Insulin pump therapy: Indication - Method - Technology 9783110853513, 9783110122657

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Austenat • Stahl Insulin Pump Therapy

Elke Austenat • Tilman Stahl

Insulin Pump Therapy Indication — Method — Technology

With the assistance of Pia Magdalena Heinze Erich Lange Margrit Reinhold Translated by Richard G. Carpenter

w Walter de Gruyter DE

G Berlin • New York 1990

This book contains 77 illustrations and 34 tables Library of Congress Cataloging-in-Publication

Data

Austenat, Elke: [Insulinpumpentherapie. English] Insulin pump therapy : indication, method, technology, acceptance / Elke Austenat, Tilman Stahl; with the assistance of Pia Magdalena Heinze, Erich Lange, Margrit Reinhold ; translated by Richard G. Carpenter, p. cm. Translation of: Insulinpumpentherapie. ISBN 0-89925-630-9 (U.S.) 1. Insulin pumps. I. Stahl, Tilman, 1952. II. Title. [DNLM: 1. Diabetes Mellitus - therapy. 2. Insulin Infusion Systems. WK 820 A9341] RC661.I63A9613 1990 90-271 616.4'6206 — dc20 CIP

CIP-Titelaufnahme der Deutschen Bibliothek Austenat, Elke: Insulin Pump Therapy : indication — method — technology — acceptance / Elke Austenat ; Tilman Stahl. With the assistance of Pia Magdalena Heinze . . . Transi, by Richard G. Carpenter. - Berlin ; New York : de Gruyter, 1990 Dt. Ausg. u. d. T.: Austenat, Elke: Insulinpumpentherapie ISBN 3-11-012265-0 NE: Stahl, Tilman:

© Copyright 1990 by Walter de Gruyter & Co., Berlin 30. All rights reserved, including those of translation into foreign languages. No part of this book may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publisher. Medical science is constantly developing. Research and clinical experience expand our knowledge, especially with regard to treatment and medication. For dosages and applications mentioned in this work, the reader may rely on the authors, editors and publishers having taken great pains to ensure that these indications reflect the standard of knowledge at the time this work was completed. Nevertheless, all users are requested to check the package leaflet of the medication, in order to determine for themselves whether the recommendations given for the dosages or the likely contraindications differ from those given in this book. This is especially true for medication which is seldom used or has recently been put on the market and for medication whose application has been restricted by the German Ministry of Health. The quotation of registered names, trade names, trade marks, etc. in this copy does not imply, even in the absence of a specific statement that such names are exempt from laws and regulations protecting trade marks, etc. and therefore free for general use. Typesetting: Arthur Collignon GmbH, Berlin. - Printing: Gerike GmbH, Berlin. — Binding: Dieter Mikolai, Berlin. - Cover design: R. Hiibler, Berlin. — Printed in Germany.

This book is dedicated to my niece Julia, for all of those who must learn to live with diabetes. Elke Austenat

Dr. med. Elke Austenat Leitende Ärztin der Diabetes-Nachtklinik Dudenstraße 6, D-1000 Berlin 61 Pia Magdalena Heinze Ärztin Fachbereich Inneres Krankenhaus Bethesda Akademisches Lehrkrankenhaus Euelsbruchstraße, D-5905 Freudenberg Dr. med. Tilman Stahl f

Dr. med. Erich Lange Chefarzt Fachbereich Chirurgie Krankenhaus Bethesda Akademisches Lehrkrankenhaus Euelsbruchstraße, D-5905 Freudenberg Dipl.-Psych. Margit Reinhold Diabetes-Nachtklinik Dudenstraße 6, D-1000 Berlin 61

Preface

In the course of writing this book Dr. Tilman Stahl passed away, suddenly and unexpectedly, at the age of 36. Diabetology meant more than a simple specialization to him; it was the center of his professional and personal life. He started in the Department of Internal Medicine at the Bethesda Hospital in Freudenberg in 1984. There he established a diabetic schooling and treatment center which soon became known throughout the country. He was absolutely dedicated to the patient. His goal was to create an optimal individually-feasible behavioral and therapeutic concept for each patient. His untimely death deeply affected all of us. We would like to express our gratitude, in the name of Dr. Stahl as well, to the personnel of Station 1 and the laboratory of Bethesda Hospital and Angelika Meier, dietary assistant at the hospital, my medical-technical assistant Ute Hegenbarth and all of the personnel at the Diabetes-Nachtklinik, Berlin. I would also like to thank my assistant Markus Rottmann for his untiring efforts on the, hopefully practice-oriented, style of the book. Furthermore, we would especially like to thank Dr. Dieter Schäfer of Hoechst for the quick and complication-free creation of the graphs. March 1990

Elke Austenat

Contents

1

Introduction

1

2 2.1 2.2 2.2.1 2.2.2 2.3

Goal of diabetic therapy Insulin secretion in healthy subjects The present state of insulin substitution procedures Discontinuous insulin therapy procedures Continuous insulin therapy procedures Comparison of insulin replacement procedures

2 4 6 7 10 10

3 3.1 3.1.1 3.1.2 3.2 3.2.1 3.2.2 3.2.3 3.2.3.1 3.2.3.2 3.2.4

Insulin p u m p therapy Theory und practice Closed loop system Open loop system Insulin pump models — similarities and differences Drive and technical properties Alarm system (security) Basal rate delivery Simple (constant) basal rate pumps Insulin pumps with programmable basal rate Differentiation of the bolus delivery according to the insulin pump

13 13 13 13 15 15 20 21 21 21 31

4 4.1 4.2

Insulin p u m p accessories Catheter material Plaster material

34 34 38

5

Insulin selection

40

6 6.1 6.2 6.3

Prerequisites for insulin p u m p therapy Requirements on the medical team Requirements on the patient Importance of blood sugar determination in insulin pump treatment

