Control of blood glucose in experimental diabetes by means of a totally implantable insulin infusion device.

Near-normal glucose tolerance tests in diabetic dogs were obtained during basal rate insulin infusions in restrained animals by use of extracorporeal infusion pumps and in conscious, unrestrained animals by means of implanted infusion pumps. Even better regulation of blood glucose in diabetic animals was obtained by the addition of predetermined pulses of insulin at higher flow rates than the basal flow rate, accomplished by use of a transcutaneously activated valve mechanism attached to the implanted infusion pump. We conclude that near-normal blood glucose concentrations can be maintained throughout the day in the dog by these means and that similar approaches, using implantable infusion pumps, in man may lead to better long-term control of diabetes than is currently available.

A totally implantable drug infusion defice: laboratory and clinical experience using a model with single flow rate and new design for modulated insulin infusion.

The Infusaid implantable infusion pump with a single delivery rate has maintained chronic intravenous heparin infusion in man for greater than 35 mo and for greater than 5 yr in the dog. Intra-arterial infuson of fluorodeoxyuridine has been maintained for greater than 8 mo in man. In a pilot study using a commercially available, transcutaneously controllable, magnetically activated valve for baseline superimposed bolus insulin infusion, the feasibility of maintaining near normal serum glucose in diabetic dogs was demonstrated. The effect of long-term intravenous cannulation was investigated; it was found that the intimal tissues of the vena cava surrounding the cannulae were largely unaltered and microemboli could not be detected in the lungs of the animals studied. Cannula plugging, which occurred on several occasions due to thrombus formation in the final centimeter of the cannula, has been solved by changes in pump design and refilling procedures. The problem of insulin precipitation in flow passages of the pump remains unsolved, but there are indications that substances entering the cannula from the blood may be involved. A new pump design for modulated insulin infusion is described.

A new peritoneovenous shunt.

For today's most common peritoneovenous shunt catheters, the high incidence of complications (disseminated intravascular coagulation [DIC], pulmonary problems, clotting of the intravascular end, and shunt kinking) results in limited use. We have designed a new peritoneovenous shunt catheter in which we improved mechanical biocompatibility with respect to both the peritoneum and the vasculature. The device consists of: a multimicroorifice ascites filter in a double-chambered collecting device, a tubular compression pump with an intratubular check-valve, and a check-valve catheter at the intravascular end for positive exclusion of blood by reflux or back diffusion. This configuration filters the proteinaceous material from the ascites fluid, transports the filtrate into the blood stream, maintains patency, act to prevent DIC by inhibiting the creation and transport of microthrombi into the cardiovascular system, and eliminates clot formation at the intravascular end.

The spring-driven implantable pump. A low-cost alternative.

In the current era of cost containment in medicine, manufacturing economics have become increasingly important. The authors devised an implantable pump powered by spring force from an elastomeric Belleville washer, which is also the outer flexible wall of the drug reservoir. Use of formed and injection molded parts provides for low-cost manufacturing, in contrast to the precision welded alternative designs. Additional advantages include insensitivity to changes in ambient temperature and pressure. Finite element modeling of the elastomer spring allows prediction of the effects of parameter changes on performance, so that expansions and reductions of scale can be made without compromising the uniform spring rate of the device. A concern that subcutaneous fibrous encapsulation might markedly alter reservoir pressure was not supported by experimental data. In a unit implanted subcutaneously in a dog, reservoir pressures measured over a 4 year period were stable. This new, simple, implantable infusion pump can serve as an economical vehicle for prolonged parenteral drug treatment of ambulatory subjects in circumstances where continuous single-rate infusion is appropriate.

A peritoneovenous shunt with an access port enables non surgical reversal of intraperitoneal catheter occlusion.

Management of chronic peritoneal ascites by transfer of the fluid to the right atrium via peritoneovenous shunt (PVS) is often complicated by occlusion of the peritoneal catheter by one, or a combination, of the following: 1) omental plugging of drain holes, 2) fibrin obstruction of the lumen, and 3) encapsulation of the peritoneal segment by a cocoon. A PVS design that includes an access port facilitates the reversal of fibrin obstruction by urokinase. Eight dogs with implanted PVS were tested weekly for patency (indicated by the flow rate of saline into the peritoneum via the access port) and performance (indicated by the percent transfer of saline from the peritoneum to the vasculature). In 256 test sessions performed to date, 15 catheter occlusions occurred. Nine of these were reversed by one or two flushes with 5,000 units of urokinase via the access port. The remaining six were found to be occluded by cocoons (two), omentum (three), and fibrin (one). Although it is an effective treatment for ascites, the PVS is not in common use, because it has a relatively high occlusion rate. The access port and other features of the authors' PVS are designed to reduce the incidence of PVS occlusion.

Portable data acquisition and control apparatus for implanted drug infusion pump interrogation.

