Emerging Treatments and Technologies ORIGINAL ARTICLE Accuracy of an Electrochemical Sensor for Measuring Capillary Blood Ketones by Fingerstick Samples During Metabolic Deterioration After Continuous Subcutaneous Insulin Infusion Interruption in Type 1 Diabetic Patients 1 1 BRUNO GUERCI, MD, PHD SEBASTIEN FOUGNOT, MD he Diabetes Control and Complica- 1 2 MURIEL BENICHOU, MD PATRICIA FRANCK, MD tions Trial (DCCT) has demon- 1 1 MICHELE` FLORIOT, MD PIERRE DROUIN, MD 1 strated that intensive diabetes HILIP OHME MD T P B , management, multiple daily injections (MDI) in two-thirds of cases, and contin- uous subcutaneous insulin infusion (CSII) in one-third of cases could reduce the risk of development and progression OBJECTIVE — This study was designed to test the accuracy of capillary ketonemia for diag- of long-term complications of type 1 dia- nosis of ketosis after interruption of insulin infusion. betes (1). CSII provides the most physio- RESEARCH DESIGN AND METHODS — A total of 18 patients with type 1 diabetes logical pattern of insulin delivery cur- treated by external pump were studied during pump stop for 5 h. Plasma and capillary ketone- rently available (2). However, it is now mia and ketonuria were determined every hour from 7:00 A.M. (time 0 min ϭ T0) to 12:00 P.M. clearly established that CSII is associated (time 300 min ϭ T300). Plasma ␤-hydroxybutyrate (␤-OHB) levels were measured by an with a substantial increase in risk of dia- enzymatic end point spectrophotometric method, and capillary ␤-OHB levels were measured by betic ketoacidosis (DKA) compared with an electrochemical method (MediSense Optium meter). Ketonuria was measured by a semiquan- MDI (3,4). In a meta-analysis of 14 stud- titative test (Ketodiastix). Positive ketosis was defined by a value of Ն0.5 mmol/l for ketonemia Ն ies, odds ratios (95% CI) were 7.20 and 4 mmol/l (moderate) for ketonuria. (2.95–17.58) for exclusive use of insulin RESULTS — After stopping the pump, concentrations of ␤-OHB in both plasma and capillary pumps compared with 1.13 (0.15–8.35) blood increased significantly at time 60 min (T60) compared with T0 (P Ͻ 0.001), reaching for MDI (4). Technical problems with maximum levels at T300 (1.30 Ϯ 0.49 and 1.23 Ϯ 0.78 mmol/l, respectively). Plasma and CSII (pump failure, catheter occlusion, capillary ␤-OHB values were highly correlated (r ϭ 0.94, P Ͻ 0.0001). For diagnosis of ketosis, skin infection) may reduce insulin deliv- capillary ketonemia has a higher sensitivity and negative predictive value (80.4 and 82.5%, ery or insulin absorption and cause DKA respectively) than ketonuria (63 and 71.8%, respectively). For plasma glucose levels Ն250 (5). Currently, the use of short-acting in- mg/dl, plasma and capillary ketonemia were found to be more frequently positive (85 and 78%, sulin analogs in external pumps is becom- respectively) than ketonuria (59%) (P ϭ 0.017). The time delay to diagnosis of ketosis was Ϯ Ϯ ϭ ing more widespread because some significantly higher for ketonuria than for plasma ketonemia (212 67 vs. 140 54 min, P studies have shown that the use of such 0.0023), whereas no difference was noted between plasma and capillary ketonemia. analogs provides better glycemic control CONCLUSIONS — The frequency of screening for ketosis and the efficiency of detection of and stability than regular insulin (6–8). ketosis definitely may be improved by the use of capillary blood ketone determination in clinical Considering the pharmacokinetic charac- practice. teristics of these analogs, a short interrup- tion of their infusion in CSII is associated Diabetes Care 26:1137–1141, 2003 with an earlier and greater metabolic de- terioration, probably due to a limited in- sulin depot in subcutaneous adipose ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● tissue (9). In a previous unpaired study, From the 1Service de Diabe´tologie, Maladies Me´taboliques & Maladies de la Nutrition, CIC-INSERM, this was not the case after nighttime insu- 2 Hoˆpital Jeanne d’Arc, Nancy, France; and the Laboratoire de Biochimie, Hoˆpital Central, Nancy, France. lin interruption (10). Address correspondence and reprint requests to Dr. Bruno Guerci, Service de Diabe´tologie, Maladies Me´taboliques & Maladies de la Nutrition, CIC-INSERM/CHU Nancy, Hoˆpital Jeanne d’Arc, Centre Hospi- Consequently, reliable self-monitor- talo-Universitaire de Nancy, B.P. 303, 54201 Toul Cedex, France. E-mail: [email protected]. ing of ketone body levels has become a Received for publication 31 July 2002 and accepted in revised form 23 December 2002. priority in detecting insulin infusion in- P.D. is deceased. terruption. Urinary ketone levels in type 1 Abbreviations: ␤-OHB, ␤-hydroxybutyrate; CSII, continuous subcutaneous insulin infusion; DKA, di- abetic ketoacidosis; MDI, multiple daily injections. diabetic patients are classically used to A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion screen for impending DKA, because de- factors for many substances. lays in the diagnosis and