42 42 42 44

7

T h e diabetes education for the p u m p patient

49

x

Contents

8

Application procedures in insulin pump therapy

52

8.1 8.1.1 8.1.2 8.2 8.3 8.4 8.4.1 8.4.2

52 53 54 57 60 65 65

8.4.3 8.4.3.1 8.4.3.2 8.4.3.3 8.5 8.5.1 8.5.1.1 8.5.1.2 8.5.1.3

Continuous intravenous insulin infusion (CIVII) Temporary intravenous insulin infusion Long-term intravenous insulin infusion Continuous intramuscular application Continuous insulin application with a dacron felt cuff Continuous intraperitoneal insulin infusion (CIPII) Operative techniques Special features of the pump and insulin selection, rinsing techniques and documentation Freudenberg-Berlin CIPII study Patient data Results Conclusions for indications and contraindications of CIPII Continuous subcutaneous insulin infusion (CSII) Berlin-Freudenberg CSII study Patient data Results Indications and contraindications of CSII

73 74 74 76 84 86 87 88 90 Ill

9

The state of implantable insulin pump therapy

115

10

Special situations in insulin pump therapy

119

10.1 10.2 10.3 10.4 10.5 10.6 10.7 10.8

Physical labor and school Strenuous physical activity Insulin pump therapy in children Insulin pump therapy during vacation Insulin pump therapy and time-shifts Insulin pump therapy and illness Insulin pumps and sexuality Insulin pump treatment during pregnancy

119 120 123 124 127 128 128 129

11

Loss of motivation

137

11.1 11.2 11.2.1 11.2.1.1 11.2.1.2 11.3

Different types of motivational losses Influences on the loss of motivation Necessity of psychological-medical teamwork Crisis intervention Group therapy Insulin pump withdrawal

139 141 141 141 142 143

12

The importance of ketoacidosis in insulin pump therapy 145

12.1 12.2

Pathophysiology and etiology of the ketoacidosis Step-by-step plan for the control of the ketoacidosis

146 147

Contents

xi

13

N u t r i t i o n tables

151

13.1 13.2 13.3 13.4

Basis of dietary calculations Flexibility in food intake Potential liberties in eating habits Injection-meal interval

151 152 153 156

14

Patient case reports

158

15

T h e future o f the insulin p u m p t h e r a p y

166

1 Introduction

T h e number of secondary complications in Type I diabetics being treated with normal insulin replacement procedures is constantly increasing. The same holds true for Type II patients. This fact is forcing us to reconsider the success of diabetological standard therapy under the aspect of the absolute imperative of normoglycemic metabolic adjustment in normal insulin concentration. We know that this therapeutic requirement can only be realized by means of a "closed loop" — the continuous insulin infusion with a glucose sensor attached. However, as long as this closed loop system is not available for daily use, it would appear reasonable to employ a therapeutic system which comes closest to fulfilling the requirements mentioned above. The insulin pump therapy offers the possibility of continuous insulin infusion, but as an "open loop" system. This procedure more nearly meets the physiological requirements than any other form of insulin therapy. Nevertheless, the number of people using an insulin pump is small in relation to the total number of diabetics. Our intention therefore, in writing this book is to increase the awareness of this therapeutic method and reduce the amount of apprehension towards it by evaluating the undeniable, but influenceable risks. Ultimately, of course, it is our desire to improve the condition of diabetic patients affected by extending the use of this therapy. It is our hope that this book will be of interest not only to the diabetologist, but for all practicing physicians and clinicians who are searching for improved methods of treating their diabetic patients. The insulin pump therapy should not be viewed as the last resort, to be applied only at the point of no return, at the onset of late complications. On the contrary, it represents the most effective means available for delaying that stage of the disease. The authors

2 Goal of diabetic therapy

The goal should be the avoidability of the disease. In the case of Type II diabetes mellitus (Non-Insulin-Dependent Diabetes mellitus = NIDDM) the approach is clearly defined. If the diabetes has clinically manifested itself, the first step is a reduction of weight, followed by physical exercise. Only then should medicinal treatment take place. The situation is somewhat different in the case of Type I diabetes (InsulinDependent Diabetes mellitus = IDDM). In most cases, its manifestation is the result of the selective deterioration of the islets of Langerhans [4,9,13,17,21]. Delaying this inflammatory process is the present goal of research. This delaying action was performed for some time to a limited extent with substances such as cyclosporine [6,24], This therapy, however, was proven to be accompanied by serious side effects. In addition, a renewed deterioration of the metabolism occurred when the medication was discontinued. Other test substances are still in the basic research stage, so at present it is not possible to classify the desired prevention of Type I diabetes as practically as in the therapy of the IDDM.

Objective of Normoglycemic

treatment:

metabolic for

control

a

High quality of life, u n b u r d e n e d late c o m p l i c a t i o n s

by

B y m e a n s of

Flexible

Knowledge

iviguviruuii Fig. 1

Aim of diabetes therapy

insulin

therapy

2 G o a l of diabetic therapy

3

The present possibilities available in the symptomatic insulin replacement therapy should therefore be oriented on the therapeutic goal (fig. 1) of insulin treatment. An active life, free of late complications, demands that the physician does not establish age limits for therapeutical efforts. Increased blood glucose levels alone do not cause either pain or impairment of the general well-being. They do however, dependant on metabolic quality [19] and the duration of the diabetes — independent of age — effect the incidence of vascular secondary complications, which are two to three times higher than that of the non-diabetic population [8, 14]. Figures 2a and 2b show the microangiopathic changes in the retinal area of elderly patients and the results of a microangiopathy in a younger patient. It is frequently postulated, particularly in the case of the elderly or Type II diabetic, that the patient's own assessment of their condition can be used as a main

