WO1981001794A1 - Systeme d'administration d'insuline basee a la demande - Google Patents
Systeme d'administration d'insuline basee a la demande Download PDFInfo
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- WO1981001794A1 WO1981001794A1 PCT/US1980/001765 US8001765W WO8101794A1 WO 1981001794 A1 WO1981001794 A1 WO 1981001794A1 US 8001765 W US8001765 W US 8001765W WO 8101794 A1 WO8101794 A1 WO 8101794A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
- A61B5/14525—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using microdialysis
- A61B5/14528—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using microdialysis invasively
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
- A61B5/14532—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue for measuring glucose, e.g. by tissue impedance measurement
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
- A61M5/14—Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
- A61M5/168—Means for controlling media flow to the body or for metering media to the body, e.g. drip meters, counters ; Monitoring media flow to the body
- A61M5/172—Means for controlling media flow to the body or for metering media to the body, e.g. drip meters, counters ; Monitoring media flow to the body electrical or electronic
- A61M5/1723—Means for controlling media flow to the body or for metering media to the body, e.g. drip meters, counters ; Monitoring media flow to the body electrical or electronic using feedback of body parameters, e.g. blood-sugar, pressure
Definitions
- This invention relates to means for ascertaining insulin demand of a patient based upon measurable changes of a body fluid physical property and to means for controlled administration of insulin.
- Diabetes mellitus is a disease characterized by hyperglycemia, polyuria, and wasting. Hyperglycemia is due to decreased utilization of glucose and also increased production of glucose.
- a further extension of the aforementioned treatment by "close control” is the use of a continuous or constant rate infusion of insulin using an insulin dispenser for infusion of this hormone into the patient.
- 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.
- glucose sensors are rate-dependent. That is. the glucose concentration in a patient's blood is indicated by the reaction rate of glucose 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 recalibration of the sensor.
- 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 manifestation 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 is particularly suitable for this purpose.
- Typical body fluids whose physical properties can be monitored for this purpose are blood, peritoneal fluid, subcutaneous fluid, or the like.
- a system for 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 generating a signal having a magnitude which is a function 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 means 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 iontophoresis, or for subcutaneous or transcutaneous infusion, as desired. Where the insulin dispenser is external to the patient's body, insulin delivery to the patient is effected via a cannula or by percutaneous catherization using a catheter made of a biocompatible material. Preferably the catheter also is provided with a barrier against infection.
- concentration of other blood constituents such as sodium or potassium levels.
- concentration of such electrolytes can be determined by implanting a secondary transducer which can be designed to measure the conductivity or ion concentration 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 the insulin dispenser.
- Another embodiment would have a primary transducer sensing osmolality and one or more secondary transducers 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 responsive to the signal or signals from one or more sensors or detectors and controlling the delivery of insulin.
- 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.
- FIGURE 1 is graphical correlation of blood glucose level and blood osmolality in normal and diabetic 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.
- FIGURE 3 is a graphical 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 representation, partly in section, of a vapor pressure osmometer
- FIGURE 6 indicates the thermocouple temperature curve for the osmometer shown in FIGURE 5;
- FIGURE 7 is a schematic representation of an implantable oncotic pressure osmometer;
- FIGURE 8 is a schematic representation, partly in section, of a freezing point osmometer;
- FIGURE 9 is a schematic representation, partly in section, of a boiling point osmometer
- FIGURE 10 is a schematic view of one embodiment of the present insulin infusion system including a supply reservoir, a micropump controlled by a microprocessor, and a dual channel catheter assembly for delivering insulin to the patient and providing signals to the microprocessor representing glucose levels in the patient;
- FIGURE 11 is an enlarged cross-section of the catheter shown in FIGURE 10;
- FIGURE 12 is an enlarged view of an exemplary replaceable sensor partly broken away to show interior detail
- FIGURE 13 is an enlarged, exploded fragmentary section of the proximal end of sensor tube of the catheter and the replaceable cap therefor;
- 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 semipermeable membrane to encase the sensors;
- FIGURE 17 is an enlarged view of a conductivity 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
- FIGURE 19 is a block diagram showing a system for controlled administration of insulin using two sensors in the body. Description of Preferred Embodiments
- insulin can affect the 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.
