Biosensors & Bioelectronics 6 (199 1) 639-646
CLINICIANS’ REQUIREMENTS FOR CHEMICAL SENSORS FOR IN VW0 MONITORING: A MULTINATIONAL SURVEY John C. Pickup & Susan Alcock We report on a survey of senior clinicians in 11 countries which asked
about what they see as the main areas where in vivo chemical sensors will be most useful in medicine, and about what their operating characteristics should be. This information may help those designing such sensors to match available and new technologies to clinical needs. INTRODUCTION The Commission of the European Communities is currently supporting, through its Biomedical Engineering Committee, a Concerted Action on ‘Chemical sensors for in vivo monitoring’. One of the first main objectives of the Action is to identify the most important clinical problems where in vivo chemical sensors are likely to be of benefit in the management of patients and which analytes should be monitored for each medical condition (Reach et al., 1989). Information is also urgently required on the desirable operating characteristics of in vivo sensors, as perceived by health care professionals in their capacity as potential users. Without such details it will be difficult to match the many existing, sensor technologies, with their varied performance specifications, to particular clinical situations and needs. Nor will it be readily possible to identify the need for the development of new technologies, nor to focus research efforts and resources on the areas where there is most clinical demand. John C. Pickup (corresponding Pathology, United Medical
author), Division of Chemical and Dental Schools, Guy’s
Susan Alcock, Biotechnology Centre, Cranfield Institute of Technology, Cranfield, Bedfordshire MK43 OAL, UK.
We report here the results of a questionnaire designed by the Concerted Action to elicit information on the above topics. It was distributed to senior clinicians with a wide range of professional interests or specializations from 11 countries throughout Europe, Canada, Australia and Japan.
HOW THE SURVEY WAS CONDUCTED The 35 scientists attending a Concerted Action workshop on ‘Clinical aspects of in vivo sensing’ (Lyon, France, 8-10 March, 1989), who represented 10 countries, were asked to distribute questionnaires to clinicians and related health professionals in their countries who had expressed a preliminary interest in the medical applications of biosensors or chemical sensors. Non-medically qualified scientists working in a clinical setting, e.g. clinical biochemists, were also included. After assessing the initial response, further questionnaires were sent to clinicians selected to cover the full range of medical specializations. Health professionals who did not perceive any use for chemical sensors in medicine were not asked to complete the questionnaire.
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The questionnaire was preceded by a guidance note which defined the term ‘sensor’, outlined the general purpose and scope of the information sought, and asked responders not to be limited by the present state of the technology; this note is shown in the appendix together with the questionnaire. Responses were posted to the central secretariat of the Concerted Action and the data entered into a textbase (STATUS software, Hat-wellComputer Power, UK) on a VAX computer for analysis.
RESULTS OF THE SURVEY The countries in which the 49 responders to the questionnaire worked are shown in Table 1. There was not equal representation from the 11 countries in which responders worked, with the largest numbers residing in the UK, Denmark and Belgium. The majority worked in a university or teaching hospital (73%) and were of senior status. Most responders (88%) were medically qualified, and 37% held both a medical degree and a PhD.
TABLE 1 Characteristics of responders to questionnaire Place of work
Country of origin
University/teaching hospital General hospital Research institute General practice Not stated
21 ‘! 3 : t f kteer
Qualifications of responders MD or equivalent
of years since qualification (mean f S.D. and Since MD Since PhD
&?:dEalent
18.9 f 9.2 2-37 16.1 f9.8 t 141 j
Number of responders: 49.
Main
TABLE 2 clinical interests of recipients
Clinical interest
No. ofknown recipients
No. of responders
Diabetes/endocrinology/metabolism Paediatrics/neonatology/pre-natal diagnosis Intensive care/anaesthetics Laboratory medicine/clinical chemistry Nephrology Radiotherapy/oncology Cardiology General medicine Obstetrics and gynaecology Pharmacology/clinical harmacology Bioengineermg/medica P physrcs General practice/community medicine Applied physiology Allergy/respiratory medicine Gastroenterology ~u$~o~y Transplantation/surgery Urology Dermatology Neurology
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Biosensors & Bioelectronics 6 (199 1) 639-646
Table 2 shows the main clinical interests of known recipients of the questionnaire, and the pattern of responses. The largest number of responding clinicians were interested in diabetes mellitus, endocrinology or metabolism (29%), with significant numbers also specializing in laboratory medicine (clinical chemistry), intensive care or anaesthetics, and nephrology. In these specialities, more than 46% of targeted clinicians responded to the questionnaire, whereas in the areas of paediatrics, neonatology or pre-natal diagnosis, less than 27% of known recipients replied. Medical problems where in vivachemical sensing would be of benefit Table 3 lists the main medical problems where clinicians considered that in viva chemical sensing would be of benefit, whether or not a suitable sensor currently exists. The largest percentage (51%) cited diabetes mellitus, with 3 1% of those clinicians whose speciality was not diabetes, endocrinology or metabolism mentioning this condition. Specific diabetic Main
TABLE 3 clinical problems where in viva chemical sensors were considered to be helpful Analyte
Clinical problem Diabetes mellitus (25)
Vital function monitoring in intensive we/ anaesthetics/ prolonged surgery (16)
Desirable operating characteristics
Glucose (24) Ketones (2) K+(3) ~’ Insulin (2) Lactate (1) PH (1) 02 (1% co2 (10) $
i;;
Electrolytes (unclassified) Gases (unclassified) (1) Na’ (1) Glucose (2) Haemoglobin (3) Osmolality (1) Lactate (1) Renal failure/monitoring dialysis (11)
(2)
urea (4) Creatkne (2) K+ (2) Atrial natriuretic peptide (1) PH (1)
The number of responders is shown in parentheses.