Fig. 2 a

A d v a n c e d b a c k g r o u n d - r e t i n o p a t h y in a 61 year old patient w i t h Type II diabetes mellitus (diabetes since 1967). O r a l antidiabetics f o r t h e last 10 years. D o s a g e in t h e last m o n t h s b e f o r e switching t o insulin — m o r n i n g s 10 m g a n d evenings 7.5 mg Glibenclamid®

4

Fig. 2 b

2 Goal of diabetic therapy

State after amputation of the III to V toes including the metatarsal bones with a month-long healing disorder in a 30 year old patient with Type I diabetes mellitus (diabetes since 1974). Therapy since manifestation with conventional insulin therapy (2 injections/die). Amputation 1987

parameter or measure for the "quality" of the metabolic state. This is not true for either the 18-year old or the 65-year old patient. It is not possible to obtain normoglycemic values for every patient. In the case of the elderly, with the increasing rigidity of the vessels (macroangiopathy and hypoglycemia = risk of acute secondary complications such as apoplexy, coronary infarction) it is not even recommendable. This problem also exists in the case of younger patients who show signs of microangiopathic and macroangiopathic changes as a result of long-term metabolic compensation. If the metabolic optimum of the normoglycemic stabilization cannot be obtained or is not recommendable, an attempt should be made to attain a metabolic stabilization near to the norm. Continuous blood glucose values of over 200 mg/ dl (11 mmol/1) must be avoided in any case.

2.1 Insulin secretion in healthy subjects It may sound like a truism to say that only non-diabetics do not suffer under any specific diabetic life-threatening acute or impairing, life-shortening secondary complications.

2 . 1 I n s u l i n s e c r e t i o n in h e a l t h y s u b j e c t s

5

T h e following questions must therefore be answered; 1. What is the range of the blood glucose level in healthy persons? 2. Which regulatory mechanisms of the insulin effects guarantee the glucose homeostasis in healthy persons? 3. Which factors promote or inhibit insulin secretion? Thus far, only the first question has been clarified. As studies on healthy persons and with the glucose stress test have proven [12,13,15,16,18,19,20,22], the blood glucose ranges between 50 and 100 mg/dl (2.78 — 5.55 mmol/1). Short-term increases up to a maximum of 140 mg/dl (7.77 mmol/1) following intake of large quantities of carbohydrates and low values of down to 30 mg/dl (1.67 mmol/1) after fasting have been observed without pathological changes. Kinetic studies under experimental conditions [10,20,23] have proven that there is a continuous basal secretion which increases in peaks during food intake (fig. 3). The general mechanisms of the glucose homeostasis have been clarified. The actual level of the blood sugar in the healthy person is determined by the enteral glucose absorption, the glycog e n o s i s and the gluconeogenesis in the liver and kidneys. The liver plays the most important part. Varying amounts of glucose are supplied to the liver, it stores Blood g l u c o s e [mmol/I J Blood glucose Insulin secretion max.

7.00

(HO)

Serum insulin concentration 100 jAll/ml

"Hypothetical " normal range of the blood g l u c o s e

min.

2.001.67

Acute illness Food intake Physical rest Hormone secretion (e.g. Cortisol, catecholamine, somatostatine. etc.) Stress

Hunger Alcohol Physical activity Acute illness ?? ?

79?

Fig. 3

S c h e m e o f t h e b l o o d g l u c o s e r e g u l a t i o n in m e t a b o l i c a l l y h e a l t h y p e r s o n s a n d p o s s i b l e disturbances

6

2 Goal of diabetic therapy

them as glycogen and provides a glucose concentration in the blood which remains within a very limited range. T h e blood sugar level is also determined by adrenergic factors, sometimes called stress factors (illness, work, exercise). Adrenaline, glucagon, glucocorticoids, S T H and thyroxine are insulin antagonists. These hormones help control the glucose level and, together with insulin, form a finelytuned regulatory mechanism. T h e fluctuations in the individual basal insulin secretion due to endogenous (endocrine secretion of insulin antagonists) or exogenous influences (e.g. stress situations, changes in living conditions) in the course of 24 hours, or even over months, have not yet been clarified. It is interesting to note that the insulin secretion of non-diabetics also fluctuates greatly in a fasting state. Davidson reported fasting peripheral serum insulin levels of 4 — 2 4 |iIU/ml [3]. Studies of this are therefore of great clinical interest, as long as there is no "closed l o o p " system available. T h e punctual basal rate insulin adjustment (rigid or individually determined) in a 24-hour period is extremely important for long-term metabolic compensation in the open loop system. We can therefore say: — there are only slight fluctuations of the blood glucose homeostasis in nondiabetics; — insulin is continuously secreted in healthy subjects; — standardized experimental conditions prove that even in the fasting state there are individual fluctuations of the serum insulin.

2.2 The present state of insulin substitution procedures By mentioning the regulation of the glucose metabolism in healthy persons' functions, it is clear that the blood glucose level represents the primacy of the continuously secreted insulin. In contrast to that, exogenously applied insulin represents the primacy in all of the presently practiced insulin therapeutic methods. T h e effect on the blood glucose level is secondary, depending on the amount of insulin, the kinetics of the insulin chosen, the site of application, the tissue properties and immunological factors. According to theoretical knowledge this inversion of the cause and effect relationship can only be remedied by an artificial Beta cell in the "closed l o o p " system [7]. If one looks at the names of the insulin therapy procedures and the kinetics of the types of insulin selected, there is no connection between the majority of them and the knowledge of the continuous insulin secretion as found in the healthy metabolism. It has been proven in comparative studies that this might be important for preventing late complications (see chapter 2.3).

2.2 The present state of insulin substitution procedures

7

The representation of the therapeutic procedure must therefore also offer information about the continuity, or discontinuity, of the insulin application.

