. In the top portion of the chamber 17 is a very small thermo-couple 19. When equilibrium of vapor pressure of the body fluid and gas is attained, the thermocouple i3 cooled several degrees by electric current (t~rough the Peltier ef~ect~. The electric current is then stopped, and the temperature of the thermocouple rises to the "dew point" as water condenses on the thermocouple. A typical time-temperature relation-ship during this procedure is shown in FIGURE 6. The "dew point" depression is the difference between ambient temperature and the dew point. As the vapor pressure decreases the dew point depression becomes larger. Lower vapor pressure indicates, o course, a -13~
lower concentration of water in the sample solution, that isy a higher concentration of solute (higher osmolality). Vapor pressure determination of osmolality has been found to be exceedingly sensitive and generally reliable method for measuring liquid osmolality. osmometer 14 can be calibrated against a known standard prior to implantation, and periodic-ally after implantation by drawing an aliquot of the patient's blood and determining the osmolality there-of extracorporeally. Alternatively, a second osmom-eter r similar to osmometer 14 bu~ with a hermetically-sealed chamber containing a known gas-water vapor mixture, can be implanted to serve as a periodic cali~ration means.
Oncotic pressure is another possible method for deteemination of osmolality. Oncotic pressure is defined as the pressure exerted across a semi-permeable membrane because of the presence o~ imper-meable solutes. If a solute cannot pass through a membrane, its concentration is different on both sides of the membrane. There then exists a gradient of water concentration across the membrane. Because such membranes are usually permeable to water, there is a transfer of water across such a membrane. Such transfer will continue until pressure gradients occur to cause an equal transfer of water in the opposite direction.
~ n osmolality sensor utilizing oncotic pressure is shown schematicall;~ in FIGURE 7. A semi-permeable membrane 21~ impermeable to certain solutes~such as glucose), is mounted on a rigid support 23 with a tube 25 leading to a pxessure transducer 27 which can be a piezoelectric gauge or the like.
Semi-permeable membrane 21, made, for example, from polysulfone film, and support 23 are positioned under the patient's skin 31 embedded in subcutaneous tissue 32. ~he tube and support are filled with a solvent for body fluid constituents, such as water for example. Water moves across the membrane due to the concentration differences of solutes in water~ and continues to move until pressure gradients on both sides of the membrane equilibrate. The pressure gradient existing at any given time is measured util-izing a pressure gauge or differential transducer.
Such pressure is proportional to the concentration of non-permeant solutes (such as glucose and/or "unmeasured osmoles") in the body fluid in contact with membrane 21.
FIGURE 8 schematically depicts a freezing point osmometer. Because of a variety of physical interactions of solutes with solvents, the freezing point of a solution decreases as its solute concen-.ration increases. Thus, freezing point depression may be used to indicate osmolality of a solution. A
body fluid sample is received in container 33 that is equipped with cooling coil 35. The sample is "super cooled," then made to freeze during agitation with stirrer 39. The temperature of solidification is determined using a thermocouple 37.
FIGURE 9 depicts yet another possibility for osmotic pressure and thus osmolality measurement, that of boiling point elevation. The device com-prises vessel 41 equipped with heating coil 43 and thermocouple 45. Since increasing solute concentra-tion results in lower solvent concentration, boiling occurs at a higher temperature. The temperature at which a body fluid sample boils is measured with thermocouple 45, the temperature elevation being effected by heating coil 43.
The vapor pressure and oncotic pressure 3 ~ ~ ~
measurements in particular may be made easily and accurately by placing the sensor in various body fluids. One particular advantage is that water is extremely diffusable, and will allow rapid equilib-rium within body fluids, such as the peritoneum. Forbedfast patients the osmometer can be a separate, free-standing unit operably associated with an insulin dispensing device.
For any of these osmolality sensors, the generated signal is ba~ed on an equilibrium condi-tion, i.e./ the signal is not dependent on the rate at which a physical change takes place at the trans-ducer, but rather on the equilibrium condition that is encountered~ The problems encountered by prior art sensors, due to fibrous or fibrinous deposits on the sensor or transducerl are thus obviated or at least minimized and stable, accurate readings are obtained.
An increase in osmolality caused by dehydra-tion or salt ingestion can also be detected by anelectrolyte concentration increase by measuring electrolytic conductivity or ion concentration measurements. In the case of electrolytic conduc-tivity, the measurement can be made by placing within the body biologically inert electrodes, such as platinum, in a fixed geometric relation and measuring the resistance value across the electrodes. Improved measurements can also be made by the application of alternating current at high frequency across the electrodes. 10l000-20,000 Hertz is a useful fre-~uency for this purpose.
Electrolytic conductivity can also be measured by means of electrical induction without the use of contacting electrodes. Such measurements are made by inducing a current in the body fluid by use ; 3 ~ ~ ~
of a coil of wire. The magnitude of the induced current which can be measured by a second coil is proportional to the conductivity of the body fluid.
Instead of or in addition to conductivity, it is also possihle to measure the ion concentration of the fluid.
Ion concentration can be determined by measuring the electromotive force (voltage) between two electrodes placed in the body fluid where one of the electrodes is surrounded by a membrane chosen by one knowledgeable in the art according to the body fluid constituent wished to be measured. Such measuréments could include total electrolytes, particular electrolytes such as potassium or sodium, pH, and disolved gases. In situations where there may be possible temperature variations, the measuring transducers could also include temperature compensators.
The osmolality, electrolytic conductivity and ion concentration sensors generate signals which are transmitted by means of an appropriate lead or leads, a radio signal, or similar expedients, to dispenser control means 12 which, in turn, energizes, or de-energizes, insulin dispenser 13, as indicated for transcutaneous delivery of the requisite dose of insulin. If a separate lead or leads to the sensor are used, the conductor portion of the lead can be coated with an inert, biocompatihle sheath.
Optionally, a fibrous cuff, e.g., 3 Dacron felt or the like, can be provided around the biocompatible sheath so as to form a barrier against infections.
Dispenser control means 12 can be a micro-processor, - a relay network, or any other switching means adapted to respond to the signal emitted by transducer means 11 and capable of energi~ing insulin dispenser 13.
~3 To ~he extent that fibrous or fibrinous deposits on a transducer may hinder the attainment of an equilibrium condition, control means 12 can include a delay means that permits energization of insulin dispenser 13 after a predetermined time period from the point in time when the signal from transducer means 11 is received. In this manner, consistent actuation of dispenser 13 can be assured as long as equilibrium can be attained at transducer means 11 within a predetermined time period. Alternatively, control means 12 can include a timing device that samples and compares signals received at predeter-mined intervals and energizes dispenser 13 only after differences among a plurality of received consecutive lS signals fall within a predetermined range.
Insulin dispenser 13 includes an insulin pool or reservoir and a pump means energizable from any convenient power source, e.g., a primary or secondary battery or gas propellant, in response to an output signal received from dispenser control 12.
Instead of an osmotic pressure measurement r the osmolality of the body fluid can also be deter-mined using any other colligative property of the body fluid. For example, the transducer means can be adapted to measure freezing point depression, vapor pressure, or boiling point evaluation.
Likewise, control of the desired dose deli-very of insulin can be effected based on electrical i~pedance measurements performed on the body fluid by means of implanted inert electrodes, e.g., ~latinum, ; and an alternating current generator. Electrical conductance measurements can also be used to obtain a signal suitable for controlling the infusion of insulin by means of dispenser 13.
In a method aspect of the present invention a body fluid of the patient is contacted with a . :
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transducer means that is responsive to a physical property of the body fluid, e.g., blood, which property is indicative of the patient's insulin deiciency, ~or example, osmolality or one of the colligative properties thereof such as vapor pressure or osmotic pressure. The transducer means i5 of the type that generates an output signal which is a function of the aforementioned physical property.
The magnitude of the output signal generated as a consequence of the transducer mean~ contactin~ tlle body fluid can then be utilized as an indicator of the patient's insulin re~uirement as well as to control the amount of insulin dispensed. Additional measure~ents of other body fluid properties such as electrolyte level, pH or dissolved gases by means of electrolytic conductivity or ion concentration measurements can be made, and the values thereof utilized in conjunction with the obtained osmolality value to provide a control signal t~ dispense the required amount of insulin. A microprocessor is well suited for this purpose.
The present invention is further illustrated by the fol1owing example.
EX~MPLE
Materials and Methods Animals: Five mongrel dogs were used. ~wo were diabetic and three were non-diabetic. All dogs except one had a permanent indwelling catheter, the tip of which was in the cranial vena cava at the level of the second intercostal space. The canula exited from the jugular vein in the middle of the neck and was tunneled under the skin to the withers where it emerged. The free end was taped to a light harness which the dog wore all the time. One dog 17 had a temporary jugular catheter implanted before the IV glucose tolerance test.
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Diabetes Induction: Diabetes was induced in two dogs (No. 17 and No. 22) with alloxan, 65 mg/kg.
Dog No. 17 had been diabetic for 4 years. The other dog, No. 22, had been diabetic for 4 months. Insulin was withheld from tlle diabetic dogs on the day of the tests.
Glucose Tolerance Tests: Intravenous glucose toler-lnce tests were performed twice on each dog with the exception of the dog who had been diabetic for 4 years. Four fasting heparinized blood samples were drawn at 30 minute intervals to estab-lish baseline values. A bolus of 50% glucose (2 ml/kg body weight) was injected via the catheter.
Blood samples were drawn at 15 minute intervals for 90 minutes and then at 30 minute intervals for one hour. Diabetic dogs were not given insulin on the day of the glucose tolerance test.
Blood samples were centrifuged in a refrig-erated centrifuge at 2000G's at 5C. for 15 minutes.
Plasma was removed, ali~uoted for subsequent tests and frozen.
Blood glucose was measured by the glucose oxidase-periodase method, Boehringer Mannheim Corp., Catalog No. 124036. Insulin was measured using the Beckton Dickenson insulin assay kit, Catalog No.
231517. Insulin antibodies were removed from the plasma of diabetic dogs prior to insulin assay according to the method of Nakagawa et al., ~iabetes 22:590-600 (1973). Osmolality was measured using the Wescor vapor pressure osmometer, Model No. 5130.