treatment of DIABETES CARE, VOLUME 26, NUMBER 4, APRIL 2003 1137 Capillary ketone bodies during CSII interruption DKA are associated with an increase in reasons of insufficient time and/or de- (BioRad, Richmond, CA) with a normal morbidity and mortality (11,12). How- mands of the experimental protocol. In- range of 4–6%. ever, commercial tests for detecting uri- sulin was infused into the abdomen, for Blood samples for determination of nary ketones are associated with well- which the infusion site was changed every ketone bodies were collected and placed known difficulties in their role as diag- 3 days. None of the patients had experi- on crushed ice. Plasma was immediately nostic and management tools for DKA enced any recent episode of DKA or re- obtained by centrifugation at 4°C. The (13). Recently, inexpensive quantitative quired a daily insulin dose Ͼ1.5 units ⅐ concentration of 3-hydroxybutyrate was Ϫ Ϫ tests of ␤-hydroxybutyrate (␤-OHB) lev- kg 1 ⅐ day 1. Patients with hyperlipid- determined by an enzymatic end point els have become available for use with emia, thyroid or liver disease, diabetic or spectrophotometric method using 3-hy- small blood samples, offering new options nondiabetic renal disease, urinary tract droxybutyrate dehydrogenase (3-HBDH), for monitoring and treating diabetes. Previ- infection, pregnancy, or acute or chronic normal range of 0.06– 0.17 mmol/l ous studies (14,15) have evaluated the ac- inflammatory syndrome were excluded (KONE Delta Automatic Analyzer). This curacy of this new electrochemical sensor from the study. None of the patients had method was used as the reference method. for measuring capillary blood ␤-OHB in proteinuria or microalbuminuria, macro- The intra-assay coefficient of variation comparison to reference plasma ketonemia vascular complications, retinopathy, or was 4.9% (17). determination. hypertension. Finally, patients were in- Capillary plasma glucose was mea- The aim of the present study was to structed to follow a weight-maintenance sured using a Medisense Optium meter determine whether use of capillary blood diet (15% of calories as protein, 35% as (MediSense/Abbott Laboratories, Abing- ketonemia was superior to that of ketonu- fat, and 50% as carbohydrate) taken as ton, U.K.), which is a combined glucose ria for detection of ketosis in terms of de- three main meals and one to three snacks and ketone sensor that produces an elec- layed diagnosis in patients treated by per day. trical current proportional to blood pump after deliberate interruption of ␤-OHB concentration. The Optium strips CSII. Study protocol were plasma calibrated on a YSI reference Patients arrived at the Clinical Research glucose analyzer (Yellow Springs Instru- RESEARCH DESIGN AND Center (CIC/INSERM-CHU de Nancy) ments, Yellow Springs, OH). METHODS the day before the interruption of CSII, at For determination of capillary blood 8:00 P.M., for a calibrated meal. The de- ketone levels, an electrochemical strip Patients sign of the protocol was similar to that was inserted into the sensor to which 5 ␮l The study comprised 18 patients with previously described (9). No hypoglyce- of capillary blood was applied. The type 1 diabetes, diagnosed according to mia episode was tolerated during the 24 h ␤-OHB, in the presence of hydroxybu- American Diabetes Association criteria before interruption of CSII. Patients tyrate deshydrogenase, was oxidized to (16), who were C-peptide negative (Ͻ0.3 fasted for 11 h, until 7:00 A.M. (no break- acetoacetate with the concomitant reduc- nmol/l, 6 min after intravenous adminis- fast), at which time the pump was tion of NADϩ to NADH. The NADH was tration of 1 mg glucagon). The patients stopped and the catheter was discon- reoxidized to NADϩ by a redox mediator, were treated with infusion of insulin via nected. Every hour from 7:00 A.M. (time 0 such that the current generated was di- an external pump (MiniMed Infusor 507, min ϭ T0) to 12:00 P.M. (time 300 min ϭ rectly proportional to the 3-hydroxybu- 507C, or 508; MiniMed Technologies, T300), plasma glucose levels and ketone- tyrate concentration. After 30 s, the Northridge, CA) and a deconnectable mia as well as capillary blood glucose lev- 3-hydroxybutyrate concentration in a catheter, either the Tender catheter (Dis- els and ketonemia were measured, along sample was displayed. This system is ac- etronic Medical Systems, Burgdorf, Swit- with ketonuria. The pump of each patient curate for 3-hydroxybutyrate levels from zerland) or the Sofset QR (MiniMed). The was then reactivated at 12:00 P.M. (T300) 0 to 6 mmol/l. On three different levels of type of insulin used in the pumps was at the patient’s usual basal rate, at which ␤-OHB (low at the mean of 0.43, moder- velosulin (Velosulin HM, U-100; Novo- time the patients ate a calibrated lunch ate at 1.08, and high at 3.55 mmol/l), the Nordisk, Boulogne-Billancourt, France) and activated their usual prelunch insulin intra-assay coefficients of variation (cal- in eight patients and lispro (Humalog boluses.