Real-Time Continuous Glucose Monitoring in Pediatric Patients During and After Cardiac Surgery

Real-Time Continuous Glucose Monitoring in Pediatric Patients During and After Cardiac Surgery
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  DOI: 10.1542/peds.2006-0347 2006;118;1176 Pediatrics Costello, Peter C. Laussen, Tom Jaksic and Michael S.D. AgusHannah G. Piper, Jamin L. Alexander, Avinash Shukla, Frank Pigula, John M. After Cardiac SurgeryReal-Time Continuous Glucose Monitoring in Pediatric Patients During and located on the World Wide Web at: The online version of this article, along with updated information and services, is   of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2006 by the American Academy published, and trademarked by the American Academy of Pediatrics, 141 Northwest Pointpublication, it has been published continuously since 1948. PEDIATRICS is owned, PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly  by guest on May 30, 2013pediatrics.aappublications.orgDownloaded from   STATE-OF-THE-ARTREVIEWARTICLE Real-Time Continuous Glucose Monitoring inPediatric Patients During and After Cardiac Surgery HannahG.Piper,MD a ,JaminL.Alexander,BA b ,AvinashShukla,MD c ,FrankPigula,MD d ,JohnM.Costello,MD e ,PeterC.Laussen,MD e ,TomJaksic,MD,PhD a ,MichaelS. D.Agus,MD b Departments of   a Surgery,  b Medicine,  c Anesthesia,  d Cardiovascular Surgery, and  e Cardiology, Children’s Hospital Boston, Harvard Medical School, Boston, Massachusetts Financial disclosure: Dr Agus is the recipient of unrestricted research grants by Medtronic Minimed to support different investigator-initiated research projects. Monitors and sensors for this project weredonated by Medtronic Minimed. ABSTRACT OBJECTIVES. Given the demonstrated benefit of euglycemia in critically ill patients aswell as the risk for hypoglycemia during insulin infusion in children, we sought tovalidate a subcutaneous sensor for real-time continuous glucose monitoring inpediatric patients during and after cardiac surgery. METHODS. Children up to 36 months of age who were undergoing cardiac bypasssurgery were recruited. After anesthetic induction, a continuous glucose-monitor-ing system sensor (CGMS, Medtronic Minimed, Northridge, CA) was insertedsubcutaneously. Sensors remained in place for up to 72 hours. Arterial bloodglucose was measured intermittently in the central laboratory (Bayer Rapidlab860, Tarrytown, NY). Sensor data, after prospective calibration with 6-hourlylaboratory values using the proprietary Medtronic Minimed Guardian RT algo-rithm, were compared with all laboratory glucose values. Statistical analysis wasperformed to test whether sensor performance was affected by body temperature,inotrope dose, or body-wall edema. RESULTS. Twenty patients were enrolled in the study for a total of 40 study days and246 paired sensor and laboratory glucose values. Consensus error grid analysisdemonstrated that 72.0% of sensor value comparisons were within zone A (noeffect on clinical action), and 27.6% of comparisons were within zone B (alteredclinical action of little or no effect on outcome), with a mean absolute relativedeviation of 17.6% for all comparisons. One comparison (0.4%) was in zone C(altered clinical action likely to affect outcome). No significant correlations werefound between sensor performance and body temperature, inotrope dose, or body-wall edema. All patients tolerated the sensors well without bleeding or tissuereaction. CONCLUSIONS. Guardian RT real-time subcutaneous blood glucose measurement issafe and potentially useful for continuous glucose monitoring in critically illchildren. Subcutaneous sensors performed well in the setting of hypothermia,inotrope use, and edema. These sensors facilitate identifying and following theeffects of interventions to control blood glucose. KeyWords glucose monitoring, cardiac surgery,hyperglycemia Abbreviations CGMS—continuous glucose-monitoringsystemCICU—cardiac ICUMARD—mean absolute relative difference Accepted for publication Apr 28, 2006Address correspondence to Michael S.D.Agus, MD, Children’s Hospital Boston, 300Longwood Ave, Main 9 South, Boston, MA02115. E-mail: michael.agus@childrens.harvard.eduPEDIATRICS(ISSNNumbers:Print,0031-4005;Online,1098-4275).Copyright©2006bytheAmericanAcademyofPediatrics 1176  PIPER et al  by guest on May 30, 2013pediatrics.aappublications.orgDownloaded from   T HE BENEFITS OF  glucose control in the perioperativeperiod are becoming increasingly clear for both di-abetic and nondiabetic patients. Clinical trials in theadult surgical population have demonstrated 35% to53% reductions in mortality and even more significantreductions in morbidity. 1,2 Although similar studies havenot been published in the pediatric patient population,critically ill infants and children may also benefit fromglycemic control while in the ICU and during the peri-operative period. 3 One of the major obstacles encountered in designinga pediatric intervention trial for tight glycemic control isthe risk of hypoglycemia from insulin administration.Infants and young children often have reduced glycogenreserve, especially in the setting of physiologic stress, 4 and insulin therapy in this setting may place them at riskfor developing hypoglycemia. Adult studies have dem-onstrated a significant increase in the incidence of hy-poglycemia among patients randomly assigned to tightglucose control ranging from 34% to 39%. 2,5 In criticallyill children, hypoglycemia can be difficult to detect clin-ically and, if not treated immediately, can lead to braindamage or death, particularly in the young, developingchild. 