- other body substances including potassium, phosphates, hydrogen, ketone bodies such as -hydroxybutyrate and aceto acetate, fatty acid levels, sodium, and glycerol.
- insulin can affect the 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.
- ketone bodies such as -hydroxybutyrate and aceto acetate
- fatty acid levels sodium, and glycerol.
- glycerol glycerol
- idiogenic osmols can accumulate to levels of up to 40 milliosmols, and can cause cerebral edema or coma during treatment of diabet
- 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.
- 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 absolute value than would be expected from the change in the blood glucose concentration.
- osmolality There may be some cases where it may be desirable to measure more than just the osmolality level.
- An increase in osmolality can sometimes 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 conductivity or ion concentration since the majority of extracellular osmoles are electrolytes.
- FIGURE 1 graphically illustrates.
- 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.
- 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.
- FIGURES 2 and 2A The time course of these osmolality changes is depicted in FIGURES 2 and 2A where various blood chemistries are depicted for one of the normal 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 nitrogen (BUN) and protein change little during a glucose load, but that osmolality shifts dramatically, first increasing, then decreasing.
- BUN blood urea nitrogen
- the swings in osmolality are believed to be due to changes in "unmeasured” " or “idiogenic” osraoles; these osmoles are indicated by the "osmol gap" calculated by subtracting out the effects of urea, Na, anions, 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 dispensing of insulin.
- 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, therefore control of osmolality also controls glucose.
- FIGURE 4 schematically illustrates a closed loop system for an effective diabetes control utilizing blood, osmolality for example, as the indicator of insulin demand. Osmolality of other body fluids is also suitable for this purpose.
- Transducer 11 such as an osmolality sensor, is introduced or implanted into patient 10 in any convenient manner, e.g., within patient's vascular space, subcutaneously, or intraperitoneally, so as to be in contact with a body fluid such as blood, subcutaneous 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.
- 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.
- 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.
- 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 as for conductivity and ion concentration can be placed in contact with any of these.
- transducer 11 utilizes one or more of the aforementioned colligative properties to generate an output signal.
- 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.”
- thermocouple 19 In the top portion of the chamber 17 is a very small thermocouple 19.
- the thermocouple When equilibrium of vapor pressure of the body fluid and gas is attained, the thermocouple is cooled several degrees by electric current (through the Peltier effect). The electric current is then stopped, and the temperature of the thermocouple rises to the "dew point” as water condenses on the thermocouple.
- the "dew point” depression is the difference between ambient temperature and the dew point.
- Osmometer 14 can be calibrated against a known standard prior to implantation, and periodically after implantation by drawing an aliquot of the patient's blood and determining the osmolality thereof extracorporeally.
- a second osmometer similar to osmometer 14 but with a hermeticallysealed chamber containing a known gas-water vapor mixture, can be implanted to serve as a periodic calibration means.
- Oncotic pressure is another possible method for determination of osmolality. Oncotic pressure is defined as the pressure exerted across a semi permeable membrane because of the presence of impermeable 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.
- FIGURE 7 An osmolality sensor utilizing oncotic pressure is shown schematically in FIGURE 7.
- 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.
- the 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 utilizing 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 concentration 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 comprises vessel 41 equipped with heating coil 43 and thermocouple 45. Since increasing solute concentration results in lower solvent concentration, boiling occurs at a higher temperature.
- thermocouple 45 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 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 equilibrium within body fluids, such as the peritoneum.
- the osmometer can be a separate, free-standing unit operably associated with an insulin dispensing device.
- the generated signal is based on an equilibrium condition, i.e., the signal is not dependent on the rate at which a physical change takes place at the transducer, but rather on the equilibrium condition that is encountered.