2.2.1. Discontinuous insulin therapy procedures Definition: Discontinuous insulin therapy procedures are characterized by the application of insulin in intervals. It is well-known that every exogenously applied insulin has an onset of action and fall-off of action with a verifiable maximum effect. To obtain a repetitive effect, it is necessary to repeat the injections. If the injections cannot be properly timed, it is possible that an insulin accumulation or deficiency will arise. At present there are basically two types of discontinuous therapeutic methods: a) conventional insulin therapy (CT) This form of therapy is defined by a maximum of three insulin injections per day. Only intermediate-acting insulin or various combinations of normal and intermediate-acting/depot insulins are administered. The combination insulins are either mixed freely or commercially available fixed mixtures. However, it is only possible to mix — either freely or as prepared mixtures — insulins of the depot principle of neutral protamine Hagedorn (NPH) with normal insulin. Figure 4 shows the combination possibilities. Depot insulins that are based on the zinc prolongation principle may not be mixed with normal insulin, because the quick effect of the regular insulin is lost when it combines with zinc. b) multiple injections therapy (MIT) This form of therapy consists of more than three injections per day. Beside the insulins used in C T (NPH prolongation principle), there are frequently types of insulin which work according to the zinc prolongation principle (fig. 5). The basis bolus concept (BBC) with Ultratard HM®, a long-term insulin based on the Lente principle, is unique amongst the discontinuous insulin therapy procedures. The philosophy of this insulin therapy is more closely connected to the continuous insulin therapy procedures. The application consists of a bedtime basal-insulin injection and preprandial normal insulin injection, due to the Ultratard HM® having an average efficacy of 24 hours. For the sake of clarity, however, it must be emphasized that this method must be classified as a discontinuous form of therapy. Middle-range observations of the development of the disease have shown that there are limits for this therapeutic procedure, e.g. in the case of the dawn phenomenon (extremely high blood sugar fluctuations in the early morning hours) [1].

8

2 Goal of diabetic therapy 2 injections per day mornings and evenings pure intermediary insulin

IU

IU

3 injections per day mornings and evenings normal and intermediary insulin in free or determined mixtures, afternoons normal insulin

IU

2 injections per day mornings and evenings normal and intermediary insulin in free or determined mixtures (NPH-depot principle)

3 injections per day mornings and evenings normal and intermediary insulin in free or determined mixtures

IU

Ì

Fig. 4

Ì

Schematic diagram of conventional therapy procedure (CT)

L injections per day mornings, afternoons, evenings, nights normal insulin

IU

f

f

)

J

¿injections per day mornings, afternoons, evenings normal insulin, at night (10 p.m.) intermediary insulin

IU

J \

\ /

t

t t

/

2i

5 injections per day mornings, afternoons, evenings, about U o'clock normal insulin at night (10 p.m.) intermediary insulin

IU

I

t

1 1

L to 5 injections per day before the main meals normal insulin, at night (10 p. m.) long - acting insulin or mornings, evenings, l o n g - a c t i n g insulin (Zn - depot - body)

IU

t

|

|

| — V

\ —

r~ 22

Fig. 5

Schematic diagram of intensive conventional therapy procedure (ICT) or multiple injections therapy (MIT)

2.2 T h e present state of insulin substitution procedures

9

>N o. rt

"i—I—r

"1—r

10

2 Goal of diabetic therapy

2.2.2 Continuous insulin therapy procedures Definition: This form of therapy is characterized by the permanent application of the insulin. Here too, the specific kinetic values of the onset of action and the maximum efficacy are valid. Both parameters are dependent on the amount of insulin applied in a certain period of time (international unit = IU). The permanent application hinders the insulin's fall-off of action. Normal insulin (short, regular) is used in this procedure. It is supplied to the body via a programmable pump system (chapter 3.2). Figure 6 shows some of the various possible ties of basal rates and additionally, the bolus application which can be programmed over a 24-hour period.

2.3 Comparison of insulin replacement procedures Unfortunately, there have only been a few prospective studies which have compared the individual therapeutic procedures with respect to the development or progression of secondary complications [2,5,11,16], Even the most critical interpretation of these medium-range studies would show that insulin pump therapy — continuous subcutaneous insulin infusion ( = CSII) — demonstrates a lower progression of the nephropathy, neuropathy and retinopathy than C T or MIT. For that reason alone it would be recommendable to increase the use of insulin pump therapy. This necessity is additionally emphasized by the reduction of the glycosilated hemoglobins ( H b A j / H b A j J after changing from C T or M I T to insulin pump treatment. We must, however, point out that all of the comparative studies describe the insulin substitution procedures cumulatively. If only the various forms of the M I T are examined — free or prepared mixture of regular insulin with N P H insulins, 4 to 6 injections/day — these cumulative studies can only indicate a tendency. The same holds true for the evaluation of the insulin pump therapy. Unfortunately, the majority of the studies do not offer a detailed description of the type of insulin pump (strict or programmable basal rates for 24 hours) or the route of insulin supply (subcutaneous, intraperitoneal or intravenous). In the end only long-term studies with 15 years with differential descriptions required. Only these, with information insights into the development of late possibility of regression.

an observation period of between 10 of the insulin substitution procedures about concomitant diseases, can offer complications, their progression and

and are real the

Arterial hypertension and hyperlipoproteinemia can serve as examples for interfering diseases which recommend additional medical treatment.