Sodium and potassium were analyzed by flame photometry~ BUN was analyzed on the Beckman ~UN
Analyzer II. Protein was determined using Folin Phenol reagent by the method of Lowrey et al., J. Biol. Chem. 193:265-275 (1951).
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Data Analysis: The mean and standard error of the mean for each variable were calculated for each time period during the IV glucose tolerance test, for the normal and diabetic dogs. The data were normalized by setting the mean baseline value for each variable to zero in each test and calcu-lating the difference between each observation and its corresponding mean baseline value. One way analysis of variance was performed on each of the normalized variables over time to determine signif-icance. Student-Newman-Reuls tests were performed to make multiple comparisons. A Student's t-t2st was used to compare the postinfusion osmole drop with baseline data. Forwar3 least squares regression analysis was used to estimate the relationship of variables and to develop an equation for osmolality incorporating all measured variables. A stepwise regression analysis was used to pick the best set of variables to predict osmolality. A calculated value for osmolality was obtained using measurements of BUN, sodium and glucose by the formula provided by Edelman, J.S., ~eibman, J., O'Meara, M.P., and Birkenfeld, L.W.: "Interrelationships between serum sodium concentration, serum osmolality and total exchangeable sodium, total exchangeable potassium and total body water." J. Clin. Invest. 37: 1236-1256, `~ 1958:
Osmolality - 1075 NA +0.0556 Glucose +0.357 BUN + 10.1 The use of this value is discussed in further detail below.
Regression analyses of variance and Student-Newman-Keuls tests were performed on the Control Data Corporation's CDC 6500 computer using the Regression and One-way Programs of the Statistical Package for the Social Sciences (SPSS).
~ ~3S ~ ~ ( Results Normal Dogs: Figure 2 shows the variation in several blood parameters of one normal dog (No.
27), during ~n IV glucose tolerance test. During tl-e 1-1/2 hour baseline period the glucose, insulin, sodium, potassium, BUN and protein remained relatively constant. Osmolality varied within a 10 mOsmole range from 290 to 300 mOsmoles/kg, After glucose infusion, blood glucose rose from 118 to 3S2 mg/dl. Insulin rose from a mean baseline value of 4UU/ml to 25g ~U/ml in 15 minutes and returned to the baseline by 45 minutes. Osmolality rose from the mean baseline value of 235 mOsmoles~kg to 310 mOsmoles/kg in 15 minutes. Over the next 30 minutes the osmolality dropped by 25 mOsmoles/kg to 285 mOsmoles/kg.
In the aforementioned normal dog the corre-lation ~Ir~ between osmolality and blood glucose was 0.80 (FIGURE 3). However t changes in blood glucose were not sufficient to explain the osmolality changes as the slope of this curve was greater than 1 mOsmole/ 180mg/L. The sodium remained relatively constant during the entire test and showed no correlation with osmolality, r = 0.00. Potassium changes were inversely proportional t~ both osmotic pressure (r = 0.64) and glucose changes (r = 0.62).
BUN and protein levels remained relatively constant and showed little correlation with osmotic changes (r - 0.25).
The mean values for the IV glucose tolerance tests on all of the dogs are illustrated in FIGURE
SYST~ FOR D~AND-BASED ADMINISTRATI~ ~F INSULIN
DESCRIPTION
Technical Field This invention relates to means for ascer-taining insulin demand of a patient based uponmeasurable changes of a body fluid physical property and to means for controlled administration vf insulin.
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Background of Invention Diabetes mellitus is a disease characteri~ed by hyperglycemia, polyuria, and wasting. Hypergly-cemia is due to decreased utilization of glucose andalso increased production of glucose.
The discovery of insulin in 1922 has made it possible to control the blood glucose level in !~ diabetic patients, at least partially. This enhanced the well ~eing and survival of diabetic patients;
however, recent studies indicate that long term complications of diabetes such as blindness, heart failure, kidney failure, neuropathy and vascular disease are not completely obviated by insulin therapy. It has been suggested that the foreyoing long term complications are due to one or more o~ the followi~g reasons~ the control of glucose levels by periodic injection of insulin is imperfect and better glucose control is important, (2) the control of metabolic substances other than glucose is important and necessary for the management of the diabetic patient, and (3) the levels of hormones other than insulin also should be adjustedl i.e., the glucagon concentration should be reduced.
To improve the control vf glucose levels, several methods have been suggested. Among such ,}.
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j 3 5 ~ ~3 ~ 2--methods are the "close controll' method whereby a patient is hospitalized with attendant frequent assays of blood sugars and frequent insulin injections (e.g., before each meal). To effect control, the individual or the clinical laboratory has to perform frequent blood sugar analyses on a regular basis.
A further extension of the aforementioned treatment by "close control" is the use of a contin-uous or constant rate infusion of insulin usin~ aninsulin dispenser for infusion of this hormone into the patient. With such a machine, the rate of insulin administration must be predetermined by a physician, and further requires the maintenance of a steady diet and a continued uniform sensitivity of the patient to insulin.
It has been proposed to use a sensor respon-sive to the patient's glucose level'for regulating the rate of insulin adminstration by the aforementioned insulin dispenser. However, all glucose sensors proposed to date have been unstable in vivo when used for time periods in excess of several weeks and thus are not very practical. A
variety of problems have been encountered with such sensors: (1) Sensors that rely on the oxidation of glucose (with glucose oxidase) exhibit stability problems due to the inherent instability or inactivation of such enzymes, (2) sensors relying on the direct oxidation of glucose (by means of electrodes) encounter undesirable polarization phenomena on the electrode surfaces, (3~ the in vivo period of reliability of heretofore known implanted glucose sensors is shortened by fibrous or fibrinous encasement, This is so because all heretofore known glucose sensors are rate dependent. That is, ~ ~;3~6 the glucose concentration in a patient's blood is indicated by the reaction rate of qlucose at the sensor. Glucose in the blood must diffuse to the electrode or to the enzyme present in the sensor.
For reliable sensor signal output, a constant mass transfer resistance of glucose to the sensing element must be maintained. Progressive fibrous or fibrinous encasement of the sensing element continuously alters such resistance and requires frequent recali~ration of the sensor~
Accordingly, there exists a pressing need for a reliable means for administering insulin to a diabetic patient utilizing a stable implantable sensor.
SummarY of the Invention It has now been discovered that the glucose level and insulin need of a patient can be reliably ascertained by measuring at substantially equilibrium conditions certain changes that have occurred in a physical property, i.e., a property not involving in its manifQstation a chemical change, of a body fluid of the patient. The requisite amount of insulin for diabetes management dispensed in response to a signal generated by such measurement. Determination of body fluid osmolality i5 particularly suitable for this purpose. Typical body fluids whose physical proper-ties can be monitored for this purpose are blood, peritoneal fluid, subcutaneous fluid, or the like.
According to the present invention, a system foe administration of insulin responsive to a ;~ patient's insulin requirement includes an insulin dispenser adapted for infusion of insulin into the ; patient, a transducer means responsive to a physical property of a body fluid of the patient and generat ing a signal having a magnitude which is a function " 5 ~35~
of the aforementioned physical property of the body fluid, and preferably a function of or proportional to osmolality of the body fluid; and a dispenser control mean~ operably associated with the transducer means and with the insulin dispenser to receive the signal and to dispense insulin in response to the magnitude of the received signal. The insulin dispenser can be adapted for implantation, for ion-tophoresis, or for subcutaneous or transcutaneous infusion, as desired. Where the insulin dispenser is externa~ to the patient's body, insulin delivery to the patient is effected via a cannula or by percuta-neous catherization using a catheter made of a bio-compatible material. Preferably the catheter also is provided with a barrier against infection.
In some cases it may be desirable to be able to measure the concentration of other blood constit-uents such as sodium or potassium levels. The concentration of such electrolytes can be determined by implanting a secondary transducer which can be designed to measure the conductivity or ion concen-tration of the blood fluid.
A preferred transducer means for the purpose of the present invention is an implantable blood or tissue fluid osmolality sensor or detector, e.g., an implantable osmometer that generates an electrical, mechanical or telemetry signal which, in turn, controls the operation of t'ne in~ulin dispenser.
Another embodiment would have a primary transducer sensing osmolality and one or more secondary trans-ducers sensing electrolytic conductivity or ion ; concentration. A preferred insulin dispenser is a portable unit that can be worn by the patient or implanted in the patient, and includes an insulin reservoir, a pump means, and a switch means respon-sive to the signal or signals from one or more . ~ i 6 sensors or detectors and controlling the delivery of insulin.
In another preferred embodiment, an implanted sensor is used in conjunction with a dual channel catheter and has a shape enabling the sensor or sensors to be either (a) removed and replaced or (b) removed, cleaned of fibrinous or other material, and replaced through a channel in the catheter other than the channel carrying insulin to the patient.
Insulin from the reservoir can be delivered to the patient intraperitoneally, intravenously, or - subcutaneously, or by any other convenient means as desired.
Brief DescriPtion of the Drawinqs In the drawings, FIGURE 1 is graphical correlation of blood glucose level and blood osmolality in normal and dia~etic mammals;
: FIGURE 2 is a graphical representation of the effect of endogenous insulin on various mammalian blood parameters;
FIGURE 2A is a graphical comparison of measured and calculated osmolality derived from the data shown in FIGURE 2.