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problems such as hypoglycaemia, ketoacidosis, diabetes management during surgery and the maintenance of long-term normoglycaemia so as to avoid tissue complications were recorded infrequently (five or fewer times for each). Nearly all those indicating diabetes as a condition where in viva sensors would be helpful cited glucose as the most appropriate analyte to measure. A large proportion of responders (33%) cited the monitoring of vital functions in the intensive care or anaesthetics settings and matched this general clinical problem with the need for sensing of oxygen, carbon dioxide and PH. A few mentioned electrolyte sensing, particularly K+. The third major clinical problem listed was renal failure (acute and chronic) and the need to monitor the effectiveness of dialysis. The analyte cited most frequently in this respect was urea. Table 4 lists three conditions which were thought to be of lesser importance: septicaemia or severe infection, where aminoglycoside levels might be monitored, status asthmaticus (theophylline, aminophylline sensing) and heart failure or arrhythmias (lignocaine, procainamide or digoxin sensing). Some other rarely mentioned problems are also listed in Table 4.
Science
Publishers
A consensus on the operating characteristics which were thought to be desirable for in viva glucose sensing is shown in Table 5. Particular points to note include the fact that continuous glucose sensing was not considered essential by all responders; nearly one-third indicated that intermittent readings at a frequency of 30 minutes to 6 hours would be adequate. In contrast, a fast response time (less than 5 minutes) was thought desirable by all clinicians. The most favoured sensing site was the subcutaneous tissue, although the venous compartment would be considered by 39%. The majority of responders indicated a sensor replacement time of l-7 days. The most likely users of in vivo glucose sensors were thought to be the diabetic patients. Nearly all responders saw an advantage in the sensor forming part of a system for closed-loop control
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Biosensors & Bioelectronics 6 (199 1) 639-646 TABLE 4
TABLE 5
Infrequently mentioned clinical problems suitable for in vivo chemical sensors
Desirable operating characteristics for in vivo glucose sensors for diabetes
Clinical problem S ticaemia/severe .“pection (3) m
Analyte
Characteristic Samplhg frequency
Gentam tin or other aminog Pycoside (2)
Continuous Intermittent
Et&toxin (1)
Status asthmaticus(3) Heart failure/arrhythmia (3)
Theoph lline or aminop Kylline (3) Lignocaine, procainamide or related anti-arrhythmic agent (3) Digoxin (2)
Hypoparathyroidism following thyrotdectomy or parathyroidectomy (2)
Calcium (2)
Exercise/work ca acity or sports medicine (1)
Luteinizmg hormone/folliclestimulating hormone
Cerebral injury/metabolism (2) Glucose 2) Lactate( \ ) Sensitivity of turnouts to cytotoxic agents (2)
Tumour P@ 1) Tumour drug i eve1 (10)
Therapeutic drug monitoring (2)
Methotrexate (2)
Chronic bronchitis/chest medicine (2)
g201)
Other (14)
PH (1)
The number of responders in each case is shown in parentheses.
of drug (insulin) delivery, i.e. an artificial endocrine pancreas. Table 6 shows the consensus on the operating characteristics for blood gas sensors. In general, no differences were drawn between oxygen and carbon dioxide sensors, and details of pH monitoring were recorded too infrequently to be useful. Of interest is the fact that continuous, rapidly responding sensing was thought desirable by most clinicians. The favoured sensing site was intraarterial, with a replacement time of one day or less. In contrast to glucose sensing, the most likely user of blood gas sensors was thought to be a senior or junior doctor, and closed-loop
642
56% 44%
Interval for intermittent sampling 10 min or less 30-60 min Longer than 4 hours
36% 21% 29%
Response time 5minorles.s 1 min or less
82% 50%
Implantation site Subcutaneous Intravenous Other
44% 36% 20%
Accuracy S-10% Infertility (2)
% of responders
73
Drift 1%/hour or less 0.1% hour or less
86% 38%
Replacement time Less than 1 day l-7 days l-2 months
11% 58% 26%
User Patient Nurse Junior doctor Senior doctor Technician
40% 23% 21% 12% 5%
Closed-loop advantage
94%
operation was only thought an advantage by half the responders.
