Implantable infusion pumps for drug delivery in man: theoretical and practical considerations.
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Biomedical subjects
Publications and source records attributed to T D Rohde.
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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.
Diabetes mellitus with resistance to insulin administered subcutaneously or intramuscularly (DRIASM) is a rare and brittle form of Type I diabetes, found predominantly in young females and characterized by inadequate glycemic response to subcutaneous or intramuscular insulin administration. DRIASM leads to frequent ketoacidosis and obligatory hospitalization for administration of intravenous insulin. The use of a totally implantable infusion pump effected dramatic improvement in the treatment of five patients with this difficult form of diabetes. Frequency of clinical ketoacidosis was reduced from 37 episodes per year to 0.4 episodes per year (99%), and average in-hospital days per month were reduced from 20.8 days to 2.2 days (89%) with a mean follow-up period of 14.4 months. Cost savings were approximately +10,000 per patient month. Quality of life was greatly improved for these individuals.
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We studied lipid profiles in 10 patients with insulin-requiring type II diabetes. Patients began the study under conventional subcutaneous insulin injection therapy. Treatment was then optimized on subcutaneous therapy and finally converted to continuous intravenous therapy from a single flow rate implantable pump. Pump management proved reliable and safe. Implantable pump therapy showed a statistically significant reduction in the average plasma cholesterol level from 205.7 to 184.7 mg/dl. The mean low-density lipoproteins (LDL)-cholesterol level decreased from 114.6 to 108.1 mg/dl, the high-density lipoproteins (HDL)-cholesterol average changed from 50.6 to 51.0 mg/dl, and the HDL/LDL ratio increased from 0.478 to 0.500. Glycemic control did not improve on single-rate intravenous therapy compared with intensive conventional subcutaneous injection during the short observation period. The authors conclude that additional studies should be performed to confirm the improvement in the lipid profile on intravenous pump therapy.
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We examined tissues of seven non-diabetic mongrel dogs and four diabetic beagle dogs treated with constant insulin infusion via totally implantable pumps for from 210 to 880 days. Kidney and skeletal muscle tissue from all dogs were stained with Congo Red and thioflavin-T and appropriately examined. Kidney tissues from the beagle dogs were examined by electron microscopy. No amyloid deposits were found in any of these tissues. Thus, we cannot confirm an earlier report of amyloid occurring in dogs given long-term intravenous insulin. It is concluded that amyloidosis is not a necessary complication of long-term intravenous insulin infusion in dogs.
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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.
Carefully age-matched, purebred male beagle dogs that underwent uninephrectomy one month after they were made diabetic with alloxan were used to establish a model of rapidly developing diabetic nephropathy in a large animal. The diabetic animals, all requiring insulin, were divided into two groups: one group with control by insulin injections permitting elevated fasting and postprandial serum glucose values and substantial glycosuria; the other with better control and with near-normal serum glucose levels and less glycosuria. By 1 year of diabetes both diabetic groups had renal lesions different from the uninephrectomized control animals but differing only slightly from one another. With light microscopy, diabetic dogs had increased mesangial thickening. With electron microscopic morphometry, glomeruli of diabetic subjects demonstrated increased fractional volumes of the total mesangium and of its cellular and matrix components and increased width of the GBM. These quantitative measures of diabetic nephropathy in the dog within 1 year of onset of the disease describe a model potentially useful in evaluating the efficacy of improved diabetic control in preventing or ameliorating diabetic nephropathy.
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Venous injection of alloxan monohydrate is a standard method to produce a canine model of diabetes. Others have reported mortalities greater than 45 per cent and yields of diabetic dogs of less than 36 per cent with this technique. In this study, a new method for alloxan diabetogenesis is reported upon: alloxan monohydrate is injected intravenously with protection of the renal arteries at the time of injection by a 7F, triple lumen double balloon catheter placed in the abdominal aorta. The balloons are inflated under fluoroscopic control to occlude the renal arteries at the time of injection. Forty-three age-matched beagle dogs were initially injected with 60 milligrams per kilogram of alloxan monohydrate: 26 or 61 per cent became diabetic-defined as persistently doubled fasting serum glucose and glucosuria; ten failed to become diabetic, 23 per cent, and seven died, 16 per cent. The ten initial failures were reinjected with 65 milligrams per kilogram of alloxan monohydrate: six or 60 per cent then became diabetic, three were persistent failures, 30 per cent, and one dog died, 10 per cent. Thus, the over-all yield of diabetic dogs was 74 per cent, with an 18 per cent mortality. Minimal renal damage occurred, as evidenced by creatinine clearance, blood urea nitrogen and renal biopsy studies. These results suggest a significantly improved method--a twofold improvement over standard success rates with a twofold less mortality--of producing diabetic dogs by alloxan injection.
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