;~ 25 FIGURE 3 is a gxaphical representation of the correlation of osmolality to glucose, Na, and K, ~ in a typical normal mammal;
. FIGURE 4 is a block diagram showing a system : for controlled administration of insulin that embodies the present invention;
~ FIGURE 5 is a schematic representationl partly in section, of a vapor pressure osmometer;
; FIGURE 6 indicates the thermocouple tempera-ture curve ~or the osmometer shown in FIGURE 5;
FIGURE 7 is a schematic representation of an implantable oncotic pressure osmometer;
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FIGURE 8 is a schematic representation, partly in section, of a freezing point os~ometer;
FIGURE 9 is a schematic representation, partly in section, of a boiling point osmometer;
FIGURE 10 is a schematic YieW of one embod-iment of the present insulin infusion system includ-ing a supply reservoir, a micropump controlled by a microprocessor, and a dual channel catheter assembly for delivering insulin to the patient and providin~
signals to the microprocessor representing glucose levels in the patient;
FIGURE 11 is an enlar~ed cross-section of the catheter shown in FIGURE 10;
FIGURE 12 is an enlarged view of an exem-plary replaceable sensor partly broken away to show interior detail;
FIGU~E 13 is an enlarged, exploded fragmen-tary section of the proximal end of sensor tube of the catheter and the replaceable cap therefori FIGURE 14 is a cross-section taken generally along plane 14-14 of FIGURE 11 showing the catheter sensor channel and insulin channel;
FIGURE 15 is similar to FIGURE 11, and is : shown here to include a secondary sensor;
FIGURE 16 shows the addition of a semiper-meable membrane to encase the sensors;
FIGURE 17 is an enlarged view of a conduc-tivity sensor partly broken away to show interior detail;
FIGURE 18 is an enlarged view of a ion concentration sensor partly broken away to show interior detail; and FIGURE 19 is a block diagram showing a : system for controlled administration of insulin using two sensors in the body.
~ . , ~3!i ~ ( Descrip~ion of Preferred_Embodiments While the major effect of insulin in the mammalian body is the lowering of the blood sugar concentrationl ;nsulin can affect t'ne concentration of a number of other body substances including potassium, phosphates, hydrogen, ketone bodies such as ~-hydroxybutyrate and aceto acetate, fatty acid levels, sodium, and glycerol. In the diabetic state, the presence of many unidentified compounds is also noted, which compounds are not normal constituents of the body but which are believed to be metabolized by the body after insulin infusion. In the brain such ~idiogenic osmols" can accumulate to levels of up to 40 milliosmols; and can cause cerebral edema or coma during treatment of diabetic ketoacidosis.
Osmolality is defined as the sum of the concentration of all solutes in a solution. Its ~ units are "osmoles" or total moles of solute per ! kilogram of solvent. In the blood, the concentration of all chemical body substances is reflected by blood osmolality whether such substances can be chemically identified or not. It has been found that in the diabetic state, the effects of insulin infusion are reflected by a measurable change in blood osmolality and in osmolality of other body fluids. Moreover, it has been found that the detectable change in blood osmolality following exogenous and/or endogenous introduction of insulin has a greater abs~lute value than would be expected from the change in ~he blood glucose concentration. Changes in other substances such as fatty acids, glycerol, or "idiogenic osmols"
are dissernible by measurement of osmolality, even i, such substances are not measured directly. Since the level of such substances is affected by the insulin level, variations in body insulin demand can be `
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readily detected and accommodated so as to maintain blood os~olality within a desired range.
There may be some cases where it may be desirable to measure more than just the osmolality level. An increase in osmolality can someti~es be caused by severe physical exertion, dehydration or ingesting large amounts of certain electrolytes, e.g.
table salt. While osmolality shows a good correlation with glucose levels, this correlation can sometimes be affected by these causes. Since a severely reduced level of water intake results in diminished water supply in both the intercellular and extracellular fluids, there is a resultant increase in the concentration of all metabolic substances. Such an increase can be detected by an increase in conduc-tivity or ion concentration since the majority of extracellular osmoles are electrolytes. As the osmolality increases due to dehydration or ingestion of salt, the concentration of electrolytes increases raising the electrolytic conductivity and ion concentration. No large increase in electrolytic conductivity or ion concentration is caused by an increase in glucose or other substances controlled by insulin. By measuring the increase in conductivity or ion concentration in conjunction with the osmolality, e.g., ~y two separate sensing means, it is possible to ~Iscreen out" increases in osmolality not caused by increases in glucose and thus avoid an injection of insulin when it may be inappropriate. The outputs from the separate sensors may be subtracted from one another or otherwise processed, for example by using a microprocessor device so as to arrive at a control signal for dispensing insulin to the patient.
FIGURE 1 graphically illustrates the relationship between blood glucose concentration and S t ~
g blood osmolality in normal and in diabetic animals during loss of diabetic control over a time period of one day. Dogs were the experimental animals, and alloxan was used to induce diabetes. Intravenous glucose infusion was used to increase blood glucose levels. Insulin was omitted in the diabetic animal for 24 hours so as to induce loss of diabetic control.
The data points were collected over a one day period and marked changes in osmolality occurred after the infusion of glucose. The slope of the early part of blood osmolality increase is relatively steep and thus provides a sensitive indication that an insulin infusion is needed.
In FIGURE 1, it is seen that in a normal animal osmolality shows a weak relationship to blood glucose during the intravenous glucose infusion.
Other solutes must be appearing or disappearing, to cause osmolar changes in the blood as opposed to glucose. In a diabetic animal, on the other hand, osmolality levels were already high, before glucose addition, and increased further in proportion to glucose levels between 200 and 400 mg~. The slope of increase is approximately 20 mOsm/kg per 200 mg%
change in glucose concentration, approximately twice that predicted by the molecular weight of glucose alone. Accordingly, there are other solutes in the serum that contribute to this increase.
~ he time course of these osmolality ch ang es is depicted in FIGURES 2 and 2A where various blood chemistries are depicted for one of the n~rmal dogs.
Samples were collected and insulin levels determined as set forth in the Example hereinbelow. Appropriate response of insulin to a glucose load is exhibited.
It is seen that sodium, potassium, blood urea nitro-gen (BUN) and protein change little during a ~ ~3~
glucose load, but that osmolality shifts dramatically,first increasing, then decreasing. The swings in osmolali~y are believed to be due to changes in "unmeasured" or `'idiogenic" osmoles; these osmoles are indicated by the "osmol gap" calculated by subtracting out the effects of urea, Na, anionsl and glucose from total osmolality. The osmolality changes are due to glucose and to other molecules, as yet unidentified.
A decrease in osmolality to a level below normal is due in part to these unidentified molecules. In a normal animal, after a glucose level increase, the pancreas functions to return osmolality to normal.
A sensor directly or indirectly responsive to osmolality changes in the body at a substantially equilibrium condition can be utilized to control the infusion of insulin and to minimize the adverse effects of diabetes. Such a sensor is sensitive to the degree of elevation of a number of important molecules besides glucose and a signal generated by the sensor controls insulin infusion, with resultant hypo-osmolality of the body stopping further dispens-ing of insulin. For implantation in a patient the sensor means should be compact and of relatively light weight, and preferably of a shape enabling removal through a catheter or cannula. As shown in FIGURES 1 and 3, osmolality is correlated with glucose, there-fore control of osmolality also controls glucose.
FIGURE 4 schematically illustrates a closed loop system for an effective diabetes control utiliz-ing blood, osmolality for example, as tlle indicator ofinsulin demand. Osmolality of other body fluids is also suitable for this purpose. Transducer ll, such as an os~olality sensor, is introduced or implanted into pati~nt 10 in any convenient manner, e.g., within i35 ~6 patient's vascular space, subcutaneously, or intraperitoneally, so as to be in contact with a body fluid such as blood, ~ubcutaneous fluid, peritoneal fluid, or the like. This transducer means can also be applied to body surfaces, e.g., mucosal membranes, so as to be in contact with extracellular fluid, if desired. In any case, the magnitude of the signal generated by the transducer is a function of the osmolality of the body fluid in contact therewith and is utilized to control insulin infusion from reservoir 13 via a catheter, cannula, or similar means utilizing a control unit that receives the transducer signal by electrical or mechanical means, by telemetry, or in any other convenient manner as will be discussed in detail hereinbelow. Thus, a reliable indication of the patient's insulin demand is obtained and the demand can be satisfied by infusion of the desired amount of insulin with attendant control of a variety of metabolic sustances including glucose.
Osmolality alone or in conjunction with electrolytic conductivity or ion concentration may be measured in a variety of body fluids. There is rapid equilibrium between the intracell~lar, vascular, and interstitial components with respect to osmolality, electrolytic conductivity and ion concentration. The interstitial components are those fluids which are outside of cells and outside of the vasculature, and include peritoneal, subcutaneous, salivary, spinal fluids, and the like. A sensor for osmolality as well ; 30 as for conductivity and ion concentration can be placed in contact with any of these.
The measurement of osmolality may be per-formed in several ways. There are four "colligative properties" of solutions, which change in proportion ; 35 to osmolality: 1) vapor pressure, 2) oncotic 3 ~ 6 pressure, 3) freezing point, and 4) boiling point. In each instance, the property measured is a function of the water concentration of the sample; water concentratio~ decreases as solute concentration increases. Accordingly, preferably transducer 11 utiliæes one or more of the aforementioned colliga-tive properties to generate an output signal.
One of the most common methods of measure-ment of osmolality uses vapor pressure, defined as the pressure which water vapor exerts leaving the surface of a fluid. In a closed chamber, this pressure reaches equilibrium with the pressure of vapor in the gas above the fluid, and this pressure is proportional to the concentration of water in the vapor. This concentration of water may be measured conveniently by observation of the "dew point."
A typical instrument for this purpose is the Wescor Vapor Pressure Osmometer. An implantable osmometer 14 utilizing the same principle is schemat-ically depicted in FIGURE 5. In this particularosmometer, a body fluid permeable membrane 15, together with housing 16 define chamber 17. In the top portion of the chamber 17 is a very small thermo-couple 19. When equilibrium of vapor pressure of the body fluid and gas is attained, the thermocouple i3 cooled several degrees by electric current (t~rough the Peltier ef~ect~. The electric current is then stopped, and the temperature of the thermocouple rises to the "dew point" as water condenses on the thermocouple. A typical time-temperature relation-ship during this procedure is shown in FIGURE 6. The "dew point" depression is the difference between ambient temperature and the dew point. As the vapor pressure decreases the dew point depression becomes larger. Lower vapor pressure indicates, o course, a -13~
lower concentration of water in the sample solution, that isy a higher concentration of solute (higher osmolality). Vapor pressure determination of osmolality has been found to be exceedingly sensitive and generally reliable method for measuring liquid osmolality. osmometer 14 can be calibrated against a known standard prior to implantation, and periodic-ally after implantation by drawing an aliquot of the patient's blood and determining the osmolality there-of extracorporeally. Alternatively, a second osmom-eter r similar to osmometer 14 bu~ with a hermetically-sealed chamber containing a known gas-water vapor mixture, can be implanted to serve as a periodic cali~ration means.