DISCUSSION Chemical sensors for most in viva applications have yet to form a part of routine clinical practice (Pickup, 1985). Although a limited number of intravascular blood gas and pH sensors are commercially available, their reliability and safety, and the indications for their use, are still undergoing active investigation. Only the non-invasive technologies of pulse oxirnetry, for
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Biosensors 8i Bioelectronics 6 (199 1) 639-646 TABLE 6
Desirable operating characteristicsfor blood gas sensors for use in intensive care Characteristic
% of responders
Sampling frequency Continuous Intermittent
79% 21%
Interval for intermittent sampling < 10 min 30 min
10% 10%
Response time 1 min or less 5 min or less
83% 100%
Implantation site Artery Vein Subcutaneous Transcutaneous Capillary
50% 30% 10% n.s n.s
Accuracy 5%
92%
Drift l%/hour or less 2%/hour Replacement -24 hr 6-8 hr
time 67% 17%
User Senior doctor Junior doctor Nurse Technician Patient Closed-loop
64% 27%
40% 36% 20%
advantage
n.s., not significant.
the measurement of arterial oxygen saturation, and transcutaneous gas electrodes have found and only in certain wide acceptance, circumstances (Burritt, 1990). Clinicians’ expectations of in vivo sensors are, therefore, not usually based on experience but on the identification of a well established clinical problem where continuous or intermittent analyte measurement within or close to the body has obvious advantages. Moreover, it is reasonable to assume that the clinicians who returned the questionnaire probably represented specialities in which there
is a clear need for in vivo chemical sensing (the large number of responders whose interests were diabetes, endocrinology and metabolism, and the low response rate in paediatrics, neonatology or pre-natal diagnosis, may reflect this).
Diabetes The most commonly cited clinical problem was
diabetes mellitus, and glucose was thought by nearly all to be the most appropriate analyte. Ketone bodies (acetoacetate, 3-hydroxybutyrate and acetone), K+, insulin and lactate were only mentioned rarely as possible analytes. Specific needs in diabetes such as detection and warning of hypoglycaemia were recorded relatively infrequently. This is surprising for two reasons. Firstly, hypoglycaemia for example is recognized by physicians as being a common and distressing complication of diabetes (Pramming, 1985) and a short-term hypoglycaemia alarm is increasingly being regarded as both feasible and a priority clinical application for implantable glucose sensors (Pickup et al., 1989). Secondly, different applications for glucose sensors will be served by sensors with different operating features. For example, management of diabetes during surgery may be accomplished via an ex vivo system with a relatively large glucose sensor in a venous-blood flow-through cell, where substantial drift could be tolerated because of the capacity to recalibrate the sensor outside the body. In contrast, for maintenance of long-term normoglycaemia with a wearable artificial endocrine pancreas (feedback-controlled insulin delivery system), a glucose sensor should be miniature, implantable within a site in the body such as the subcutaneous tissue, and have low drift. These discrepancies may explain the disparate views of clinicians in this survey as to the replacement time for an in vivo glucose sensor. It is also of interest that many clinicians regarded intermittent glucose measurement at frequencies between 30 minutes and 6 hours, rather than continuous measurement, as adequate for diabetes management. In this respect, it is worth noting that Furler et al. (1985) have shown that satisfactory glycaemic control can be achieved in
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insulin-dependent diabetic patients using a semi-closed-loop algorithm in which the basal infusion rate is adjusted on the basis of blood glucose measurements at 3 hour intervals. The almost universal appreciation in the survey of the advantages of glucose sensors for feedback-controlled insulin delivery partly reflects the widespread acceptance that modem insulin therapy should be based on mimicking non-diabetic insulin delivery (Pickup and Rothwell, 1984) where insulin secretion from the pancreatic p-cell is under closed-loop glucose control via a ‘glucose sensor’ in the p-cell itself (Ramussen et al., 1990). Clinicians may also have been influenced by the already partially successful incorporation of implantable glucose sensors in closed-loop systems on a short-term, experimental basis (Shichiri et al., 1983, 1984; Rebrin et al., 1989). Intensive care and anaesthetics The second most commonly cited clinical problem in the questionnaire was vital function monitoring in intensive care and anaesthetics, with oxygen, carbon dioxide and hydrogen ions being the preferred analytes for sensing. Although no clinician specifically justified the need for continuous or discontinuous in viva sensing compared with conventional in vitro analysis of blood gases and pH by discrete laboratory analysers, the presumed application for in vivo devices in this setting would be to detect sudden, unexpected and rapid changes in the metabolic condition of the patient (Fogt, 1990). The preference for intravascular monitoring (compared with the subcutaneous site for glucose sensors) is consistent with both the intention to replace the sensor after 24 hours or less, thus minimizing thrombosis and infection, and the stated expectation that sensors will mostly be used by doctors in the controlled conditions of the operating theatre or intensive care suite.
Renal failure The management of renal failure by the monitoring of haemodialysis was the third main
644
clinical problem mentioned by responders, and was recorded about half as frequently as diabetes. Urea sensing in vivo was most often chosen for dialysis monitoring but only by about half of those citing this procedure as a suitable application for chemical sensing. The justification for urea measurement in vivo probably arises from efforts in recent years to reduce dialysis time without sacrificing the adequacy of treatment or producing unpleasant symptoms (von Albertini, 1988). It is possible that dialysis may be tailored to the needs of individual patients by closed-loop control of urea removal.
Electrolytes and other analytes Although there was no strong agreement that electrolyte sensing would be of value in individual conditions, taken together, K+ ion sensing was mentioned by some 20% of responders. There is justification, therefore, for further study of the possible clinical indications for in vivo monitoring of this ion. The response rates indicated for certain other clinical interests in Table 2 and the large number of other clinical problems and analytes listed in Table 4 should act as a stimulus for further enquiry, but the information concerning these options in this study is too sparse to form firm conclusions.