Now that implantable drug infusion pumps are well established clinically, methods for diagnosing suspected pump failures are needed. The authors previously constructed a benchtop data acquisition and control apparatus to assist our work in developing new pump technology. Although this device is technically capable of in vivo pump monitoring, it is cumbersome. Thus, they recently created a portable interrogation unit with more limited features. This portable pump interrogation apparatus consists of a 32 bit MS-DOS labtop computer, data acquisition software, an analog/ASCII interface, a pressure transducer, and appropriate fluid conduits. Communication between the device and the implanted pump is via a percutaneous needle puncture of the drug reservoir refill septum. This procedure is identical to that employed in a standard pump refill. Pump performance is evaluated by incrementally filling the pump reservoir while simultaneously measuring reservoir pressure. The resulting data are presented on the computer screen as a plot of pressure versus volume that quickly and simply either eliminates or confirms the reservoir pressure source as a failure mode. Diagnostic runs are saved on file for archival purposes. Their benchtop apparatus has been a valuable and reliable tool over many years of use. The authors believe that their portable apparatus will be equally beneficial.

Advances and new concepts in the designing of peritoneovenous shunts for the treatment of refractory ascites.

From August 1984 to December 1987, 10 patients received the Minnesota peritoneovenous shunt at our institution. Four of these patients previously had received seven Denver catheters with clinical and/or radiologic evidence of malfunction. Eight patients had the diagnosis of benign intractable ascites and two malignant ascites. In two hypercoagulable patients re-exploration of the intravascular limbs was necessary for fibrin plugging, but in no case have we seen catheter tip blood clot thrombosis. One shunt failed to work properly because of adhesions. At present, six of these patients are alive with a functioning shunt and four have died of nonshunt-related complications. The longest period of continuous function with a Minnesota shunt was 100 weeks. Data from this trial are compared retrospectively with data from patients who received LeVeen (n = 8) or Denver shunts (n = 7) at the University of Minnesota Hospitals during the same time period. Performance of the Minnesota shunt was comparable to the commercially available LeVeen and Denver shunts in most respects and appeared to offer advantages in longer functional life and reduction of intensive care unit admissions.

In vitro and in vivo testing of a new valved intravascular catheter design.

Long-term intravascular catheterization carries a finite risk of catheter occlusion. A catheter tip valve design is presented (Buchwald-Wigness, Strato Medical Corporation, Beverly, MA) which incorporates features designed to decrease the risk of thromboembolism and reduce the need for maintenance procedures. Aspiration and infusion are controlled by separate valves, making it possible to engineer optimized inlet and outlet parameters. The outlet valve is an elastic sleeve expanded around the sidewall outlet ports which opens under injection pressure. The inlet valve is a tubular elastic element compressed against the inlet port from within the lumen, opening under aspiration pressure. A series of valves were prototyped with outlet pressures ranging from 2 to 100" H2O, and inlet pressures ranging from -40-70" H2O, and flowrates at 36" H2O of greater than 1,400 ml/hr. Dog implants of two prototypes with outlet valve pressures of 10" H2O, and inlet pressures of -40" H2O, demonstrated that dormant periods of up to 7.5 weeks could be achieved without detectable blood cell entry into the lumen. No significant hemolysis was observed in blood samples aspirated with a 6 cc syringe (8% scored "slightly hemolyzed" vs. 44% with the nonvalved controls) indicating that a hemodialysis application is likely.

An implantable pump for long-term intravascular drug infusion.

A totally implantable infusion pump has been developed that can provide chronic, continuous, low-rate drug infusions in ambulatory patients. The device relies on vapor pressure for its power source, and thus needs no recharging other than periodic drug refills. It is implanted surgically under the skin of the chest or abdomen, with the delivery cannula placed in an appropriate blood vessel. Pumps implanted in this way have delivered heparin, 5-fluorodeoxyuridine, or other drugs in patients; some outpatients have received continuous intravenous heparin infusions for more than 4 years.

Macromolecule analysis based on electrophoretic mobility in air: globular proteins.

Globular proteins ranging in molecular mass from 5.7 to 669 kDa were separated and analyzed using an aerosol technique based on the electrophoretic mobility of singly-charged molecular ions in air. The ions were produced by electrospraying and drying 100-nm-diameter droplets of a liquid suspension of the proteins, using ionized air to remove the droplet charge due to the spray process. The electrophoretic mobility was measured using a modified commercial continuous-flow differential mobility analyzer operated near atmospheric pressure. An unmodified commercial condensation particle counter was used for detection. The concentrations analyzed ranged from 0.02 to 200 µg of protein/mL of buffer, with a liquid sample flow rate of approximately 50 nL/min. Sampling time of 3 min was used for each complete distribution measured. The electrophoretic mobilities measured were determined entirely from air flow rates, apparatus geometry, and applied potentials. Results were expressed as electrophoretic mobility equivalent diameters using a Millikan formula.