Oncotic pressure is another possible method for deteemination of osmolality. Oncotic pressure is defined as the pressure exerted across a semi-permeable membrane because of the presence o~ imper-meable solutes. If a solute cannot pass through a membrane, its concentration is different on both sides of the membrane. There then exists a gradient of water concentration across the membrane. Because such membranes are usually permeable to water, there is a transfer of water across such a membrane. Such transfer will continue until pressure gradients occur to cause an equal transfer of water in the opposite direction.
~ n osmolality sensor utilizing oncotic pressure is shown schematicall;~ in FIGURE 7. A semi-permeable membrane 21~ impermeable to certain solutes~such as glucose), is mounted on a rigid support 23 with a tube 25 leading to a pxessure transducer 27 which can be a piezoelectric gauge or the like.
Semi-permeable membrane 21, made, for example, from polysulfone film, and support 23 are positioned under the patient's skin 31 embedded in subcutaneous tissue 32. ~he tube and support are filled with a solvent for body fluid constituents, such as water for example. Water moves across the membrane due to the concentration differences of solutes in water~ and continues to move until pressure gradients on both sides of the membrane equilibrate. The pressure gradient existing at any given time is measured util-izing a pressure gauge or differential transducer.
Such pressure is proportional to the concentration of non-permeant solutes (such as glucose and/or "unmeasured osmoles") in the body fluid in contact with membrane 21.
FIGURE 8 schematically depicts a freezing point osmometer. Because of a variety of physical interactions of solutes with solvents, the freezing point of a solution decreases as its solute concen-.ration increases. Thus, freezing point depression may be used to indicate osmolality of a solution. A
body fluid sample is received in container 33 that is equipped with cooling coil 35. The sample is "super cooled," then made to freeze during agitation with stirrer 39. The temperature of solidification is determined using a thermocouple 37.
FIGURE 9 depicts yet another possibility for osmotic pressure and thus osmolality measurement, that of boiling point elevation. The device com-prises vessel 41 equipped with heating coil 43 and thermocouple 45. Since increasing solute concentra-tion results in lower solvent concentration, boiling occurs at a higher temperature. The temperature at which a body fluid sample boils is measured with thermocouple 45, the temperature elevation being effected by heating coil 43.
The vapor pressure and oncotic pressure 3 ~ ~ ~
measurements in particular may be made easily and accurately by placing the sensor in various body fluids. One particular advantage is that water is extremely diffusable, and will allow rapid equilib-rium within body fluids, such as the peritoneum. Forbedfast patients the osmometer can be a separate, free-standing unit operably associated with an insulin dispensing device.
For any of these osmolality sensors, the generated signal is ba~ed on an equilibrium condi-tion, i.e./ the signal is not dependent on the rate at which a physical change takes place at the trans-ducer, but rather on the equilibrium condition that is encountered~ The problems encountered by prior art sensors, due to fibrous or fibrinous deposits on the sensor or transducerl are thus obviated or at least minimized and stable, accurate readings are obtained.
An increase in osmolality caused by dehydra-tion or salt ingestion can also be detected by anelectrolyte concentration increase by measuring electrolytic conductivity or ion concentration measurements. In the case of electrolytic conduc-tivity, the measurement can be made by placing within the body biologically inert electrodes, such as platinum, in a fixed geometric relation and measuring the resistance value across the electrodes. Improved measurements can also be made by the application of alternating current at high frequency across the electrodes. 10l000-20,000 Hertz is a useful fre-~uency for this purpose.
Electrolytic conductivity can also be measured by means of electrical induction without the use of contacting electrodes. Such measurements are made by inducing a current in the body fluid by use ; 3 ~ ~ ~
of a coil of wire. The magnitude of the induced current which can be measured by a second coil is proportional to the conductivity of the body fluid.
Instead of or in addition to conductivity, it is also possihle to measure the ion concentration of the fluid.
Ion concentration can be determined by measuring the electromotive force (voltage) between two electrodes placed in the body fluid where one of the electrodes is surrounded by a membrane chosen by one knowledgeable in the art according to the body fluid constituent wished to be measured. Such measuréments could include total electrolytes, particular electrolytes such as potassium or sodium, pH, and disolved gases. In situations where there may be possible temperature variations, the measuring transducers could also include temperature compensators.
The osmolality, electrolytic conductivity and ion concentration sensors generate signals which are transmitted by means of an appropriate lead or leads, a radio signal, or similar expedients, to dispenser control means 12 which, in turn, energizes, or de-energizes, insulin dispenser 13, as indicated for transcutaneous delivery of the requisite dose of insulin. If a separate lead or leads to the sensor are used, the conductor portion of the lead can be coated with an inert, biocompatihle sheath.
Optionally, a fibrous cuff, e.g., 3 Dacron felt or the like, can be provided around the biocompatible sheath so as to form a barrier against infections.
Dispenser control means 12 can be a micro-processor, - a relay network, or any other switching means adapted to respond to the signal emitted by transducer means 11 and capable of energi~ing insulin dispenser 13.
~3 To ~he extent that fibrous or fibrinous deposits on a transducer may hinder the attainment of an equilibrium condition, control means 12 can include a delay means that permits energization of insulin dispenser 13 after a predetermined time period from the point in time when the signal from transducer means 11 is received. In this manner, consistent actuation of dispenser 13 can be assured as long as equilibrium can be attained at transducer means 11 within a predetermined time period. Alternatively, control means 12 can include a timing device that samples and compares signals received at predeter-mined intervals and energizes dispenser 13 only after differences among a plurality of received consecutive lS signals fall within a predetermined range.
Insulin dispenser 13 includes an insulin pool or reservoir and a pump means energizable from any convenient power source, e.g., a primary or secondary battery or gas propellant, in response to an output signal received from dispenser control 12.
Instead of an osmotic pressure measurement r the osmolality of the body fluid can also be deter-mined using any other colligative property of the body fluid. For example, the transducer means can be adapted to measure freezing point depression, vapor pressure, or boiling point evaluation.
Likewise, control of the desired dose deli-very of insulin can be effected based on electrical i~pedance measurements performed on the body fluid by means of implanted inert electrodes, e.g., ~latinum, ; and an alternating current generator. Electrical conductance measurements can also be used to obtain a signal suitable for controlling the infusion of insulin by means of dispenser 13.
In a method aspect of the present invention a body fluid of the patient is contacted with a . :
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transducer means that is responsive to a physical property of the body fluid, e.g., blood, which property is indicative of the patient's insulin deiciency, ~or example, osmolality or one of the colligative properties thereof such as vapor pressure or osmotic pressure. The transducer means i5 of the type that generates an output signal which is a function of the aforementioned physical property.
The magnitude of the output signal generated as a consequence of the transducer mean~ contactin~ tlle body fluid can then be utilized as an indicator of the patient's insulin re~uirement as well as to control the amount of insulin dispensed. Additional measure~ents of other body fluid properties such as electrolyte level, pH or dissolved gases by means of electrolytic conductivity or ion concentration measurements can be made, and the values thereof utilized in conjunction with the obtained osmolality value to provide a control signal t~ dispense the required amount of insulin. A microprocessor is well suited for this purpose.
The present invention is further illustrated by the fol1owing example.
EX~MPLE
Materials and Methods Animals: Five mongrel dogs were used. ~wo were diabetic and three were non-diabetic. All dogs except one had a permanent indwelling catheter, the tip of which was in the cranial vena cava at the level of the second intercostal space. The canula exited from the jugular vein in the middle of the neck and was tunneled under the skin to the withers where it emerged. The free end was taped to a light harness which the dog wore all the time. One dog 17 had a temporary jugular catheter implanted before the IV glucose tolerance test.
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Diabetes Induction: Diabetes was induced in two dogs (No. 17 and No. 22) with alloxan, 65 mg/kg.
Dog No. 17 had been diabetic for 4 years. The other dog, No. 22, had been diabetic for 4 months. Insulin was withheld from tlle diabetic dogs on the day of the tests.
Glucose Tolerance Tests: Intravenous glucose toler-lnce tests were performed twice on each dog with the exception of the dog who had been diabetic for 4 years. Four fasting heparinized blood samples were drawn at 30 minute intervals to estab-lish baseline values. A bolus of 50% glucose (2 ml/kg body weight) was injected via the catheter.
Blood samples were drawn at 15 minute intervals for 90 minutes and then at 30 minute intervals for one hour. Diabetic dogs were not given insulin on the day of the glucose tolerance test.
Blood samples were centrifuged in a refrig-erated centrifuge at 2000G's at 5C. for 15 minutes.
Plasma was removed, ali~uoted for subsequent tests and frozen.
Blood glucose was measured by the glucose oxidase-periodase method, Boehringer Mannheim Corp., Catalog No. 124036. Insulin was measured using the Beckton Dickenson insulin assay kit, Catalog No.
231517. Insulin antibodies were removed from the plasma of diabetic dogs prior to insulin assay according to the method of Nakagawa et al., ~iabetes 22:590-600 (1973). Osmolality was measured using the Wescor vapor pressure osmometer, Model No. 5130.
Sodium and potassium were analyzed by flame photometry~ BUN was analyzed on the Beckman ~UN
Analyzer II. Protein was determined using Folin Phenol reagent by the method of Lowrey et al., J. Biol. Chem. 193:265-275 (1951).