ACKNOWLEDGEMENTS We are grateful to the Commission of the European Communities for financial support, and the Sugar Free group, the University of London Academic Initiative, the British Diabetic Association and the BUPA Medical Foundation Ltd for additional grants. The Project Management Croup of the EC Concerted Action on Chemical Sensors For In viva Monitoring (Project Leader, Professor A.P.F. Turner, Cranfield Institute of Technology) provided much help and useful discussion in the preparation and analysis of this study. We also thank Dr J.M. Dicks for assistance with the database. This paper has been independently refereed.
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REFERENCES Burr&, M. F. (1990). Current analytical approaches to measuring blood analytes. Clin. Gem. 36,1562-66. Fogt, E. J. (1990). Continuous ex vivo and in vivo monitoring with chemical sensors. C/in. Chem. 36,1573-80. Furler, S. M., Kraegen, E. W., Smallwood, R. H. & Chishohn, D. J. (1985). Blood glucose control by intermittent loop closure in the basal mode: computer simulation studies with a diabetic model. Diabetes Cure 8,553-H. Pickup, J. C. (1985). Biosensors: a clinical perspective. Lancet ii, 817-20. Pickup, J. C. & Rothwell, D. (1984). Technology and the diabetic patient. Med. Biol. Eng. Comput. 22,385400. Pickup, J. C., Shaw, G. W. & Claremont, D. J. (1989). In vivo molecular sensing in diabetes mellitus: an implantable glucose sensor with direct electron transfer. Diubetologiu 32,213-7. Ramming, S., Thorsteinsson, B., Bendtson, I., ROM, R. & Binder, C. (1985). Nocturnal hypoglycaemia in patients receiving conventional treatment with insulin. British Medical Journal 291,376-9.
Rasmussen, H., Zawalich, K. C., Ganesan, S., Calle, R. & Zawalich, W. S. (1990). Physiology and pathophysiology of insulin secretion. Diabetes Cure 13,655-66. Reach, G., Thevenot, D. R. & Coulet, P. (1989). Chemical sensors for in vivo monitoring: clinical aspects. Anal. Lett. 22, 2393-401. Rebrin, K., Fischer, U., von Woedtke, T., Abel, P & Brunstein, E. (1989). Automated feedback control of subcutaneous glucose concentration in diabetic dogs. Diubetologiu 32,573-6. Shichiri, M., Kawamori, R., Goriya, Y., Yamasski, Y., Nomura, M., Hakui, N. & Abe, H. (1983). Glycaemic control in pancreatectomized dogs with a wearable artificial endocrine pancreas. Diubetologiu 24, 179-84. Shichiri, M., Kawamori, R., Hakui, N., Yamasaki, Y. & Abe, H. (1984). Closed-loop glycemic control with a wearable artificial endocrine pancreas. Diabetes 33,1200-2. Von Albertini, B. (1988). High efficiency hemodialysis: an overview. Cont. Nephrol. 61,37-45.
APPENDIX The questionnaire was preceded by the following guidance note: “A simple definition of a sensor is a small, probe-type device which can rapidly and specifically measure the concentration of a substance, in our case one of biomedical interest, ideally without added reagent. An example would be a glucose sensor for use in diabetes mellitus. This questionnaire is designed by the Project Management Group of a European Community Concerted Action which is investigating the need and strategies for producing in vivo chemical sensors for use in clinical medicine (research and practice). We define “in vivo” as measurements made inside the body (implanted), on the surface, or close to the body as fluid passes over the sensor (strictly, an ex vivo device). The questions will tell us what clinicians and related professionals think are the main problems where sensors will be helpful, and what the clinical requirements am. In your responses, we would ask you not to be limited by the present state of assay technology or management of diseases, but to try and look ahead and predict what might be the problems and requirements in, say, 20 years time”.
Questionnaire on chemical sensors for in viwo monitoring l
Name
l
Qualification (circle one or more)
PhD
MD
Other (state)
l
Name of main hospital or institution where you are based
l
Address of above
l
Country
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Biosensors& Bioektronics 6 (I 99 1) 639-646
l
Type of Institute (circle)
l
Approx. number of beds
l
What is your clinical speciality?
l
Number of years since qualification
l
l
University/ Teaching Hosp
Genemill other Hosp
since MD
since PhD
List the clinical problems where you consider in vivo sensors would be. helpful (whether or not a suitable sensor currently exists). For each problem that you have identified, choose an analyte (chemical), the in vivo sensing of which would be clinically helpful. Please photocopy this page, if necessary, and use a separate sheet for each problem and its analyte.,
l
Clinical problem (one only)
l
Analyte
l
Recommended sampling frequency (circle one)
l
If intermittent, what should be the time between measurements?
l
What response time would you like for the sensor?
l
What sensing site would you choose?
l
Why would you choose this site?
l
What level of accuracy would be needed for the sensor to be clinically useful?
l
Approximately what level of drift (loss of sensitivity) would be acceptable?
l
What would be the miniium sensor life-time (i.e. before replacement or resiting)?
l
Who would use the sensor? (circle)
l
Would there be an advantage for the sensor to be part of a closed-loop system for delivery of therapy?