Literature

11

Literature [1] Austenat, E.: Insulintherapie mit dem Basis-Bolus-Konzept. M M W 130 (1988) 76. [2] Dahl-Jorgensen, K., O. Brickmann-Hansen, K. F. Hanssen et al.: Rapid fighthening of blood blucose control leads to transient deterioration in retinopathy in insulindependent diabetes mellitus - T h e Oslo Study. Br. Med. J. 290 (1985) 811. [3] Davidson, J. K.: Insulin therapy. In: Clinical Diabetes Mellitus (Ed. J. K. Davidson), p. 219. Thieme, Stuttgart - New York 1986. [4] Eisenbarth, C. S.: Type I Diabetes, A Chronic Autoimmune Disease. N. Engl. J. Med. 314 (1986) 1 3 6 0 - 1 3 6 8 . [5] Feldt-Rasmussen, B., E. R. Mathiesen, T. Deckert: Effect on the progression of diabetic renal disease during 2 years of strict metabolic control insulin-dependent diabetes. Diabetes 35 (1986) 425 A. [6] Feutren, G., L. Papoz, R. Assan et al: Cyclosporin Increases the Rate and Length of Remissions. In: Insulin Dependent Diabetes of Recent Onset. Lancet 2 (1986) 119 — 124. [7] Fischer, U., E. Jutzi, E.-J. Freys et al.: Derivation and experimental proof of a new algorithm for the artificial B-cell based on the induvidual analysis of the physiological insulin-glucose relationship. Endokrinologie 71 (1978) 65 — 75. [8] Goldberg, S., M . Alex, H. T. Blumenthal: Sequielae of atherosclerosis of the aorta and coronary arteries. A statistical study in diabetes mellitus. Diabetes 7 (1978) 98. [9] Gorsuch, A. N., K. N. Spencer et al.: Evidence for a long prediabetic period in Type I (insulind dependent) diabetes mellitus. Lancet 2 (1981) 1363 — 1365[10] Halter, J. B., R. J. Graff, D. J. Porte: Potentiation of insulin secretary responses by plasma glucose levels in man: evidence that hyperglycaemia in diabetes compensate for impaired glucose potentiation. J. Clin. Endocrinol. Metab. 48 (1979) 946. [11] Hansen, K. F., K. Dahl-Jorgensen, T. Lauritzen et al.: Diabetic control and microvascular complications: the near-normoglycaemic experience. Diabetologia 29 (1986) 677. [12] Haselbeck, M.: Untersuchungen zur Regulation der Blutglucose bei Stoffwechselgesunden und bei Diabetikern, München 1975. [13] Jackson, R., N. Peters, U. Adrani et al.: Forearm glucose uptake during the oral glucose tolerance test in normal subjects. Diabetes 22 (1973) 442. [14] Kannel, W. B., D. L. McGee: Diabetes and glucose tolerance as risk factors for cardiovascular disease: T h e Framingham Study. Diabetes Care 2 (1979) 120. [15] Köberling, J., R. Kattermann, A. Arnold: Follow up of non diabetic relative of diabetics by retesting orol glucose tolerance after 5 years. Diabetologia 11 (1975) 451. [16] Kroc Study Group: Effect of diabetic control on retinopathy. Follow-up report of the Kroc randomized clinical trial. Invest. Ophthalmol. Vi. Sei. (Suppl. 1) 5 (1985) 85. [17] Kuglin, B., J. Bertrams, F. A. Gries et al.: Inselzellantikörper und IgG-Insulinautoantikörper (IgG-IAA) bei Angehörigen von Patienten mit Typ-I-Diabetes. Akt. Endokrin. Stoffw. 8 (Abstract) (1987) 94. [18] Mosenthal, H., E. Barry: Criteria for an interpretation of normal glucose tolerance tests. Ann. Intern. Med. 33 (1950) 1175. [19] Nielsen, N. V., J. Ditzel: Prevalence of Macro- and Microvascular Disease as Related to Glycosylated Hemoglobin in Typ I and II Diabetic Subjects. An Epidemiologic Study in Denmark. In: Macrovascular Disease in Diabetic Mellitus (Eds. H. K. Janka, H. Mehmol, E. Standi), p. 19. Thieme, Stuttgart - N e w York 1985. [20] Owens, D., U. Wragg, J. Briggs et al.: Comparison of the metabolic response to a glucose tolerance test and a standardized test meal in normal healthy subjects. Diabetes Care 2 (1979) 409.

12

2 Goal of diabetic therapy

[21] Riley, W., J. Krischer, D. Clare et al.: Islet cell antibodies: Relative risk (RR) of developing insulin dependent diabetes (IDD) is 166. Diabetes (Suppl. 1) 36 (Abstract) (1987) 70 A. [22] Seltzer, H . S., E. W. Allen, A. L. Herron et al.: Insulin secretion in response to glycemic stimulans: relation of delayed insulin to carbohydrate intolerance in mild diabetes mellitus. J. Clin. Invest. 46 (1967) 323. [23] Suarez, L., E. Barrett-Connor: Seasonal variation of fasting plasma glucose lenks in man. Diabetologia 22 (1982) 250. [24] Stiller, C. R., J. Dupre, M . Gent et al.: Effects of Cyclosporine Immunosuppression in Insulin-Dependent Diabetes Mellitus of Recent Onset. Sei 223 (1984) 1 3 6 2 - 1 3 6 7 .

3 Insulin pump therapy

3.1 Theory and practice The first regulation system which allowed a physiological insulin supply was introduced in the mid 70's. It was the "artificial Beta cell" which had been developed in Germany by a group working with Pfeiffer [16,17] and at the same time a group working with Albisser [1,2]. With the help of this system (Biostator) it became possible to continuously monitor the blood glucose and simultaneously apply the appropriate levels of insulin or glucose or neutral electrolytic solution. The present goal remains, as it was at that time, to reduce the size of this closed loop so that it can be implanted in the diabetic patient.