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Data Analysis: The mean and standard error of the mean for each variable were calculated for each time period during the IV glucose tolerance test, for the normal and diabetic dogs. The data were normalized by setting the mean baseline value for each variable to zero in each test and calcu-lating the difference between each observation and its corresponding mean baseline value. One way analysis of variance was performed on each of the normalized variables over time to determine signif-icance. Student-Newman-Reuls tests were performed to make multiple comparisons. A Student's t-t2st was used to compare the postinfusion osmole drop with baseline data. Forwar3 least squares regression analysis was used to estimate the relationship of variables and to develop an equation for osmolality incorporating all measured variables. A stepwise regression analysis was used to pick the best set of variables to predict osmolality. A calculated value for osmolality was obtained using measurements of BUN, sodium and glucose by the formula provided by Edelman, J.S., ~eibman, J., O'Meara, M.P., and Birkenfeld, L.W.: "Interrelationships between serum sodium concentration, serum osmolality and total exchangeable sodium, total exchangeable potassium and total body water." J. Clin. Invest. 37: 1236-1256, `~ 1958:
Osmolality - 1075 NA +0.0556 Glucose +0.357 BUN + 10.1 The use of this value is discussed in further detail below.
Regression analyses of variance and Student-Newman-Keuls tests were performed on the Control Data Corporation's CDC 6500 computer using the Regression and One-way Programs of the Statistical Package for the Social Sciences (SPSS).
~ ~3S ~ ~ ( Results Normal Dogs: Figure 2 shows the variation in several blood parameters of one normal dog (No.
27), during ~n IV glucose tolerance test. During tl-e 1-1/2 hour baseline period the glucose, insulin, sodium, potassium, BUN and protein remained relatively constant. Osmolality varied within a 10 mOsmole range from 290 to 300 mOsmoles/kg, After glucose infusion, blood glucose rose from 118 to 3S2 mg/dl. Insulin rose from a mean baseline value of 4UU/ml to 25g ~U/ml in 15 minutes and returned to the baseline by 45 minutes. Osmolality rose from the mean baseline value of 235 mOsmoles~kg to 310 mOsmoles/kg in 15 minutes. Over the next 30 minutes the osmolality dropped by 25 mOsmoles/kg to 285 mOsmoles/kg.
In the aforementioned normal dog the corre-lation ~Ir~ between osmolality and blood glucose was 0.80 (FIGURE 3). However t changes in blood glucose were not sufficient to explain the osmolality changes as the slope of this curve was greater than 1 mOsmole/ 180mg/L. The sodium remained relatively constant during the entire test and showed no correlation with osmolality, r = 0.00. Potassium changes were inversely proportional t~ both osmotic pressure (r = 0.64) and glucose changes (r = 0.62).
BUN and protein levels remained relatively constant and showed little correlation with osmotic changes (r - 0.25).
The mean values for the IV glucose tolerance tests on all of the dogs are illustrated in FIGURE
2. During the baseline studies, the ranges in the measured variables for normal dogs were glucose:
105-110 mg/dl; osmolali~y 286-290 mOsmoles/kg;
insulin; 17-32 ~U/ml; sodium: 147-150 mEq/l; X:
,.., .
105-110 mg/dl; osmolali~y 286-290 mOsmoles/kg;
insulin; 17-32 ~U/ml; sodium: 147-150 mEq/l; X:
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4.1-4.4 mEq/l; BUN: 10-12 mg/dl, plasma protein:
5.4-5.9 g/dl. After intraveneous glucose adminis-tration, glucose rose to 230 mg/dl. This represents a 12.7 mOsmoles/kg contribution to osmolality. How-ever, during this time the mean measured osmolalityrose only 9 mOsmoles/kg, and then fell to 7 mOsmolesfkg below the mean baseline level.
The maximum decrease in measured osmolali~y for each dog occurred from 60 to 120 minutes after glucose administration and is therefore obscured in the mean data. The magnitude of the decrease ranged from 2 to 18 mOsmoles/kg below the baseline. The mean decrease in measured osmolality after intra-venous administration of glucose was 10 + 3 mOsmoles/kg below baseline. A Student's t-test showed this drop to be signiEicant at the ~= .05 level: t3_of5 - 2.352, calculated t = 2.94. This decrease of osmolality below baseline cannot be explained by a drop in any specific solute below - 20 baseline levels.
Analysis of variancè showed no significant diff~rences over time in mean sodium, BUN, and protein levels after glucose infusion. The mean potassium level dropped slightly at 30 minutes, probably in response to the increase in insulin. The potassium level then rose and was significantly (p = 0.05~ higher from 120 to 150 minutes.
Diabetic Dogs: FIGURE 1 also shows the variation in several blood parameters for one diAhetic dog ~No. 22) during an IV glucose tolerance test. During the 1 1/2 hour baseline period the blood ~lucose fell spontaneously from 544 to 436 mg/dli ~easured osmolali'y varied between 306 and 310 mOsmoles/~g; sodium rose from 126.1 to 138.0 mEq/l during the baseline period. Insuli~, potassi~m and , 3 5 ~ ~>
protein xemained relatively constant both during the baseline period and after the infusion of glucose.
After glucose infusion the blood glucose rose by 294 mg/dl. In 2 1/2 hours glucose returned to the initial level of 440 mg/dl. After the glucose infusion, the measured osmolality rose only 5 mOsmoles/kg above the baseline value at 15 minutes. Osmolality continued to - rise at 30 minutes to 315 mOsmoles/kg even as the glucose level was decreasing. The measured osmolality then fell to a minimum of 304 mOsmoles/kg at 60 - minutes. It then rose to a maximum of 322 mOsmoles/kg at 2 1/2 hours. Sodium decreased 3 mOsmoles after glucose infusion, returned to the zero time level by 90 minutes, and then decreased again.
In this particular test the correlation between blood glucose and osmolality was very low:
r = 0.03. The correlation between blood glucose and osmolality in other IV glucose tolerance tests on diabetic dogs were much higher: r = 0.95 and r = 0.75.
; 20 In this test on dog No. 22 there was a slight corre-lation between sodium and osmolality (r - 0.24).
Osmolality was inversely proportional to potassium (r = 0.36), ~UN (r = 0.38), and protein (r = 0.30), however, these correlations are low.
The mean values of the measured plasma constituents of all diabetic animals during IV glu-; cose tolerance tests are also shown in FIGURE 2. Over the baseline period, the values were: glucose, 418-439 mg/dl; sodium, 134-137 mEq/l; potassium, 4.0-4.2 mEq/l; BUN 13-15 mg/dl; protein, 5.6-5.9 g/dl. The measured osmolality over the baseline period was 297-302 mOsmoles/kg.
After glucose infusion, in diabetic dogs the mean blood glucose rose to 810 mg/dl and returned to 424 mg/dl by 2 1/2 hours. The insulin level remained 35~ ( relatively unchanged throu~hout the test. Sodium levels decreased to 133 mEq/1 at 15 minutes and then increased above baseline levels reaching a maximum of 142 mEq/l at 2 1/2 hours. Potassium levels remained within the baseline range except for a 3.9 mEq/l value - at 75 minutes. BUN decreased slightly showing a minimum value of 12 mg/dl at 90 minutes. Protein also showed a slight tendency to decrease after glucose - infusion, reaching a minimum value at 75 minutes.
The increase in blood glucose after glucose infusion represents a 21.2 mOsmoles/kg contribution to osmolality. However, the mean measured osm~lality after glucose infusion rose only 16 mOsmoles/kg above the average baseline value. It then dropped to a minimum of 301 mOsmoles/kg at 75 minutes and subse-quently rose again to 309 mOsmoles~kg at 150 minutes.
After the initial rise following glucose infusion osmolality did not decrease below the base-line value in the long-term diabetic dog (NoO 17). In the other diabetic dog (No. 223 the decrease was 3-6 mOsmoles/kg below baseline between 60 and ~5 minutes.
This decrease is not significantt however (p >.05).
In practicing the present invention, insulin - can be infused as required utilizing a semi-permanently implanted percutaneous cat'neter, preferably of the type provided with a subcutaneously positioned fibrous cuff, made of polyester felt or similar material, that permits the ingrowth of tissue and capillary blood vessels therein. In this manner the catheter is not only fixed within the patient but also a barrier against bacterial invasion is effectlvely maintained.
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.
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i . .
The continuous infusion of insulin suhcutan-eously, intraperitonially or into a vein in response to a change in the physical property of a body fluid provides a more effective control of the patient's blood sugar level than is currently possible. More-over, through the continuous infusion of insulin, t~e rate of insulin absorption is not influenced by such factors as exercise and temperature. In addition to the continuous delivery of insulin to the patient as controlled by transducer or sensor 11, the system shown in the aforementioned copending application permits the patient to elect to have an additional infusion (bolus) as required, for example, at or shortly before a meal.
The system includes a reservoir and a pump j pack adapted to be strapped to the torso of a patient at an implanted catheter. The catheter is adapted to extend under the skin down the front of the chest witl the ti? near the entrance to the heart in a central vein.
This system includes a wearable pack includ-ing a one-piece prefilled insulin reservoir bag. When the insulin supply becomes exhausted and must be replaced, the pump segment (the heavy tube portion that is engaged by rollers in the pump) is removed by ; the roller section of the pump and the pump segment of a new supply is threaded through the pump there~y eliminating the pump as a contaminant to the system.
The delivery from the pump is controlled by a microprocessor programmed to respond to an input or inputs from the implanted osmolality sensor and possi~ly secondary sensors and is also designed to ~, .
P~35 ~6 permit the patient to anticipate the need for an extra quantity (bolus) of insulin. In the latter instance a push-button control on the side of the wearable pack can be actuated for the bolus infusion. The micro-processor can also be programmed to prevent thepatient from activating the bolus injection more than a predetermined number of times a day, depending upon the physician's prescription which can be prese~ in the microprocessor.
In another system embodyin~ the present invention a reservoir and pump pack are adapted to be strapped to the torso of the patient. A dual channel catheter is adapted to extend under the skin ~subcu-taneously) down under the chest with the tip of the catheter near the entrance of a central vein. Other methods of vascular access may be employed depending on the requirements of the patient. Likewise, sub-cutaneous or peritoneal infusion of insulin may be effected. The catheter carries a cuff or sleeve of "Dacron" or other material into which the patient's tissue and blood vessels grow for permanent i~planta tion, thereby reducing or obviating the possibility of bacterial infection.