6 Giventhepotentialrisksofestablishingstrictglycemiccontrol in pediatric patients, the use of a continuousglucose monitor is the only viable option to ensure max-imal safety. The US Food and Drug Administration ap-proved the continuous glucose-monitoring system(CGMS, Medtronic Minimed, Northridge, CA) in 1999for clinical use. The CGMS relies on the interstitial fluidfor measuring blood glucose. This device is the first suchsystem to be available worldwide and has been used inmultiple published studies, including use in adult pa-tients undergoing cardiac surgery. 7 However, it is a ret-rospective monitor, because data are collected over a72-hour period and then correlated with values obtainedfrom the patient’s hand-held glucose meter, which isconsidered the gold standard. In 2005, a new real-timeglucose monitor became available: Guardian RT(Medtronic Minimed). Although it uses the same hard-ware as the CGMS, the data from the sensor are inter-preted in real time, and glucose concentration is dis-played live every 5 minutes.It is unknown whether glucose concentrations in theinterstitial fluid remain in equilibrium with blood con-centrations during conditions that could compromisesubcutaneous tissue perfusion. Infants undergoing con-genital cardiac surgery are ideal for study in this regard.They are subject to changes in cardiac output, bodytemperature, and edema related to both cardiopulmo-nary bypass and the induced systemic inflammatory re-sponse. In addition, these infants have altered myocar-dial physiology related to the underlying disease andsurgical procedure itself.This study was designed to evaluate the real-timeglucose sensor under varying physiologic conditions in acohort of neonates and infants undergoing pediatric car-diac surgery with the hypothesis that the glucose levelmeasured by the Guardian RT will be accurate whencompared with the gold standard of direct blood glucosemeasurement. METHODS Patient Enrollment The study was approved by the Children’s Hospital Bos-ton institutional review board, and written informedconsent was obtained from the parent or guardian ofeach patient. We prospectively enrolled a conveniencesample of children   36 months of age who weighed atleast 2 kg and were referred for elective cardiac surgery. CGMS The Guardian RT is a CGMS composed of 3 parts: asubcutaneous glucose sensor, a battery-powered moni-tor, and a Com-Station for downloading stored data to acomputer. The sensor is a platinum microelectrodecoated with glucose oxidase and covered with a semi-permeable membrane. Ambient glucose from interstitialfluid interacts with the enzyme to produce an electriccurrent proportional to glucose concentration. The sen-sor is inserted through a small needle into the subcuta-neous tissue (most often in the abdomen or lower ex-tremity) and then attached to the small monitor by aflexible cord (Fig 1). The monitor receives an electricsignal from the sensor every 10 seconds and stores amean glucose measurement every 5 minutes. The datacan be downloaded to a computer for review at any time by using the CGMS Com-Station and software. Sensor Insertion and Monitoring Sensors were inserted after induction of general anes-thesia in the operating room. In all cases, the sensorswere placed by hand into the subcutaneous tissue of theproximal lateral thigh to prevent interference with thesurgical field. After a 5-minute equilibration period, thesensor was connected with the continuous glucose mon-itor. The external portion of the sensor was then coveredwith a transparent adhesive dressing. Sensors remainedin place for a maximum of 72 hours unless the patientwastransferredoutofthecardiacICU(CICU)beforethattime point. Sensor removal was performed at the pa-tient’s bedside and did not require additional sedation.Intraoperative arterial whole-blood glucose concentra-tions were obtained approximately every 30 minutesand analyzed in the clinical laboratory using the NovaBiomedical (Waltham, MA) Critical Care Express ma-chine. Postoperative arterial whole-blood samples weredrawn every 4 to 8 hours and analyzed in the clinicallaboratory using the Bayer Diagnostics (Tarrytown, NY)Rapidlab 860 machine. The intraoperative and postop- PEDIATRICS Volume 118, Number 3, September 2006  1177  by guest on May 30, 2013pediatrics.aappublications.orgDownloaded from   erative whole-blood samples (arterial values) were usedas the gold-standard blood glucose values for all com-parisons. Calibration The live glucose readings were calculated by using theGuardian RT proprietary prospective interpretive algo-rithm developed by Medtronic Minimed. This algorithmrequired calibration using arterial values at least every12 hours, and for this study, calibration values wereenteredevery6hours.Aftercalibration,allsensorvalueswere compared with time-matched arterial samples. Ar-terial values used as part of the calibration algorithmwere compared with the sensor value 5 minutes beforethe time of arterial measurement. Real-time glucoseconcentrations were not available to the bedside clinicalteam and were not used to alter clinical management. Sensor Performance Under Physiologic Stress The following parameters were used to evaluate theperformance of the Guardian RT under different physi-ologic conditions:1. Body temperature at the time of glucose value com-parison: Temperature was measured continuouslywhile in the operating room and then intermittentlywhile in the CICU.2. Inotrope