- An increase in osmolality caused by dehydration or salt ingestion can also be detected by an electrolyte concentration increase by measuring electrolytic conductivity or ion concentration measurements.
- electrolytic conductivity 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. 10,000-20,000 Hertz is a useful frequency for this purpose.
- Electrolytic conductivity can also be measured by means of electrical induction without the use cf contacting electrodes. Such measurements are made by inducing a current in the body fluid by use 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 possible 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 measurements 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.
- 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.
- the conductor portion of the lead can be coated with an inert, biocompatible sheath.
- a fibrous cuff e.g., a 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 energizing insulin dispenser 13.
- 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.
- control means 12 can include a timing device that samples and compares signals received at predetermined intervals and energizes dispenser 13 only after differences among a plurality of received consecutive 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 fiom dispenser control 12.
- 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 fiom dispenser control 12.
- the osmolality of the body fluid can also be determined using any other colligative property of the body fluid.
- the transducer means can be adapted to measure freezing point depression, vapor pressure, or boiling point evaluation.
- control of the desired dose delivery of insulin can be effected based on electrical impedance measurements performed on the body fluid by means of implanted inert electrodes, e.g., platinum, 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.
- a body fluid of the patient is contacted with a 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 deficiency, for example, osmolality or one of the colligative properties thereof such as vapor pressure or osmotic pressure.
- the transducer means is 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 means contacting the body fluid can then be utilized as an indicator of the patient's insulin requirement as well as to control the amount of insulin dispensed. Additional measurements 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 to dispense the required amount of insulin.
- a microprocessor is well suited for this purpose.
- the present invention is further illustrated by the following example.
- Animals Five mongrel dogs were used. Two 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. 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 the diabetic dogs on the day of the tests.
- Glucose Tolerance Tests Intravenous glucose tolerance 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 establish 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.
- Plasma samples were centrifuged in a refrigerated centrifuge at 2000G's at 5°C for 15 minutes. Plasma was removed, aliquoted 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., Diabetes 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 BUN Analyzer II. Protein was determined using Folin Phenol reagent by the method of Lowrey et al., J. Biol. Chem.
- 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., Leibraan, 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 1.75 NA +0.0556 Glucose +0.357 BUN + 10.1 The use of this value is discussed in further detail below.
- Figure 2 shows the variation in several blood parameters of one normal dog (No. 27), during an IV glucose tolerance test. During the 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 352 mg/dl. Insulin rose from a mean baseline value of
- the ranges in the measured variables for normal dogs were glucose: 105-110 mg/dl; osmolality 286-290 mOsmoles/kg; insulin: 17-32 u ⁇ /ml; sodium: 147-150 mEq/1; K: 4.1-4.4 mEq/1; BUN: 10-12 mg/dl; plasma protein: 5.4-5.9 g/dl.
- glucose rose to 230 mg/dl. This represents a 12.7 mOsmoles/kg contribution to osmolality.
- the mean measured osmolality rose only 9 mOsmoles/kg, and then fell to 7 mOsmoles/kg below the mean baseline level.
- the maximum decrease in measured osmolality 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 intravenous administration of glucose was 10 + 3 mOsmoles/kg below baseline.
- FIGURE 1 also shows the variation in several blood parameters for one diabetic dog (No. 22) during an IV glucose tolerance test.
- the blood glucose fell spontaneously from 544 to 436 mg/dl; measured osmolality varied between 306 and 310 mOsmoles/kg; sodium rose from 126.1 to 138.0 mEq/1 during the baseline period.
- Insulin, potassium and protein remained relatively constant both during the baseline period and after the infusion of glucose.
- glucose infusion the blood glucose rose by 294 mg/dl.
- glucose returned to the initial level of 440 mg/dl.
- the measured osmolality rose only 5 mOsmoles/kg above the baseline value at 15 minutes.
- the mean measured osmolality 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 subsequently rose again to 309 mOsmoles/kg at 150 minutes.