The catheter itself is designed for prolonged implantation and can be constructed of a flexible silicone rubber (Silastic)*or other physiologicall~
compatible material having two parallel channels therethrough. One of these channels is the insulin infusion channel that is externally connected to the insulin pump. The other channel receives a lead wire or wires for the osmolality sensor and possible secondary sensors which project from and are posi-tioned by the distal end of the sensor channel.
~n important as~pect of the present invention is that the dual channel catheter permits the removal *Trade Mark .~
3~
and replacement (or removal, cleaning and replacement) of the osmolality sensor and any secondary sensor without the removal of the catheter itself. ~ecause of fibrous or fibrinous deposits or the general degradation of the transducer means or sensors after a . prolonged period of use it is necessary that they be periodically replaced or cleaned to prevent it adversely affecting the insulin delivery function.
Toward this end, the external end of the catheter is split defining an insulin tube connectable to the insulin pump and a sensor tube having a releasable and removable cap through which sensor lead wires project.
This cap has a conical projection that fits in and over and seals the end of the sensor tube. The cap also has a central bore therethrough that sealingly receives the sensor lead wires.
After a certain period of use, for example six months, a sensor can be replaced or cleaned, if desired, by removin~ the cap and withdrawing the sensor through the. sensor channel and thereafter replacing the cleaned sensor or replacing it with a new sensor and cap. The position of the cap on the sensor lead wire determines the extent of projection and positioning of the sensor itself from the distal ~5 end of the sensor channel.
: Referring to FIGURE 10, the insuli.n infusion system utilizin~ a dual lumen tchannel) catheter is seen to include a replaceable insulin supply 51, small roller pump 52 controlled by a microprocessor 53 and an implanted catheter 54 connected to tl~e insulin supply 51 through a releasable connector assembly 56.
In lieu of pump 52 other types of small pumps can be used, for example a piezoelectric micropump of the general type shown in ~.S. Patent No. 3,963,380 and the like.
& 3 ~
WhilP not shown in FIGURE 10, the insulin supply 51~ small pump 52 g and microprocessor 53 can be assembled into a single pack adapted to be worn by the patient in any convenient manner, e.g., strapped to the torso, or, if sufficiently small, adapted for implantation.
Insulin supply 51 is a one piece plastic insert and includes a polyethylene insulin reservoir bag 57, tube section 58, pump segment 59, and outlet tube 60 and supply connector 61, the latter forming part of the connector assembly 56~ The p~ump segment 59 of the insulin supply can be a segment of tube section 58 or a relatively heavy-walled section 67 terminàting in pump blocks 65 and 66. Heavy walled section 67 is adapted to be engaged by the rollers 55 of the micropump 52. When the insulin supply 51 is replaced, the patient discards the exha~sted supply unit, threads the pump section 59 of a new supply through the pump 52, and connects connector 61 to the connector assembly 56.
The pump 52 can be a relatively small roller pum~. The microprocessor 51 can be a digital logic system appropriately programmed for controlling the infusion rate of pump 5~ in accordance with signals provided by osmolality sensor 70 carried intracorpor eally by the catheter 54 and providing signals ~o the - microprocessor through a lead wire 71. The details of the necessary logic in the microprocessor 53 are readily apparent to an electronics engineer ?f ordinary skill given the intended function so the detailed 3~6 schematic therefor is not included in the drawings.
Suffice it to say that the microprocessor 53 includes a variable pulse generator for driving stepper motor 61 associated with pump 52 at a variable rate. An input circuit in microprocessor 53 responsive to changes in signal levels in sensor lead wire 71 biases the vari-able pulse generator and will increase the pulse rate to the stepper motor 61 in response to increases in the insulin demand, e.g., glucose level as sensed by sensor 70 in the patient's circulatory system and decreases the pulse rate to the pump 52 in response to decreased insulin demand sensed by sensor 70. In ~his manner insulin infusion rate is increased as patient's osmolality and glucose levels increase, and insulin infusion rate is decreased in response to decreased osmolality and/or glucose levels in a substantially continuous manner throughout the day.
The microprocessor 51 can also be progra~med to provide automatically a higher insulin infusion rate at predetermined time periods durin~ a 24-hour cycle, or the microprocessor can be pr~grammed to make and store a series of insulin demand determinations at predetermined intervals, to extrapolate therefrom an anticipated peak demand, and to control insulin infusion rate accordingly, As seen in greater detail in FIGURE 11, catheter 54 includes a left external section, an intermediate subcutaneous section A and an intraven-tricular section B. A tissue-impregnable cuff 72 surrounds the catheter 54 at the juncture of the external and subcutaneous sections to provide the catheter during prolonged implantation with an excel-lent bacteriological barrier. The catheter 54 in-cludes an insulin passage 73 having a connector 74 at the end thereof adapted to be connected to connector 56 ~ ~ ~ 3 5 s ~
to receive insulin from pump 52. Passage 73 has a relatively narrow section 75 at its distal end that extends intravascularly.
: The catheter also includes a smaller dia-meter sensor channel 77 that receives the replaceable sensor lead wire 71 and positions the sensor 70 adja-cent its intravascular distal end 79. The distal end 73 of t'ne catheter passage is spaced a considerable distance from the distal end of the insulin passage 75.
The external end of the catheter 54 is splity forming an insulin tube 80 and a sensor tube 81. A
replaceable cap 82 is provided for the sensor tube 81 to seal the sensor and also to permit the re~oval and cleaning or removal and replacement of the sensor 53 periodically to prevent fibrous or fibrinous buiId up or other degradation of the sensor 70 from adversely affecting the response of the microprocessor 53.
- As illustrated in FIGURE 13, the proximal end of tube 81 has a plurality of annular integral projec-tions 83 that hold and form a labyrinth seal with corresponding annular recesses 84 in the interior bore 85 of cap 82. To further seal sensor passage 77 from contamination, cap 82 has a narrow central opening 87 therethrough that sealingly receives lead wire 71 from sensor 70. The cap 82 is positioned on the lead wire 71 at a distance so that when the sensor is replaced, the sensor head 70 will be properly positioned the desired distance from the distal end 79 of the sensor : passage 77 within the patient's blood vessel.
When periodic replacement of tne sensor 70 is required, cap 82 is removed and the lead wire 71 withdrawn, withdrawing sensor 70 through sensor pas-sage 77. A temporary cap may be attached to the catheter to prevent infection in the interior. There-after the cleaned sensor or a new sensor 70 is .' ' ' .
.~ .
' ~3~
inserted, with the new cap 82, and the cap replaced connected to tube 81 and to the correct position of cap 82 on wire 71. The sensor 70 is then properly positioned.
The osmolality sensor 70 as shown in FIGURE 12 is a vapor pressure osmometer of the type illustrated in FIGURE 5 and comprises a pair of matched thermo-couples 91 and 93 situated in respective chambers 95 and 97. Chamber 95 is a hermetically sealed enclosure containing water vapor in equilibrium with liquid water at body temperatures. Chamber 97 is substantially the same as chamber 95 but for the fact that a wall portion 98 thereof is made of a semi-permeable membrane such as polysulfone film, cellulose acetate film, or the like, so as to permit e~uilibration of water vapor pressure within chamber 97 with that of the surrounding body fluid. Standard dialysis membranes that prevent the passage of the relatively smaller solute molecules but that keep out proteins are also suitable for this purpose. To minimize accumulation within the chambers between measurements, ~he chambers can be pressurized to drive out the substances contained therein and to permit a new equilibrium to be established prior to making the next measurement A sterile dry air or gaseous nitrogen sweep of the chambers can also be utilized for this purpose. Thermocouple 91 in chamber 95 provides a reference value for dew point of water at the body temperature e~isting at the time the osmolality measurement is made. For ascertaining sodium ion concentration in the body fluid, particularly suitable is a glucose-impermeable, sodium ion-permeable cellulose acetate membrane commercially avail-ble from Osmonics Corporation, Hopkins, Minnesota, under the designation Sepa-2.
The use of two sensing tran`sucers is shown in FIGURE 15 which is a modification of FIGURE 11. The osmolality sensor 70 and its lead 71 are as before, added are a secondary sensor 100 and its lead 99. The choice of this secondary sensor can be for conductivity or ion concentration.
The addition of semipermeable membrane capsule 101 which can be placed around the sensors shown in FIGURE 16. This capsule can be attached to the sensors and be withdrawn with them. In a preferred embodiment the semipermeable membrane w~uld be impermeable to bacteria but permeable to ~lucose and electrolytes and would form a seal about the distal end of the catheter 79, thus providing a second barrier against infection.
A cutaway view of the conductivity is shown in FIGURE 17. The sensor has an open end 104 in the casing 103 and the ~wo electrodes 102. Fluid enters the casing, and measurements are made by measuring resistance across the two electrodes.
In FIGURE 18 is shown a cutaway view of an electromotive force detector with its casing 107, an open end 108, the exposed electrode 106, the sealed electrode 109 and the membrane 105. The membrane is chosen by one knowledgeable in the art depending on the body fluid constituent wished to be measured. This includes pH, total ion concentration or the concentration of partic~lar ions such as potassium or sodium.
FIGURE 19 is a modification of FIGURE 4 to show the use of a secondary transducer 110 placed in the body 10 to provide an additional input for the microprocessor 12 which controls delivery of insulin from the reservoir 130 The foregoing discussion and the accompany-ing drawings are intended as illustrative, and are not to be taken as limiting. Still other variations and rearrangements of parts within the spirit and scope of . , ~, ....
~3 the present invention are pos6ible and will readily present themselves to one skilled in the art.
i ' : 25 , ~
~ .., , ., ,
The maximum decrease in measured osmolali~y for each dog occurred from 60 to 120 minutes after glucose administration and is therefore obscured in the mean data. The magnitude of the decrease ranged from 2 to 18 mOsmoles/kg below the baseline. The mean decrease in measured osmolality after intra-venous administration of glucose was 10 + 3 mOsmoles/kg below baseline. A Student's t-test showed this drop to be signiEicant at the ~= .05 level: t3_of5 - 2.352, calculated t = 2.94. This decrease of osmolality below baseline cannot be explained by a drop in any specific solute below - 20 baseline levels.