use at the time of glucose value comparison:This was used as an index of critical illness. Increasedinotrope use is often a marker of increased physio-logic stress and severity of illness. Inotrope use wascalculated by the inotrope score as follows: inotropescore    (dopamine dose   g/kg per min    1)    (do- butamine dose   g/kg per min    1)    (epinephrinedose   g/kg per min  100)  (milrinone dose   g/kgper min  10)  (phenylephrine dose   g/kg per min   100)    (norepinephrine dose   g/kg per min   100). This formula was adapted from Wernovsky etal. 8 3. Body-wall edema at the time of glucose comparison:A radiologic index of body-wall edema was calculatedfrom chest radiographs at the time of glucose valuecomparison. This index was defined as the ratio of thewidth of the soft tissue at the height of the eighth ribto the diameter of the eighth rib at the midclavicularline. Ratios   2 were arbitrarily considered evidenceof some edema for the purpose of comparing edem-atous and nonedematous patients. This radiographicindex has been published and used for neonates un-dergoing cardiac surgery. 9 Statistical Analysis The mean absolute relative difference (MARD) as well asthe Pearson correlation coefficient was calculated for allmatched Guardian RT and reference arterial values, ex-cluding points used for initial calibration. In addition, allmatched points were plotted on a Clarke error grid. 10 Clarke error analysis was designed specifically to evalu-ate the accuracy of capillary blood glucose testing sys-tems for ambulatory diabetics. The graph is divided into5 zones. Comparison points within zone A representCGMS and reference values that differ from each other by no more than 20%. Zone B includes comparisonpoints that differ by   20% but do not result in analteration in treatment. Comparison points in zone Cwould result in an overcorrection of an acceptable glu-cose value, and those in zone D would not result incorrection when, in truth, treatment should be admin-istered. Comparisons in zone E would prompt inversetreatment. All comparison points were also plotted on aconsensus error grid, which is similar to the Clarke errorgrid but is based on the consensus of 100 endocrinolo-gists. 11 The 5 defined risk categories include A (no effecton clinical action), B (altered clinical action with little orno effect on outcome), C (altered clinical action likely toaffect outcome), D (altered clinical action that couldhave significant medical risk), and E (altered clinicalaction that could have dangerous consequences). Sensor FIGURE 1 Guardian RT sensor (A) and monitor (B). 1178  PIPER et al  by guest on May 30, 2013pediatrics.aappublications.orgDownloaded from   performance was correlated with the temperature, ino-trope score, and index of body-wall edema using theSpearman correlation coefficient with significance at  P   .05. MARDs under different conditions were compared by using the Wilcoxon rank-sum test with significance at P   .05. RESULTS A total of 20 patients were enrolled, and all completedthe study (Table 1). All patients underwent cardiac sur-gery, and 16 required cardiopulmonary bypass. TheGuardian RT was in use for an average of 48  19 hoursfor each patient (Fig 2). Although each sensor can beused for up to 72 hours, the most common indication forpremature removal in our study was transfer of thepatient from the CICU to the cardiac ward.Sensors were well tolerated in all patients. There wereno instances of adverse skin reactions, infections, orsensor dislodgment within our patient population. Overall Performance Throughout the study a total of 246 blood glucose valueswere compared between the sensors and our arterialgold-standard values. The number of comparison pointsobtained for each sensor in the study ranged from 1 to26, with an average of 12 comparisons per sensor. Theoverall MARD between sensor glucose values and arte-rial samples was 17.6%; the Pearson’s correlation coef-ficient was 0.787 ( P   .001). However, because some ofthe sensors had very few comparison points, we alsoanalyzed the pooled data for all sensors tested. Whencomparison points were plotted on the traditional Clarkeerror grid, 66.3% of values were in zone A, 32.5% inzone B, 1.2% in zone D, and 0% in zones C or E (Fig 3).When using the consensus error grid, 72.0% of pointswere found in zone A, 27.6% in zone B, and 0.4% inzone C (Fig 4).In 20 patients there were 20 initial calibrations and109 recalibrations. At 2 of these recalibrations, the dif-ference between sensor glucose and laboratory glucoseexceeded the sensor’s limit and the sensors were auto-matically deactivated until a confirmatory laboratoryglucose measurement could be performed. In the re- FIGURE 2 Representativesamplesofbloodglucosetracingsfrom4subjectsareshowninAthroughD. Solid and hatched bars on the x-axis specify intraoperative (OR) and postoperative(ICU)periods.Opencirclesrepresentcentrallaboratoryarterialbloodglucoseconcentra-tions, and the solid line indicates continuous sensor tracing. TABLE 1  Patient Characteristics  Total No. of Patients 20Male/female 7:13Age, mean  SD, mo 9.9  10.6Weight, mean  SD, kg 7.2  3.7Primary diagnosis,  n  (%) Tetralogy of Fallot 4(20)Ventricular septal defect 4(20)Hypoplastic left heart syndrome 4(20)Complete atrioventricular canal defect 3(15)Hypoplastic right heart 3(15) Tricuspid atresia 2(10)PEDIATRICS Volume 118, Number 3, September 2006  1179  by guest on May 30, 2013pediatrics.aappublications.orgDownloaded from 
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