- insulin can be infused as required utilizing a semi-permanently implanted percutaneous catheter, 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.
- a semi-permanently implanted percutaneous catheter 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.
- a semi-permanently implanted percutaneous catheter 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.
- Co-pending United States patent application Serial No. 072,264 filed on 4 September 1979, discloses an insulin infusion system that is suitable for continuous as well as intermittent delivery of insulin to the patient when used in conjunction with an osmolality sensor described hereinabove and is incorporated herein
- the continuous infusion of insulin subcutaneously, 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. Moreover, through the continuous infusion of insulin, the rate of insulin absorption is not influenced by such factors as exercise and temperature.
- 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 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 with the tip near the entrance to the heart in a central vein.
- This system includes a wearable pack including a one-piece prefilled insulin reservoir bag.
- 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 thereby 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 possibly secondary sensors and is also designed to permit the patient to anticipate the need for an extra quantity (bolus) of insulin.
- a push-button control on the side of the wearable pack can be actuated for the bolus infusion.
- the microprocessor can also be programmed to prevent the patient from activating the bolus injection more than a predetermined number of times a day, depending upon the physician's prescription. which can be preset in the microprocessor.
- 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 (subcutaneously) 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, subcutaneous 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 implantation, 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 physiologically 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 positioned by the distal end of the sensor channel.
- the dual channel catheter permits the removal and replacement (or removal, cleaning and replacement) of the osmolality sensor and any secondary sensor without the removal of the ' catheter itself. Because 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.
- 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.
- a sensor can be replaced or cleaned, if desired, by removing 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 end of the sensor channel.
- the insulin infusion system utilizing a dual lumen (channel) 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 the insulin supply 51 through a releasable connector assembly 56.
- pump 52 other types of small pumps can be used, for example a piezoelectric micropump of the general type shown in U.S. Patent No. 3,963,380 and the like.
- the connector assembly 56 may take the form of the connector assembly disclosed in the aforementioned co-pending United States patent application Serial No. 072,264 filed on 4 September 1979, the detailed description of which is incorporated herein by reference to the extent pertinent.
- the insulin supply 51, small pump 52, 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 pump segment 59 of the insulin supply can be a segment of tube section 58 or a relatively heavy-walled section 67 terminating in pump blocks 65 and 66. Heavy walled section 67 is adapted to be engaged by the rollers 55 of the micropump 52.
- the patient discards the exhausted 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 pump.
- the microprocessor 51 can be a digital logic system appropriately programmed for controlling the infusion rate of pump 52 in accordance with signals provided by osmolality sensor 70 carried intracorporeally by the catheter 54 and providing signals to the microprocessor through a lead wire 71.
- the details of the necessary logic in the microprocessor 53 are readily apparent to an electronics engineer of ordinary skill given the intended function so the detailed 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.
- 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 programmed to provide automatically a higher insulin infusion rate at predetermined time periods during a 24-hour cycle, or the microprocessor can be programmed 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.
- catheter 54 includes a left external section, an intermediate subcutaneous section A and an intraventricular 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 excellent bacteriological barrier.
- the catheter 54 includes an insulin passage 73 having a connector 74 at the end thereof adapted to be connected to connector 56 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 diameter sensor channel 77 that receives the replaceable sensor lead wire 71 and positions the sensor 70 adjacent its intravascular distal end 79.
- the distal end 79 of the catheter passage is spaced a considerable distance from the distal end of the insulin passage 75,
- the external end of the catheter 54 is split, 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 removal and cleaning or removal and replacement of the sensor 53 periodically to prevent fibrous or fibrinous build up or other degradation of the sensor 70 from adversely affecting the response of the microprocessor 53.
- the proximal end of tube 81 has a plurality of annular integral projections 83 that hold and form a labyrinth seal with corresponding annular recesses 34 in the interior bore 35 of cap 82.
- cap 32 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.
- cap 32 is removed and the lead wire 71 withdrawn, withdrawing sensor 70 through sensor passage 77.