Analysis of variancè showed no significant diff~rences over time in mean sodium, BUN, and protein levels after glucose infusion. The mean potassium level dropped slightly at 30 minutes, probably in response to the increase in insulin. The potassium level then rose and was significantly (p = 0.05~ higher from 120 to 150 minutes.
Diabetic Dogs: FIGURE 1 also shows the variation in several blood parameters for one diAhetic dog ~No. 22) during an IV glucose tolerance test. During the 1 1/2 hour baseline period the blood ~lucose fell spontaneously from 544 to 436 mg/dli ~easured osmolali'y varied between 306 and 310 mOsmoles/~g; sodium rose from 126.1 to 138.0 mEq/l during the baseline period. Insuli~, potassi~m and , 3 5 ~ ~>
protein xemained relatively constant both during the baseline period and after the infusion of glucose.
After glucose infusion the blood glucose rose by 294 mg/dl. In 2 1/2 hours glucose returned to the initial level of 440 mg/dl. After the glucose infusion, the measured osmolality rose only 5 mOsmoles/kg above the baseline value at 15 minutes. Osmolality continued to - rise at 30 minutes to 315 mOsmoles/kg even as the glucose level was decreasing. The measured osmolality then fell to a minimum of 304 mOsmoles/kg at 60 - minutes. It then rose to a maximum of 322 mOsmoles/kg at 2 1/2 hours. Sodium decreased 3 mOsmoles after glucose infusion, returned to the zero time level by 90 minutes, and then decreased again.
In this particular test the correlation between blood glucose and osmolality was very low:
r = 0.03. The correlation between blood glucose and osmolality in other IV glucose tolerance tests on diabetic dogs were much higher: r = 0.95 and r = 0.75.
; 20 In this test on dog No. 22 there was a slight corre-lation between sodium and osmolality (r - 0.24).
Osmolality was inversely proportional to potassium (r = 0.36), ~UN (r = 0.38), and protein (r = 0.30), however, these correlations are low.
The mean values of the measured plasma constituents of all diabetic animals during IV glu-; cose tolerance tests are also shown in FIGURE 2. Over the baseline period, the values were: glucose, 418-439 mg/dl; sodium, 134-137 mEq/l; potassium, 4.0-4.2 mEq/l; BUN 13-15 mg/dl; protein, 5.6-5.9 g/dl. The measured osmolality over the baseline period was 297-302 mOsmoles/kg.
After glucose infusion, in diabetic dogs the mean blood glucose rose to 810 mg/dl and returned to 424 mg/dl by 2 1/2 hours. The insulin level remained 35~ ( relatively unchanged throu~hout the test. Sodium levels decreased to 133 mEq/1 at 15 minutes and then increased above baseline levels reaching a maximum of 142 mEq/l at 2 1/2 hours. Potassium levels remained within the baseline range except for a 3.9 mEq/l value - at 75 minutes. BUN decreased slightly showing a minimum value of 12 mg/dl at 90 minutes. Protein also showed a slight tendency to decrease after glucose - infusion, reaching a minimum value at 75 minutes.
The increase in blood glucose after glucose infusion represents a 21.2 mOsmoles/kg contribution to osmolality. However, the mean measured osm~lality after glucose infusion rose only 16 mOsmoles/kg above the average baseline value. It then dropped to a minimum of 301 mOsmoles/kg at 75 minutes and subse-quently rose again to 309 mOsmoles~kg at 150 minutes.
After the initial rise following glucose infusion osmolality did not decrease below the base-line value in the long-term diabetic dog (NoO 17). In the other diabetic dog (No. 223 the decrease was 3-6 mOsmoles/kg below baseline between 60 and ~5 minutes.
This decrease is not significantt however (p >.05).
In practicing the present invention, insulin - can be infused as required utilizing a semi-permanently implanted percutaneous cat'neter, preferably of the type provided with a subcutaneously positioned fibrous cuff, made of polyester felt or similar material, that permits the ingrowth of tissue and capillary blood vessels therein. In this manner the catheter is not only fixed within the patient but also a barrier against bacterial invasion is effectlvely maintained.
~. i ; !
$~
.
3 5 ~ ~ ~
-2~
i . .
The continuous infusion of insulin suhcutan-eously, intraperitonially or into a vein in response to a change in the physical property of a body fluid provides a more effective control of the patient's blood sugar level than is currently possible. More-over, through the continuous infusion of insulin, t~e rate of insulin absorption is not influenced by such factors as exercise and temperature. In addition to the continuous delivery of insulin to the patient as controlled by transducer or sensor 11, the system shown in the aforementioned copending application permits the patient to elect to have an additional infusion (bolus) as required, for example, at or shortly before a meal.
The system includes a reservoir and a pump j pack adapted to be strapped to the torso of a patient at an implanted catheter. The catheter is adapted to extend under the skin down the front of the chest witl the ti? near the entrance to the heart in a central vein.
This system includes a wearable pack includ-ing a one-piece prefilled insulin reservoir bag. When the insulin supply becomes exhausted and must be replaced, the pump segment (the heavy tube portion that is engaged by rollers in the pump) is removed by ; the roller section of the pump and the pump segment of a new supply is threaded through the pump there~y eliminating the pump as a contaminant to the system.
The delivery from the pump is controlled by a microprocessor programmed to respond to an input or inputs from the implanted osmolality sensor and possi~ly secondary sensors and is also designed to ~, .
P~35 ~6 permit the patient to anticipate the need for an extra quantity (bolus) of insulin. In the latter instance a push-button control on the side of the wearable pack can be actuated for the bolus infusion. The micro-processor can also be programmed to prevent thepatient from activating the bolus injection more than a predetermined number of times a day, depending upon the physician's prescription which can be prese~ in the microprocessor.
In another system embodyin~ the present invention a reservoir and pump pack are adapted to be strapped to the torso of the patient. A dual channel catheter is adapted to extend under the skin ~subcu-taneously) down under the chest with the tip of the catheter near the entrance of a central vein. Other methods of vascular access may be employed depending on the requirements of the patient. Likewise, sub-cutaneous or peritoneal infusion of insulin may be effected. The catheter carries a cuff or sleeve of "Dacron" or other material into which the patient's tissue and blood vessels grow for permanent i~planta tion, thereby reducing or obviating the possibility of bacterial infection.
The catheter itself is designed for prolonged implantation and can be constructed of a flexible silicone rubber (Silastic)*or other physiologicall~
compatible material having two parallel channels therethrough. One of these channels is the insulin infusion channel that is externally connected to the insulin pump. The other channel receives a lead wire or wires for the osmolality sensor and possible secondary sensors which project from and are posi-tioned by the distal end of the sensor channel.
~n important as~pect of the present invention is that the dual channel catheter permits the removal *Trade Mark .~
3~
and replacement (or removal, cleaning and replacement) of the osmolality sensor and any secondary sensor without the removal of the catheter itself. ~ecause of fibrous or fibrinous deposits or the general degradation of the transducer means or sensors after a . prolonged period of use it is necessary that they be periodically replaced or cleaned to prevent it adversely affecting the insulin delivery function.
Toward this end, the external end of the catheter is split defining an insulin tube connectable to the insulin pump and a sensor tube having a releasable and removable cap through which sensor lead wires project.
This cap has a conical projection that fits in and over and seals the end of the sensor tube. The cap also has a central bore therethrough that sealingly receives the sensor lead wires.
After a certain period of use, for example six months, a sensor can be replaced or cleaned, if desired, by removin~ the cap and withdrawing the sensor through the. sensor channel and thereafter replacing the cleaned sensor or replacing it with a new sensor and cap. The position of the cap on the sensor lead wire determines the extent of projection and positioning of the sensor itself from the distal ~5 end of the sensor channel.
: Referring to FIGURE 10, the insuli.n infusion system utilizin~ a dual lumen tchannel) catheter is seen to include a replaceable insulin supply 51, small roller pump 52 controlled by a microprocessor 53 and an implanted catheter 54 connected to tl~e insulin supply 51 through a releasable connector assembly 56.
In lieu of pump 52 other types of small pumps can be used, for example a piezoelectric micropump of the general type shown in ~.S. Patent No. 3,963,380 and the like.
& 3 ~
WhilP not shown in FIGURE 10, the insulin supply 51~ small pump 52 g and microprocessor 53 can be assembled into a single pack adapted to be worn by the patient in any convenient manner, e.g., strapped to the torso, or, if sufficiently small, adapted for implantation.
Insulin supply 51 is a one piece plastic insert and includes a polyethylene insulin reservoir bag 57, tube section 58, pump segment 59, and outlet tube 60 and supply connector 61, the latter forming part of the connector assembly 56~ The p~ump segment 59 of the insulin supply can be a segment of tube section 58 or a relatively heavy-walled section 67 terminàting in pump blocks 65 and 66. Heavy walled section 67 is adapted to be engaged by the rollers 55 of the micropump 52. When the insulin supply 51 is replaced, the patient discards the exha~sted supply unit, threads the pump section 59 of a new supply through the pump 52, and connects connector 61 to the connector assembly 56.
The pump 52 can be a relatively small roller pum~. The microprocessor 51 can be a digital logic system appropriately programmed for controlling the infusion rate of pump 5~ in accordance with signals provided by osmolality sensor 70 carried intracorpor eally by the catheter 54 and providing signals ~o the - microprocessor through a lead wire 71. The details of the necessary logic in the microprocessor 53 are readily apparent to an electronics engineer ?f ordinary skill given the intended function so the detailed 3~6 schematic therefor is not included in the drawings.
Suffice it to say that the microprocessor 53 includes a variable pulse generator for driving stepper motor 61 associated with pump 52 at a variable rate. An input circuit in microprocessor 53 responsive to changes in signal levels in sensor lead wire 71 biases the vari-able pulse generator and will increase the pulse rate to the stepper motor 61 in response to increases in the insulin demand, e.g., glucose level as sensed by sensor 70 in the patient's circulatory system and decreases the pulse rate to the pump 52 in response to decreased insulin demand sensed by sensor 70. In ~his manner insulin infusion rate is increased as patient's osmolality and glucose levels increase, and insulin infusion rate is decreased in response to decreased osmolality and/or glucose levels in a substantially continuous manner throughout the day.