3.1.1 Closed loop system It was possible with the help of the Biostator to create the closed loop system, but due to its size, the equipment is not suited to extracorporal use under outpatient conditions (fig. 7). This innovation was followed by the enthusiastic search for an implantable glucose sensor [4,23,26]. Thus far, however, it has not been possible to find the correct material which would allow a continuous monitoring of the glucose in vivo. The reasons are multiple; fibrin threads precipitate on the electrodes [3,6,7,25], the implanted material is treated as a foreign body and stimulates immunological reactions which then encase the sensor [19,21]. The site for the measurement of the glucose represents yet another problem. The best suited tissue has not yet been determined. Solutions to these problems are being intensively sought after [5,30]. Nevertheless, the result is that the desired closed loop system is not presently relevant for diabetology.

3.1.2 Open loop system The research into sensors and the continued development of the Biostator was accompanied by the beginnings of the development of portable insulin dosage

14

Fig. 7

3 Insulin pump therapy

Biostator (Pfeiffer et al. [16])

devices [18,24], The first models were quite large and heavy. Only since the beginning of the 80's has it been possible to routinely perform insulin pump therapy with devices which are of acceptable size and weight for the patient. The open loop system lacks the glucose sensor and the glucose donator. This explains why the loop is open. The glucose sensor is replaced by external blood glucose assays, the glucose donator by the correct adjustment of the diet to the blood glucose values. The constant miniaturization of the open loop system has helped this method to gain considerable favor in the treatment of diabetes. By 1988 the number of insulin pump patients had grown to 2,000 in Germany and 15,000 in the USA [13].

3.2 Insulin pump models — similarities and differences

15

3.2 Insulin pump models — similarities and differences A large number of different insulin pump models are available today. The differences consist mainly in the basal rate delivery, energy supply, the size of the reservoir, price and in the size of the pump.

3.2.1 Drive and technical properties Insulin pumps are divided into four different types based upon the mechanisms: a) b) c) d)

roller/peristaltic pumps syringe pumps piston/valve pumps gas pressure pumps.

a) Several cylinders which are attached at right angles to a drive axle compressing a flexible hose and thereby transport the insulin. The best-known model is the

Fig. 8

Promedos E-l (Siemens), the first insulin pump in Germany

16

3 Insulin p u m p therapy

Promedos E l pump from Siemens (fig. 8). The Promedos has been very important in furthering the development of insulin pump therapy. b) The insulin is stored in a syringe-like container and ejected by means of a plunger. This plunger is connected to the motor, either directly (fig. 9) or indirectly by means of a lead screw (fig. 10). c) Pressure is created by a piston which transports the insulin to the patient on one side (outlet valve) and draws it into the chamber from the reservoir on the other side (inlet valve) (fig. 11). d) The gas pressure pump employs the physical properties of the differing aggregation states of fluids or gases under pressure (fig. 12). The most interesting feature of this system is that it functions completely without electricity. From the multitude of insulin pumps on the market, we have selected those which are most commonly used in the German-speaking world. Drive Button Positioned When Loading

Fig. 9

Principle of the syringe p u m p with direct transmission of the m o t o r to the pinion (e.g. Nordisk-Infuser) (Rothwell, 1984) Actuator

Fig. 10

Principle of the syringe p u m p with indirect transmission of the m o t o r via a leadscrew on the pinion (e. g. Betatron-Lilly, Autosyringe-Travenol, MRS-Infuser = H - T r o n H o e c h s t (Rothwell, 1984)

3.2 Insulin pump models — similarities and differences

Outlet Valve

Fig. 11

17

Inlet Valve

Principle of the piston-valve pump (e.g. the implantable PIMS) (Pickup and Rothwell, 1984) INLET SEPTUM NEEDLE STOP OUTLET FLOW RESTRICTOR SIDEPORT

BACTERIAL FILTER

IILICONE ÌUBBER :OATING

SUTURE

NEEDLE CLIP OUTLET CATHETER

Fig. 12

DRUG CHAMBER

BELLOWS

, „CHARGING FLUID CHAMBER

Principle of the gas pressure pump (e. g. the implantable Infusaid) (Infusaid Corporation, N o r w o d d MA./USA)

All are syringe pumps with the exception of the B + D model 1000. The B + D model 1000 is a peristaltic pump. Patients expect the following characteristics from the pump when deciding to undergo insulin pump therapy: 1. An uncomplicated energy supply, which is not necessarily the case in all insulin pumps (tab. 1). 2. The insulin reservoir should be large enough that it need not be refilled every day.

3.2 Insulin p u m p models — similarities a n d differences

19

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Excerpt f r o m a patient's diary

normal o o

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good

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48

6 Prerequisites for insulin p u m p therapy

lower than it is" and " T h e light was too poor for a precise reading" are two popular explanations for incorrect assessments. Such mood-dependent misreadings do not occur in a comparable amount with reflectometer determinations. However, it must be pointed out that both methods must be performed exactly and precisely in the time sequence. Otherwise, incorrect readings will occur. Figure 29 shows an example of the procedure for hemo-glucotest strips. Figure 30 is an example of a patient's diary.