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Research Institute
Continuous
Intermittent
% change per hour
junior doctor
senior doctor
nurse
yes
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specialist technician
patient
no
01991 Elsevier Science Publishers Ltd.
CLINICIANS’ REQUIREMENTS FOR CHEMICAL SENSORS FOR IN VW0 MONITORING: A MULTINATIONAL SURVEY John C. Pickup & Susan Alcock We report on a survey of senior clinicians in 11 countries which asked
about what they see as the main areas where in vivo chemical sensors will be most useful in medicine, and about what their operating characteristics should be. This information may help those designing such sensors to match available and new technologies to clinical needs. INTRODUCTION The Commission of the European Communities is currently supporting, through its Biomedical Engineering Committee, a Concerted Action on ‘Chemical sensors for in vivo monitoring’. One of the first main objectives of the Action is to identify the most important clinical problems where in vivo chemical sensors are likely to be of benefit in the management of patients and which analytes should be monitored for each medical condition (Reach et al., 1989). Information is also urgently required on the desirable operating characteristics of in vivo sensors, as perceived by health care professionals in their capacity as potential users. Without such details it will be difficult to match the many existing, sensor technologies, with their varied performance specifications, to particular clinical situations and needs. Nor will it be readily possible to identify the need for the development of new technologies, nor to focus research efforts and resources on the areas where there is most clinical demand. John C. Pickup (corresponding Pathology, United Medical
author), Division of Chemical and Dental Schools, Guy’s
Susan Alcock, Biotechnology Centre, Cranfield Institute of Technology, Cranfield, Bedfordshire MK43 OAL, UK.
We report here the results of a questionnaire designed by the Concerted Action to elicit information on the above topics. It was distributed to senior clinicians with a wide range of professional interests or specializations from 11 countries throughout Europe, Canada, Australia and Japan.
HOW THE SURVEY WAS CONDUCTED The 35 scientists attending a Concerted Action workshop on ‘Clinical aspects of in vivo sensing’ (Lyon, France, 8-10 March, 1989), who represented 10 countries, were asked to distribute questionnaires to clinicians and related health professionals in their countries who had expressed a preliminary interest in the medical applications of biosensors or chemical sensors. Non-medically qualified scientists working in a clinical setting, e.g. clinical biochemists, were also included. After assessing the initial response, further questionnaires were sent to clinicians selected to cover the full range of medical specializations. Health professionals who did not perceive any use for chemical sensors in medicine were not asked to complete the questionnaire.
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Biosensors & Bioelectronics 6 (1991) 63-46
The questionnaire was preceded by a guidance note which defined the term ‘sensor’, outlined the general purpose and scope of the information sought, and asked responders not to be limited by the present state of the technology; this note is shown in the appendix together with the questionnaire. Responses were posted to the central secretariat of the Concerted Action and the data entered into a textbase (STATUS software, Hat-wellComputer Power, UK) on a VAX computer for analysis.
RESULTS OF THE SURVEY The countries in which the 49 responders to the questionnaire worked are shown in Table 1. There was not equal representation from the 11 countries in which responders worked, with the largest numbers residing in the UK, Denmark and Belgium. The majority worked in a university or teaching hospital (73%) and were of senior status. Most responders (88%) were medically qualified, and 37% held both a medical degree and a PhD.
TABLE 1 Characteristics of responders to questionnaire Place of work
Country of origin
University/teaching hospital General hospital Research institute General practice Not stated
21 ‘! 3 : t f kteer
Qualifications of responders MD or equivalent
of years since qualification (mean f S.D. and Since MD Since PhD
&?:dEalent
18.9 f 9.2 2-37 16.1 f9.8 t 141 j
Number of responders: 49.
Main
TABLE 2 clinical interests of recipients
Clinical interest
No. ofknown recipients
No. of responders
Diabetes/endocrinology/metabolism Paediatrics/neonatology/pre-natal diagnosis Intensive care/anaesthetics Laboratory medicine/clinical chemistry Nephrology Radiotherapy/oncology Cardiology General medicine Obstetrics and gynaecology Pharmacology/clinical harmacology Bioengineermg/medica P physrcs General practice/community medicine Applied physiology Allergy/respiratory medicine Gastroenterology ~u$~o~y Transplantation/surgery Urology Dermatology Neurology
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Biosensors & Bioelectronics 6 (199 1) 639-646
Table 2 shows the main clinical interests of known recipients of the questionnaire, and the pattern of responses. The largest number of responding clinicians were interested in diabetes mellitus, endocrinology or metabolism (29%), with significant numbers also specializing in laboratory medicine (clinical chemistry), intensive care or anaesthetics, and nephrology. In these specialities, more than 46% of targeted clinicians responded to the questionnaire, whereas in the areas of paediatrics, neonatology or pre-natal diagnosis, less than 27% of known recipients replied. Medical problems where in vivachemical sensing would be of benefit Table 3 lists the main medical problems where clinicians considered that in viva chemical sensing would be of benefit, whether or not a suitable sensor currently exists. The largest percentage (51%) cited diabetes mellitus, with 3 1% of those clinicians whose speciality was not diabetes, endocrinology or metabolism mentioning this condition. Specific diabetic Main
TABLE 3 clinical problems where in viva chemical sensors were considered to be helpful Analyte
Clinical problem Diabetes mellitus (25)
Vital function monitoring in intensive we/ anaesthetics/ prolonged surgery (16)
Desirable operating characteristics
Glucose (24) Ketones (2) K+(3) ~’ Insulin (2) Lactate (1) PH (1) 02 (1% co2 (10) $
i;;
Electrolytes (unclassified) Gases (unclassified) (1) Na’ (1) Glucose (2) Haemoglobin (3) Osmolality (1) Lactate (1) Renal failure/monitoring dialysis (11)
(2)
urea (4) Creatkne (2) K+ (2) Atrial natriuretic peptide (1) PH (1)
The number of responders is shown in parentheses.