DNA analysis using an electrospray scanning mobility particle sizer.

A scanning mobility particle sizer (SMPS) allows size separation of gas phase particles according to their electrophoretic mobilities. The addition of an electrospray source (ES) recently allowed extension of SMPS analysis to the macromolecular range. We demonstrate here the application of ES-SMPS to nucleic acids analysis. Single- and double-stranded DNA molecules ranging from 6.1 kDa (single-stranded DNA 20 nucleotides in length) to 300 kDa (500 base-pair double-stranded DNA) were separated and detected by ES-SMPS at the picomole to femtomole levels. The measured electrophoretic mobility diameters were found to correlate with the analytes' molecular weights, while the peak areas could yield quantitative information. No fragmentation of DNA was observed under the conditions employed. Different apparent densities were observed for single-stranded and double-stranded DNAs, showing a different behavior for each type of biomolecule. The total analysis time was about 3 min/spectrum. Further optimization of ES-SMPS is expected to make it a fast and sensitive technique for biopolymer characterization.

Electrospray-condensation particle counter: a molecule-counting LC detector for macromolecules.

A new detector for macromolecular separations is described. The detector counts individual macromolecules (molecular weights greater than about 10,000) and reports counts per second. The chromatographic effluent is electrosprayed, neutralized, and swept to the detector by a stream of air. The detector is a condensation particle counter that detects individual particles by light scattering from droplets condensed on the particles. When used as the detector for a size exclusion separation of proteins, the detector has a linear range of 4 orders of magnitude with detection limits as low as 0.1 microgram/mL. The detector can be directly interfaced (no makeup flow) with effluent flows as low as 10 nL/min. A Monte Carlo model based on size measurements of the electrosprayed droplets correctly predicts the observed detector behavior.

Restoration and maintenance of intravenous insulin infusion in the vapor-pressure powered implantable infusion device.

Of the reasons to discontinue continuous implantable insulin pump therapy, flow rate reduction is the most common, occurring in 27 of 42 pumps in the University of Minnesota series. Thrombosis at the catheter tip appears to be a major reason for flow reduction. Six different procedures to restore flow in pumps were performed. Two of the procedures involve the infusion of an alkaline solution through the device, replacing the insulin/glycerol solution normally infused; the other four procedures are surgical ones involving manipulation of the catheter. In restoring flow the non-operative procedures achieved a success rate of 50%, having taken as long as 3 months to restore flow, and having allowed up to 1 year of further insulin pump therapy; flow in all the pumps so treated eventually decreased again. The operative procedures were nearly 100% successful, restored flow immediately, and allowed longer periods of adequate flow, but flow rate did again decrease. When flow rate reduction occurs further flow improvement procedures may be attempted without difficulty and are well tolerated. In implantable pumps the biocompatibility of the blood-catheter tip interface needs to be improved to deal with the recurrent problems of insulin infusion device flow rate decrease.

Catheter with an anchoring tip for chronic joint capsule perfusion.

An orthopedic catheter for long-term access to the synovial joint is anchored by a hollow threaded tap that penetrates the capsule through a hole drilled in the surrounding bone. The proximal end of the catheter is connected to either an implantable drug infusion pump or an implantable access port for continuous or intermittent perfusion or sampling. Four catheters were evaluated in dogs. Three were attached to ports, the fourth to a pump. Water (one trial, 22 weeks) and hyaluronic acid (HA) (5 mg/ml; two trials of 8 weeks each) were administered through ports twice weekly in 1.5 ml boluses; 5 mg/ml HA was delivered by pump (1 trial of 33 weeks) at 0.31 ml/day.

The use of an implantable insulin pump in the treatment of type II diabetes.

We treated five patients with Type II diabetes by means of a subcutaneously implanted intravenous insulin pump and compared their metabolic response with that observed during conventional insulin therapy. The use of the pump improved control of glycemia, as manifested by reductions in mean plasma glucose (from 188 +/- 46 to 106 +/- 12 mg per deciliter [mean +/- S.D.]), fasting glucose (from 187 +/- 42 to 80 +/- 13 mg per deciliter), and postprandial glucose (from 287 +/- 74 to 182 +/- 29 mg per deciliter), together with a diminution of glycemic excursion and normalization of glycosylated hemoglobin A1 (from 12.1 +/- 2 to 8.0 +/- 1 per cent). At the end of the study the pumps had been in place for a mean of 7.0 months (range, 5.5 to 9.7 months) without mishap and with good patient acceptance. Our data suggest that improved blood glucose control can be achieved by means of a permanently implanted continuous insulin-infusion device in ambulatory patients with Type II diabetes who require insulin, and that the need for daily insulin injections can thereby be eliminated.