7 The diabetes education for the pump patient

The success of the diabetes therapy depends on the patient's knowledge about the disease and the schooling of the patient with regards to diet and insulin therapy. This has been shown in numerous studies [1,2,3], For that reason, diabetes education programs have become an essential part of the treatment of diabetic patients. The same holds true for the insulin pump user. The following points should be included in the education program of the insulin pump user. 1. Knowledge Unit.

about diet based on the calculation

of the Carbohydrate

Exchange

2. Developing from that the calculation of foodstuffs using the Glycemic Index (GI) As a result of the personal adaptation of the normal insulin before meals and the separation of the preprandially required insulin from the basal insulin, the insulin pump user can enjoy more freedom of choice in foods than with any other type of insulin application. At the same time, new studies have shown that the Carbohydrate Exchange Unit is not sufficient, in and of itself, for the determination of the postprandial increase of the blood glucose (chap. 13). 3. Pathophysiological

correlations

in Diabetes

mellitus

4. The effect of insulin It is not important that the patient have in-depth knowledge about the different insulins on the market. But he must learn about the kinetics, storage and proper handling of a normal insulin and an intermediary insulin provided especially for him. The patient must know that there is no detectable insulin effect after an average of 6 hours after the last injection of regular insulin. Should the insulin pump break down or be intentionally taken off (e.g. on vacation) it is necessary that an injection be given after 6 hours at the latest. It is recommended that the patient be taught an alternative therapeutic regimen and supplied with the necessary materials if desired, especially for vacation. We have found that in such situations the insulin pump tends to be removed more often than therapists thought before, (chap. 10.4). 5. Controlling and avoiding acute complications Insulin pump wearers must be able to recognize, and avoid, not only hypoglycemia, but approaching hyperglycemic precomatose metabolic decompensations as well.

50

7 The diabetes education for the pump patient

6. Teaching self-monitoring techniques The self-monitoring of the blood glucose level is of primary importance for the insulin pump wearer. The patients must be taught to perform reflectometer determinations as well as the visual reading of the test strips. The pump wearers should primarily perform the reflectometer determinations. In addition, insulin pump wearers with a Type I (IDDM) diabetes must be trained in the symptoms of a developing ketoacidotic metabolic decompensation. For that reason, the training must deal with the use of acetone test strips and the correct assessment thereof. Practical exercises in this technique should be performed as a method of testing the patient's comprehension of the technique. 7. Insulin pump training Not only the use and the handling of the pump should be taught, but breakdowns, error analysis and their repair should be repeatedly simulated as well. Furthermore, the patient must learn to properly deal with the catheter and needle materials. This includes knowledge of the length of time that the needle may remain at the injection site (max. 3 days). 8. Testing knowledge Individual centers deal with the testing of the patient's knowledge in different ways. In some, the knowledge is tested in a separate lesson, while others use constant repetition. In the Diabetes-Nachtklinik, Berlin we have a special evening entitled "What would you do in the following situation?". This evening has proven itself to be especially profitable because the patients learn to review both their theoretical and practical knowledge. In addition to these points we should like to emphasize that strict rules for the training have proven to be inappropriate. This special part of the organization must be integrated into the particular pump center. Experience has shown that the future insulin pump wearer should be trained in their own groups, rather than with other patients who undergo another therapy. This is especially true for the subjects of dietary calculation. Here, the insulin pump wearer is less restricted than the patient who is treated with CT, for instance. It has also been shown that testing the individual knowledge at the beginning and again at the end of the training, by means of semi-structured questionnaires pays off [2,3]. Besides objectifying the knowledge, this also allows the training to deal with specific needs of the individual. In conclusion we should like to emphasize the need to offer various training methods for dealing with the different areas of the training. It is not absolutely necessary to deal with all of the subjects during the patient's stay in the hospital. Some of the training subjects can be handled under out-patient conditions. Selfmonitoring is a prime example of such a subject. By training this procedure until pump therapy starts, the acceptance of the self-monitoring can be estimated, and the documentation and indirectly the motivation of the patient can be tested. This

Literature

51

is valid for b a s i c subjects like p a t h o p h y s i o l o g y , acute and s e c o n d a r y c o m p l i c a t i o n s a n d diet, t o o . T h i s p r o c e d u r e a l l o w s shortening of the hospital stay needed for initiation of p u m p therapy, so that this time can be used f o r clarification of individual difficulties.

Literature [1] Assal, J. P., J. Miihlhauser, A. Pernet et al.: Patient education as the basis for diabetes care in clinical practice and research. Diabetologia 28 (1985) 602. [2] Berger, M., U. Jörgens, J . Miihlhauser et al.: Die Bedeutung der Diabetikerschulung der der Therapie des Typ-I-Diabetes. Dtsch. Med. Wochenschr. 108 (1983) 424. [3] Miihlhauser, J., U. Jörgens, M . Berger et al.: Bicentric Evaluation of a Teaching and Treatment Programme for Typ I (Insulin-Dependent) Diabetic Patients: Inprovement of Metabolic Control and Other Methods of Diabetic Care for up to 22 Months. Diabetologia 25 (1983) 470.

8 Application procedures in insulin pump therapy

At present, distinctions are drawn between four different methods of application for the continuous supply of normal insulin. Three of these methods, which share the common aspect of being regularly practiced, will be discussed in the following chapter.

8.1 Continuous intravenous insulin infusion (CIVII) Intravenous application of medication has been a standard medicinal practice for decades. Recompensation and parenteral alimentation of a comatose, dehydrated patient were the most favored methods in diabetology for years. At the same time the gastro-intestinal tract had to be avoided due to possible atony of the tract and the danger of aspiration. T h e intravenous insulin application in coma therapy was for the most part administered in the form of discontinuous — usually high — bolus injections in conjunction with i.m or s.c. insulin application [24]. Only after the discovery by Turner in 1971, that the half-life of intravenously applied insulin is 4 — 5 minutes, did the use of continuous intravenous insulin infusion begin to spread. This was carried out in the form of a so-called "low d o s e " insulin infusion [1,19,21]. This method was chosen because an equally good inhibition of the hepatic gluconeogenesis [5], the lipolysis [35] and the ketogenesis when compared to those of discontinuously applied insulin. Plasma insulin levels of over 40 U/ml are considered to be sufficient [42]. An increased glucose transport in the muscle cells can be observed in plasma insulin levels of over 300 U/ml. However, extremely high plasma insulin levels, such as those proven to result from discontinuous, high-dosage bolus injections, lead to the danger that the blood glucose drops off quickly if left unmonitored. This may in turn result in hypokalemia, in an arrhythmia (due to the increased intracellular potassium immigration) and the development of a dysequilibrium syndrome (brain edema). For that reason, intravenous insulin infusion is understood as continuous application of a low-dose of insulin. In short-term infusion, which is performed today by means of controllable devices (Perfusor), it is necessary to add an either undiluted haemacel solution or 1%

8.1 C o n t i n u o u s i n t r a v e n o u s insulin i n f u s i o n (CIVII)

53

albumin solution [13], so as to avoid the absorption (up to 7 0 % ) of the insulin on the surface of the glass or plastic vessels.