The microprocessor 51 can also be progra~med to provide automatically a higher insulin infusion rate at predetermined time periods durin~ a 24-hour cycle, or the microprocessor can be pr~grammed to make and store a series of insulin demand determinations at predetermined intervals, to extrapolate therefrom an anticipated peak demand, and to control insulin infusion rate accordingly, As seen in greater detail in FIGURE 11, catheter 54 includes a left external section, an intermediate subcutaneous section A and an intraven-tricular section B. A tissue-impregnable cuff 72 surrounds the catheter 54 at the juncture of the external and subcutaneous sections to provide the catheter during prolonged implantation with an excel-lent bacteriological barrier. The catheter 54 in-cludes an insulin passage 73 having a connector 74 at the end thereof adapted to be connected to connector 56 ~ ~ ~ 3 5 s ~
to receive insulin from pump 52. Passage 73 has a relatively narrow section 75 at its distal end that extends intravascularly.
: The catheter also includes a smaller dia-meter sensor channel 77 that receives the replaceable sensor lead wire 71 and positions the sensor 70 adja-cent its intravascular distal end 79. The distal end 73 of t'ne catheter passage is spaced a considerable distance from the distal end of the insulin passage 75.
The external end of the catheter 54 is splity forming an insulin tube 80 and a sensor tube 81. A
replaceable cap 82 is provided for the sensor tube 81 to seal the sensor and also to permit the re~oval and cleaning or removal and replacement of the sensor 53 periodically to prevent fibrous or fibrinous buiId up or other degradation of the sensor 70 from adversely affecting the response of the microprocessor 53.
- As illustrated in FIGURE 13, the proximal end of tube 81 has a plurality of annular integral projec-tions 83 that hold and form a labyrinth seal with corresponding annular recesses 84 in the interior bore 85 of cap 82. To further seal sensor passage 77 from contamination, cap 82 has a narrow central opening 87 therethrough that sealingly receives lead wire 71 from sensor 70. The cap 82 is positioned on the lead wire 71 at a distance so that when the sensor is replaced, the sensor head 70 will be properly positioned the desired distance from the distal end 79 of the sensor : passage 77 within the patient's blood vessel.
When periodic replacement of tne sensor 70 is required, cap 82 is removed and the lead wire 71 withdrawn, withdrawing sensor 70 through sensor pas-sage 77. A temporary cap may be attached to the catheter to prevent infection in the interior. There-after the cleaned sensor or a new sensor 70 is .' ' ' .
.~ .
' ~3~
inserted, with the new cap 82, and the cap replaced connected to tube 81 and to the correct position of cap 82 on wire 71. The sensor 70 is then properly positioned.
The osmolality sensor 70 as shown in FIGURE 12 is a vapor pressure osmometer of the type illustrated in FIGURE 5 and comprises a pair of matched thermo-couples 91 and 93 situated in respective chambers 95 and 97. Chamber 95 is a hermetically sealed enclosure containing water vapor in equilibrium with liquid water at body temperatures. Chamber 97 is substantially the same as chamber 95 but for the fact that a wall portion 98 thereof is made of a semi-permeable membrane such as polysulfone film, cellulose acetate film, or the like, so as to permit e~uilibration of water vapor pressure within chamber 97 with that of the surrounding body fluid. Standard dialysis membranes that prevent the passage of the relatively smaller solute molecules but that keep out proteins are also suitable for this purpose. To minimize accumulation within the chambers between measurements, ~he chambers can be pressurized to drive out the substances contained therein and to permit a new equilibrium to be established prior to making the next measurement A sterile dry air or gaseous nitrogen sweep of the chambers can also be utilized for this purpose. Thermocouple 91 in chamber 95 provides a reference value for dew point of water at the body temperature e~isting at the time the osmolality measurement is made. For ascertaining sodium ion concentration in the body fluid, particularly suitable is a glucose-impermeable, sodium ion-permeable cellulose acetate membrane commercially avail-ble from Osmonics Corporation, Hopkins, Minnesota, under the designation Sepa-2.
The use of two sensing tran`sucers is shown in FIGURE 15 which is a modification of FIGURE 11. The osmolality sensor 70 and its lead 71 are as before, added are a secondary sensor 100 and its lead 99. The choice of this secondary sensor can be for conductivity or ion concentration.
The addition of semipermeable membrane capsule 101 which can be placed around the sensors shown in FIGURE 16. This capsule can be attached to the sensors and be withdrawn with them. In a preferred embodiment the semipermeable membrane w~uld be impermeable to bacteria but permeable to ~lucose and electrolytes and would form a seal about the distal end of the catheter 79, thus providing a second barrier against infection.
A cutaway view of the conductivity is shown in FIGURE 17. The sensor has an open end 104 in the casing 103 and the ~wo electrodes 102. Fluid enters the casing, and measurements are made by measuring resistance across the two electrodes.
In FIGURE 18 is shown a cutaway view of an electromotive force detector with its casing 107, an open end 108, the exposed electrode 106, the sealed electrode 109 and the membrane 105. The membrane is chosen by one knowledgeable in the art depending on the body fluid constituent wished to be measured. This includes pH, total ion concentration or the concentration of partic~lar ions such as potassium or sodium.
FIGURE 19 is a modification of FIGURE 4 to show the use of a secondary transducer 110 placed in the body 10 to provide an additional input for the microprocessor 12 which controls delivery of insulin from the reservoir 130 The foregoing discussion and the accompany-ing drawings are intended as illustrative, and are not to be taken as limiting. Still other variations and rearrangements of parts within the spirit and scope of . , ~, ....
~3 the present invention are pos6ible and will readily present themselves to one skilled in the art.
i ' : 25 , ~
~ .., , ., ,
Claims (23)
1. A system suitable for administration of insulin to a patient in response to insulin require-ment of said patient which comprises an insulin dis-penser for transcutaneous infusion of insulin into said patient, a transducer means responsive to a physical property of a body fluid of said patient and generating a signal having a magnitude which is a function of said physical property, a dispenser con-trol means to receive said signal and operably asso-ciated with said dispenser to deliver insulin to said patient in response to the received signal.
2. The system in accordance with claim 1 wherein the transducer means generates a signal pro-portional to osmolality of the body fluid.
3. The system in accordance with claim 1 wherein the body fluid is blood of the patient and the transducer means generates a signal proportional to osmolality of said blood.
4. The system in accordance with claim 1 wherein the body fluid is blood, the physical pro-perty is oncotic pressure, and the transducer means is responsive to the oncotic pressure.
5. The system in accordance with claim 1 wherein the body fluid is blood, the physical pro-perty is vapor pressure, and the transducer means is responsive to the vapor pressure.
6. The system in accordance with claim 1 wherein the body fluid is blood, the physical pro-perty is freezing point, and the transducer means is responsive to the freezing point.
7. The system in accordance with claim 1 wherein the body fluid is blood, the physical pro-perty is boiling point, and the transducer means is responsive to the boiling point.
8. The system in accordance with claim 1 wherein the body fluid is peritoneal fluid of the patient and the transducer means generates a signal proportional to osmolality of said peritoneal fluid.
9. The system in accordance with claim 1 wherein the body fluid is peritoneal fluid, the physical property is oncotic pressure, and the trans-ducer means is responsive to the oncotic pressure.
10. The system in accordance with claim 1 wherein the body fluid is peritoneal fluid, the physical property is vapor pressure, and the trans-ducer means is responsive to the vapor pressure.
11. The system in accordance with claim 1 wherein the body fluid is peritoneal fluid, the physical property is freezing point, and the trans-ducer means is responsive to the freezing point.
12. The system in accordance with claim 1 wherein the body fluid is peritoneal fluid, the physical property is boiling point, and the trans-ducer means is responsive to the boiling point.
13. The system in accordance with claim 1 wherein the body fluid is subcutaneous fluid of the patient and the transducer means generates a signal proportional to osmolality of said subcutaneous fluid.
14. The system in accordance with claim 1 wherein the body fluid is subcutaneous fluid, the physical property is oncotic pressure, and the trans-ducer means is responsive to the oncotic pressure.
15. The system in accordance with claim 1 wherein the body fluid is subcutaneous fluid, the physical property is vapor pressure, and the trans-ducer means is responsive to the vapor pressure.
16. The system in accordance with claim 1 wherein the body fluid is subcutaneous fluid, the physical property is freezing point, and the transducer means is responsive to the freezing point.
17. The system in accordance with claim 1 wherein the body fluid is subcutaneous fluid, the physical property is boiling point, and the transducer means is responsive to the boiling point.
18. The system in accordance with claim 1 wherein the transducer means is implantable into the patient.
19. The system in accordance with claim 2 including a second transducer means which generates signals proportional to the electrolyte concentration of the body fluid.
20. The system in accordance with claim 19 wherein the second transducer means is an electrolytic conductivity sensor.
21. The system in accordance with claim 19 wherein the second transducer means is a device to measure ion concentration.
22. The system in accordance with claim 19 wherein the second transducer means is adapted to generate a signal proportional to the electromotive force between two electrodes placed within the body.
23. The system in accordance with claim 2 including a plurality of secondary transducers each set in different membranes to generate signals proportional to the concentrations of the body fluid constituents wished to be measured.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000367629A CA1163516A (en) | 1980-12-29 | 1980-12-29 | System for demand based administration of insulin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000367629A CA1163516A (en) | 1980-12-29 | 1980-12-29 | System for demand based administration of insulin |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1163516A true CA1163516A (en) | 1984-03-13 |
Family
ID=4118783
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000367629A Expired CA1163516A (en) | 1980-12-29 | 1980-12-29 | System for demand based administration of insulin |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1163516A (en) |
-
1980
- 1980-12-29 CA CA000367629A patent/CA1163516A/en not_active Expired
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