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problems such as hypoglycaemia, ketoacidosis, diabetes management during surgery and the maintenance of long-term normoglycaemia so as to avoid tissue complications were recorded infrequently (five or fewer times for each). Nearly all those indicating diabetes as a condition where in viva sensors would be helpful cited glucose as the most appropriate analyte to measure. A large proportion of responders (33%) cited the monitoring of vital functions in the intensive care or anaesthetics settings and matched this general clinical problem with the need for sensing of oxygen, carbon dioxide and PH. A few mentioned electrolyte sensing, particularly K+. The third major clinical problem listed was renal failure (acute and chronic) and the need to monitor the effectiveness of dialysis. The analyte cited most frequently in this respect was urea. Table 4 lists three conditions which were thought to be of lesser importance: septicaemia or severe infection, where aminoglycoside levels might be monitored, status asthmaticus (theophylline, aminophylline sensing) and heart failure or arrhythmias (lignocaine, procainamide or digoxin sensing). Some other rarely mentioned problems are also listed in Table 4.
Science
Publishers
A consensus on the operating characteristics which were thought to be desirable for in viva glucose sensing is shown in Table 5. Particular points to note include the fact that continuous glucose sensing was not considered essential by all responders; nearly one-third indicated that intermittent readings at a frequency of 30 minutes to 6 hours would be adequate. In contrast, a fast response time (less than 5 minutes) was thought desirable by all clinicians. The most favoured sensing site was the subcutaneous tissue, although the venous compartment would be considered by 39%. The majority of responders indicated a sensor replacement time of l-7 days. The most likely users of in vivo glucose sensors were thought to be the diabetic patients. Nearly all responders saw an advantage in the sensor forming part of a system for closed-loop control
Ltd.
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Biosensors & Bioelectronics 6 (199 1) 639-646 TABLE 4
TABLE 5
Infrequently mentioned clinical problems suitable for in vivo chemical sensors
Desirable operating characteristics for in vivo glucose sensors for diabetes
Clinical problem S ticaemia/severe .“pection (3) m
Analyte
Characteristic Samplhg frequency
Gentam tin or other aminog Pycoside (2)
Continuous Intermittent
Et&toxin (1)
Status asthmaticus(3) Heart failure/arrhythmia (3)
Theoph lline or aminop Kylline (3) Lignocaine, procainamide or related anti-arrhythmic agent (3) Digoxin (2)
Hypoparathyroidism following thyrotdectomy or parathyroidectomy (2)
Calcium (2)
Exercise/work ca acity or sports medicine (1)
Luteinizmg hormone/folliclestimulating hormone
Cerebral injury/metabolism (2) Glucose 2) Lactate( \ ) Sensitivity of turnouts to cytotoxic agents (2)
Tumour P@ 1) Tumour drug i eve1 (10)
Therapeutic drug monitoring (2)
Methotrexate (2)
Chronic bronchitis/chest medicine (2)
g201)
Other (14)
PH (1)
The number of responders in each case is shown in parentheses.
of drug (insulin) delivery, i.e. an artificial endocrine pancreas. Table 6 shows the consensus on the operating characteristics for blood gas sensors. In general, no differences were drawn between oxygen and carbon dioxide sensors, and details of pH monitoring were recorded too infrequently to be useful. Of interest is the fact that continuous, rapidly responding sensing was thought desirable by most clinicians. The favoured sensing site was intraarterial, with a replacement time of one day or less. In contrast to glucose sensing, the most likely user of blood gas sensors was thought to be a senior or junior doctor, and closed-loop
642
56% 44%
Interval for intermittent sampling 10 min or less 30-60 min Longer than 4 hours
36% 21% 29%
Response time 5minorles.s 1 min or less
82% 50%
Implantation site Subcutaneous Intravenous Other
44% 36% 20%
Accuracy S-10% Infertility (2)
% of responders
73
Drift 1%/hour or less 0.1% hour or less
86% 38%
Replacement time Less than 1 day l-7 days l-2 months
11% 58% 26%
User Patient Nurse Junior doctor Senior doctor Technician
40% 23% 21% 12% 5%
Closed-loop advantage
94%
operation was only thought an advantage by half the responders.