- a temporary cap may be attached to the catheter to prevent infection in the interiors. Thereafter the cleaned sensor or a new sensor 70 is 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 thermocouples 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 equilibration 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.
- the 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 existing at the time the osmolality measurement is made.
- a glucose-impermeable, sodium ion-permeable cellulose acetate membrane commercially available from Osmonics Corporation, Hopkins, Minnesota, under the designation Sepa-2.
- the use of two sensing transucers 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.
- 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.
- the semipermeable membrane would be impermeable to bacteria but permeable to glucose 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 two electrodes 102. Fluid enters the casing, and measurements are made by measuring resistance across the two electrodes.
- 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 particular 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 13.
Abstract
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU67794/81A AU6779481A (en) | 1979-12-28 | 1980-12-24 | System for demand-based administration of insulin |
DE19803050155 DE3050155A1 (de) | 1979-12-28 | 1980-12-24 | System for demand-based administration of insulin |
DE8181900385T DE3070407D1 (en) | 1979-12-28 | 1980-12-24 | System for demand-based administration of insulin |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10796579A | 1979-12-28 | 1979-12-28 | |
US107965 | 1979-12-28 | ||
US06/218,710 US4403984A (en) | 1979-12-28 | 1980-12-22 | System for demand-based adminstration of insulin |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1981001794A1 true WO1981001794A1 (fr) | 1981-07-09 |
Family
ID=26805392
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1980/001765 WO1981001794A1 (fr) | 1979-12-28 | 1980-12-24 | Systeme d'administration d'insuline basee a la demande |
Country Status (8)
Country | Link |
---|---|
US (1) | US4403984A (fr) |
EP (1) | EP0042431B1 (fr) |
JP (1) | JPS56501714A (fr) |
DE (1) | DE3070407D1 (fr) |
GB (1) | GB2082331B (fr) |
IT (1) | IT1146975B (fr) |
SE (1) | SE8105081L (fr) |
WO (1) | WO1981001794A1 (fr) |
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EP4159114A1 (fr) | 2007-10-09 | 2023-04-05 | DexCom, Inc. | Système d'administration d'insuline intégré avec un capteur de glucose en continu |
EP4098177A1 (fr) | 2007-10-09 | 2022-12-07 | DexCom, Inc. | Système d'administration d'insuline intégré avec un capteur de glucose en continu |
WO2009055736A1 (fr) | 2007-10-25 | 2009-04-30 | Dexcom, Inc. | Systèmes et méthodes de traitement de données de détecteurs |
EP4250312A2 (fr) | 2007-10-25 | 2023-09-27 | DexCom, Inc. | Systèmes et méthodes de traitement de données de détecteurs |
GB2446247B (en) * | 2007-11-27 | 2008-12-17 | Robert Joseph Wagener | Homeostatic insulin pump |
GB2446247A (en) * | 2007-11-27 | 2008-08-06 | Robert Joseph Wagener | Implantable valve for the control of an insulin pump |
US9933385B2 (en) | 2007-12-10 | 2018-04-03 | Ascensia Diabetes Care Holdings Ag | Method of using an electrochemical test sensor |
US10690614B2 (en) | 2007-12-10 | 2020-06-23 | Ascensia Diabetes Care Holdings Ag | Method of using an electrochemical test sensor |
Also Published As
Publication number | Publication date |
---|---|
US4403984A (en) | 1983-09-13 |
GB2082331B (en) | 1984-09-26 |
JPS56501714A (fr) | 1981-11-26 |
SE8105081L (sv) | 1981-08-27 |
DE3070407D1 (en) | 1985-05-02 |
GB2082331A (en) | 1982-03-03 |
EP0042431B1 (fr) | 1985-03-27 |
IT1146975B (it) | 1986-11-19 |
IT8050475A0 (it) | 1980-12-29 |
EP0042431A1 (fr) | 1981-12-30 |
EP0042431A4 (fr) | 1982-04-29 |
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