8.1.1 Temporary intravenous insulin infusion Temporary intravenous insulin infusion is the basic form of therapy in the treatment of precomatose or comatose diabetes. It is not however, the definition coma (unconsciousness) which is important for the use of this method, but rather the extent of the secondary biochemical metabolic imbalance. A second, relative indication is the situation wherein metabolic decompensation could lead to vital complications, such as in the case of longer operations (perioperative) or delivery (perinatal). While the first case is a matter of therapeutics, the second is prophylactic and takes advantage of the good control permitted by i.v. insulin infusion to avoid a decompensation. A closed loop system (chap. 3.1.1), in the form of an artificial Beta cell along the lines of the Biostator, would be ideal for both indications. Such a system allows the time frame and the amount of blood glucose to be preprogrammed for the desired blood glucose range. T h e price of these devices is however prohibitive, so that it is not possible that every hospital which treats comatose diabetic patients or every operation room or delivery ward be equipped with a Biostator. Perfusor-controlled insulin infusion is an open loop system. Monitoring of the desired blood glucose levels is performed externally. The following guidelines are employed for the treatment of diabetic coma with insulin substitution: 1. Ketoacidotic precoma — diabetic coma -

Adults

• Initial bolus of 10 IU i.v. (varies according to literature [5,6]) • 0.1 units/kg BW/h as approximate value for an undiluted haemacel solution or 1% albumin solution (fluctuations between 0.01 and 1.0 IU/kg BW/h possible) • Basis of calculation of the IU/hour: 0.5 IU - 10 IU per hour

-

Children

• Initial bolus 0 . 1 - 0 . 2 5 IE i.v. 0.1 units/kg BW/h as approximate value for an undiluted haemacel solution or 1% albumin solution

54

8 Application p r o c e d u r e s in insulin p u m p t h e r a p y

2. Hyperosmolar - nonketoacidotic diabetic coma - Adults

• Initial bolus of 0.1 IU i.v. (varies according to literature [5,6]) • 0.1 units/kg BW/h as approximate value for an undiluted haemacel solution or 1% albumin solution

Note: Insulin units per body weight and hour can be dramatically higher with secondary concomitant symptoms. Monitoring the efficacy is only possible by means of very frequent blood glucose measurements [1]. Following the metabolic compensation, which must be both clinically and biochemically confirmed, the rate of intravenous insulin application may be reduced till it is discontinued. This phasing out of the intravenous insulin application is to be conducted simultaneously to the commencement of the continuous or discontinuous s.c. insulin therapy. This "temporary" (days to weeks) intravenous application of insulin is usually performed on a central vein. Due to the risk of thrombosis and infection, the catheter should not be in place for longer than this period. The importance of recognizing and treating comatose imbalances, particularly with respect to insulin pump therapy, will be dealt with in greater detail in chapter 12.

8.1.2 Long-term intravenous insulin infusion Some teams, such as those working with Irsigler [15, 17], Schade [30], Walter, [36, 38], Pickup and Williams [23, 39, 40], Bayliss [2] and Selam [33], have reported on the long-term use of continuous intravenous insulin infusion (CIVII) in the long-term treatment of Diabetes mellitus. In the mid-70's Irsigler et al. began implanting intravenous and intraperitoneal catheter systems, combined with implanted or external pumps (implanted pumps: 52 i.v. catheter, 61 i.p. catheter; external pumps: 42 i.v. catheter, 68 i.p. catheter). They presented these numbers in 1988 and summarized their findings in a study [15]. They compared the data of the i.p. supply with that of the i.v. method. The maximum catheter dwelling time for the i.p. route was 4.2 years, for the i.v. 3.6 years. The survival times after 0.5, 1, 2 and 3 years for the i.p. catheter were 70, 39, 12 and 4%, respectively. For the i.v. route the values were 70, 41, 13 and 6%. Catheter obstruction by insulin precipitates, thrombus formation as a result of fibrin deposits and cell immigration in the catheters placed blindly and especially with the intraperitoneal catheters, (tissue growth phenomenon) [17] are the most common limiting factors for catheter dwelling time. Insulin precipitates have been dissolved by rinsing the catheter with an alkaline buffer solution. Plasmine solutions were used in the case of fibrin and tissue

8.1 Continuous intravenous insulin infusion (CIVII)

55

deposits. Urokinase has also been used for dissolving obstructions in intravenous catheters. Preventive catheter rinsing has reduced the number of catheter obstructions considerably [15]. Breaking off of the external part of the catheter leads to shortened survival times in the case of externally worn pumps. Studies by Walter [36] showed that the concentrations of free plasma insulin increases immediately in the case of i.v. insulin infusion and that the concentration levels off after 10-15 minutes of a constant supply. The plasma insulin concentration drops sharply when the infusion is discontinued, returning to the initial insulin concentration after about 30 minutes (fig. 31). Figure 32 shows a comparison of the insulin concentrations following i.v. and i.p. administration. The concentration increases slowly with the latter method. The peak is attained after 6 0 - 8 0 minutes, but is maintained for a longer period after the infusion is stopped, and returns to the initial concentration only 3 hours later. 300

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