DISCUSSION Chemical sensors for most in viva applications have yet to form a part of routine clinical practice (Pickup, 1985). Although a limited number of intravascular blood gas and pH sensors are commercially available, their reliability and safety, and the indications for their use, are still undergoing active investigation. Only the non-invasive technologies of pulse oxirnetry, for
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Biosensors 8i Bioelectronics 6 (199 1) 639-646 TABLE 6
Desirable operating characteristicsfor blood gas sensors for use in intensive care Characteristic
% of responders
Sampling frequency Continuous Intermittent
79% 21%
Interval for intermittent sampling < 10 min 30 min
10% 10%
Response time 1 min or less 5 min or less
83% 100%
Implantation site Artery Vein Subcutaneous Transcutaneous Capillary
50% 30% 10% n.s n.s
Accuracy 5%
92%
Drift l%/hour or less 2%/hour Replacement -24 hr 6-8 hr
time 67% 17%
User Senior doctor Junior doctor Nurse Technician Patient Closed-loop
64% 27%
40% 36% 20%
advantage
n.s., not significant.
the measurement of arterial oxygen saturation, and transcutaneous gas electrodes have found and only in certain wide acceptance, circumstances (Burritt, 1990). Clinicians’ expectations of in vivo sensors are, therefore, not usually based on experience but on the identification of a well established clinical problem where continuous or intermittent analyte measurement within or close to the body has obvious advantages. Moreover, it is reasonable to assume that the clinicians who returned the questionnaire probably represented specialities in which there
is a clear need for in vivo chemical sensing (the large number of responders whose interests were diabetes, endocrinology and metabolism, and the low response rate in paediatrics, neonatology or pre-natal diagnosis, may reflect this).
Diabetes The most commonly cited clinical problem was
diabetes mellitus, and glucose was thought by nearly all to be the most appropriate analyte. Ketone bodies (acetoacetate, 3-hydroxybutyrate and acetone), K+, insulin and lactate were only mentioned rarely as possible analytes. Specific needs in diabetes such as detection and warning of hypoglycaemia were recorded relatively infrequently. This is surprising for two reasons. Firstly, hypoglycaemia for example is recognized by physicians as being a common and distressing complication of diabetes (Pramming, 1985) and a short-term hypoglycaemia alarm is increasingly being regarded as both feasible and a priority clinical application for implantable glucose sensors (Pickup et al., 1989). Secondly, different applications for glucose sensors will be served by sensors with different operating features. For example, management of diabetes during surgery may be accomplished via an ex vivo system with a relatively large glucose sensor in a venous-blood flow-through cell, where substantial drift could be tolerated because of the capacity to recalibrate the sensor outside the body. In contrast, for maintenance of long-term normoglycaemia with a wearable artificial endocrine pancreas (feedback-controlled insulin delivery system), a glucose sensor should be miniature, implantable within a site in the body such as the subcutaneous tissue, and have low drift. These discrepancies may explain the disparate views of clinicians in this survey as to the replacement time for an in vivo glucose sensor. It is also of interest that many clinicians regarded intermittent glucose measurement at frequencies between 30 minutes and 6 hours, rather than continuous measurement, as adequate for diabetes management. In this respect, it is worth noting that Furler et al. (1985) have shown that satisfactory glycaemic control can be achieved in
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insulin-dependent diabetic patients using a semi-closed-loop algorithm in which the basal infusion rate is adjusted on the basis of blood glucose measurements at 3 hour intervals. The almost universal appreciation in the survey of the advantages of glucose sensors for feedback-controlled insulin delivery partly reflects the widespread acceptance that modem insulin therapy should be based on mimicking non-diabetic insulin delivery (Pickup and Rothwell, 1984) where insulin secretion from the pancreatic p-cell is under closed-loop glucose control via a ‘glucose sensor’ in the p-cell itself (Ramussen et al., 1990). Clinicians may also have been influenced by the already partially successful incorporation of implantable glucose sensors in closed-loop systems on a short-term, experimental basis (Shichiri et al., 1983, 1984; Rebrin et al., 1989). Intensive care and anaesthetics The second most commonly cited clinical problem in the questionnaire was vital function monitoring in intensive care and anaesthetics, with oxygen, carbon dioxide and hydrogen ions being the preferred analytes for sensing. Although no clinician specifically justified the need for continuous or discontinuous in viva sensing compared with conventional in vitro analysis of blood gases and pH by discrete laboratory analysers, the presumed application for in vivo devices in this setting would be to detect sudden, unexpected and rapid changes in the metabolic condition of the patient (Fogt, 1990). The preference for intravascular monitoring (compared with the subcutaneous site for glucose sensors) is consistent with both the intention to replace the sensor after 24 hours or less, thus minimizing thrombosis and infection, and the stated expectation that sensors will mostly be used by doctors in the controlled conditions of the operating theatre or intensive care suite.
Renal failure The management of renal failure by the monitoring of haemodialysis was the third main
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clinical problem mentioned by responders, and was recorded about half as frequently as diabetes. Urea sensing in vivo was most often chosen for dialysis monitoring but only by about half of those citing this procedure as a suitable application for chemical sensing. The justification for urea measurement in vivo probably arises from efforts in recent years to reduce dialysis time without sacrificing the adequacy of treatment or producing unpleasant symptoms (von Albertini, 1988). It is possible that dialysis may be tailored to the needs of individual patients by closed-loop control of urea removal.
Electrolytes and other analytes Although there was no strong agreement that electrolyte sensing would be of value in individual conditions, taken together, K+ ion sensing was mentioned by some 20% of responders. There is justification, therefore, for further study of the possible clinical indications for in vivo monitoring of this ion. The response rates indicated for certain other clinical interests in Table 2 and the large number of other clinical problems and analytes listed in Table 4 should act as a stimulus for further enquiry, but the information concerning these options in this study is too sparse to form firm conclusions.
ACKNOWLEDGEMENTS We are grateful to the Commission of the European Communities for financial support, and the Sugar Free group, the University of London Academic Initiative, the British Diabetic Association and the BUPA Medical Foundation Ltd for additional grants. The Project Management Croup of the EC Concerted Action on Chemical Sensors For In viva Monitoring (Project Leader, Professor A.P.F. Turner, Cranfield Institute of Technology) provided much help and useful discussion in the preparation and analysis of this study. We also thank Dr J.M. Dicks for assistance with the database. This paper has been independently refereed.
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REFERENCES Burr&, M. F. (1990). Current analytical approaches to measuring blood analytes. Clin. Gem. 36,1562-66. Fogt, E. J. (1990). Continuous ex vivo and in vivo monitoring with chemical sensors. C/in. Chem. 36,1573-80. Furler, S. M., Kraegen, E. W., Smallwood, R. H. & Chishohn, D. J. (1985). Blood glucose control by intermittent loop closure in the basal mode: computer simulation studies with a diabetic model. Diabetes Cure 8,553-H. Pickup, J. C. (1985). Biosensors: a clinical perspective. Lancet ii, 817-20. Pickup, J. C. & Rothwell, D. (1984). Technology and the diabetic patient. Med. Biol. Eng. Comput. 22,385400. Pickup, J. C., Shaw, G. W. & Claremont, D. J. (1989). In vivo molecular sensing in diabetes mellitus: an implantable glucose sensor with direct electron transfer. Diubetologiu 32,213-7. Ramming, S., Thorsteinsson, B., Bendtson, I., ROM, R. & Binder, C. (1985). Nocturnal hypoglycaemia in patients receiving conventional treatment with insulin. British Medical Journal 291,376-9.
Rasmussen, H., Zawalich, K. C., Ganesan, S., Calle, R. & Zawalich, W. S. (1990). Physiology and pathophysiology of insulin secretion. Diabetes Cure 13,655-66. Reach, G., Thevenot, D. R. & Coulet, P. (1989). Chemical sensors for in vivo monitoring: clinical aspects. Anal. Lett. 22, 2393-401. Rebrin, K., Fischer, U., von Woedtke, T., Abel, P & Brunstein, E. (1989). Automated feedback control of subcutaneous glucose concentration in diabetic dogs. Diubetologiu 32,573-6. Shichiri, M., Kawamori, R., Goriya, Y., Yamasski, Y., Nomura, M., Hakui, N. & Abe, H. (1983). Glycaemic control in pancreatectomized dogs with a wearable artificial endocrine pancreas. Diubetologiu 24, 179-84. Shichiri, M., Kawamori, R., Hakui, N., Yamasaki, Y. & Abe, H. (1984). Closed-loop glycemic control with a wearable artificial endocrine pancreas. Diabetes 33,1200-2. Von Albertini, B. (1988). High efficiency hemodialysis: an overview. Cont. Nephrol. 61,37-45.
APPENDIX The questionnaire was preceded by the following guidance note: “A simple definition of a sensor is a small, probe-type device which can rapidly and specifically measure the concentration of a substance, in our case one of biomedical interest, ideally without added reagent. An example would be a glucose sensor for use in diabetes mellitus. This questionnaire is designed by the Project Management Group of a European Community Concerted Action which is investigating the need and strategies for producing in vivo chemical sensors for use in clinical medicine (research and practice). We define “in vivo” as measurements made inside the body (implanted), on the surface, or close to the body as fluid passes over the sensor (strictly, an ex vivo device). The questions will tell us what clinicians and related professionals think are the main problems where sensors will be helpful, and what the clinical requirements am. In your responses, we would ask you not to be limited by the present state of assay technology or management of diseases, but to try and look ahead and predict what might be the problems and requirements in, say, 20 years time”.
Questionnaire on chemical sensors for in viwo monitoring l
Name
l
Qualification (circle one or more)
PhD
MD
Other (state)
l
Name of main hospital or institution where you are based
l
Address of above
l
Country
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l
Type of Institute (circle)
l
Approx. number of beds
l
What is your clinical speciality?
l
Number of years since qualification
l
l
University/ Teaching Hosp
Genemill other Hosp
since MD
since PhD
List the clinical problems where you consider in vivo sensors would be. helpful (whether or not a suitable sensor currently exists). For each problem that you have identified, choose an analyte (chemical), the in vivo sensing of which would be clinically helpful. Please photocopy this page, if necessary, and use a separate sheet for each problem and its analyte.,
l
Clinical problem (one only)
l
Analyte
l
Recommended sampling frequency (circle one)
l
If intermittent, what should be the time between measurements?
l
What response time would you like for the sensor?
l
What sensing site would you choose?
l
Why would you choose this site?
l
What level of accuracy would be needed for the sensor to be clinically useful?
l
Approximately what level of drift (loss of sensitivity) would be acceptable?
l
What would be the miniium sensor life-time (i.e. before replacement or resiting)?
l
Who would use the sensor? (circle)
l
Would there be an advantage for the sensor to be part of a closed-loop system for delivery of therapy?
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Research Institute
Continuous
Intermittent
% change per hour
junior doctor
senior doctor
nurse
yes
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specialist technician
patient
no
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