Performance of an Electronic Decision Support System as a Therapeutic Intervention During a Multicenter PICU Clinical Trial: Heart and Lung Failure-Pediatric Insulin Titration Trial (HALF-PINT).

BACKGROUND: The use of electronic clinical decision support (CDS) systems for pediatric critical care trials is rare. We sought to describe in detail the use of a CDS tool (Children's Hospital Euglycemia for Kids Spreadsheet [CHECKS]), for the management of hyperglycemia during the 32 multicenter Heart And Lung Failure-Pediatric Insulin Titration trial. RESEARCH QUESTION: In critically ill pediatric patients who were treated with CHECKS, how was user compliance associated with outcomes; and what patient and clinician factors might account for the observed differences in CHECKS compliance? STUDY DESIGN AND METHODS: During an observational retrospective study of compliance with a CDS tool used during a prospective randomized controlled trial, we compared patients with high and low CHECKS compliance. We investigated the association between compliance and blood glucose metrics. We describe CHECKS and use a computer interface analysis framework (the user, function, representation, and task analysis framework) to categorize user interactions. We discuss implications for future randomized controlled trials. RESULTS: Over a 4.5-year period, 658 of 698 children were treated with the CHECKS protocol for ≥24 hours with a median of 119 recommendations per patient. Compliance per patient was high (median, 99.5%), with only 30 patients having low compliance (<90%). Patients with low compliance were from 16 of 32 sites, younger (P = .02), and less likely to be on inotropic support (P = .04). They were more likely to be have been assigned randomly to the lower blood glucose target (80% vs 48%; P < .001) and to have spent a shorter time (53% vs 75%; P < .001) at the blood glucose target. Overrides (classified by the user, function, representation, and task analysis framework), were largely (89%) due to the user with patient factors contributing 29% of the time. INTERPRETATION: The use of CHECKS for the Heart And Lung Failure-Pediatric Insulin Titration trial resulted in a highly reproducible and explicit method for the management of hyperglycemia in critically ill children across varied environments. CDS systems represent an important mechanism for conducting explicit complex pediatric critical care trials. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01565941, registered March 29 2012; https://clinicaltrials.gov/ct2/show/NCT01565941?term=HALF-PINT&draw=2&rank=1.

Amount and Type of Dietary Fat, Postprandial Glycemia, and Insulin Requirements in Type 1 Diabetes: A Randomized Within-Subject Trial.

OBJECTIVE: The American Diabetes Association recommends individuals with type 1 diabetes (T1D) adjust insulin for dietary fat; however, optimal adjustments are not known. This study aimed to determine 1) the relationship between the amount and type of dietary fat and glycemia and 2) the optimal insulin adjustments for dietary fat. RESEARCH DESIGN AND METHODS: Adults with T1D using insulin pump therapy attended the research clinic on 9-12 occasions. On the first six visits, participants consumed meals containing 45 g carbohydrate with 0 g, 20 g, 40 g, or 60 g fat and either saturated, monounsaturated, or polyunsaturated fat. Insulin was dosed using individual insulin/carbohydrate ratio as a dual-wave 50/50% over 2 h. On subsequent visits, participants repeated the 20-60-g fat meals with the insulin dose estimated using a model predictive bolus, up to twice per meal, until glycemic control was achieved. RESULTS: With the same insulin dose, increasing the amount of fat resulted in a significant dose-dependent reduction in incremental area under the curve for glucose (iAUCglucose) in the early postprandial period (0-2 h; P = 0.008) and increase in iAUCglucose in the late postprandial period (2-5 h; P = 0.004). The type of fat made no significant difference to the 5-h iAUCglucose. To achieve glycemic control, on average participants required dual-wave insulin bolus: for 20 g fat, +6% insulin, 74/26% over 73 min; 40 g fat, +6% insulin, 63/37% over 75 min; and 60 g fat, +21% insulin, 49/51% over 105 min. CONCLUSIONS: This study provides clinical guidance for mealtime insulin dosing recommendations for dietary fat in T1D.

Continuous Glucose Monitoring Linked to an Artificial Intelligence Risk Index: Early Footprints of Intraventricular Hemorrhage in Preterm Neonates.

OBJECTIVE: To develop and validate a new risk score for intraventricular hemorrhage (IVH) in preterm neonates based on continuous glucose monitoring (CGM). STUDY DESIGN: We retrospectively analyzed CGM traces obtained from 50 very preterm neonates, grouped into two sub-cohorts started on CGM within 12 and 48 h of birth, respectively. A CGM linked to an Artificial Intelligence Risk (CLAIR) index was developed to quantify glucose variability during the first 72 h of life in neonates with and without IVH. Brain-US was performed at least twice a day for the first 5 days of birth. An integrated remote monitoring platform was developed to capture major clinical events in real time and gather data for the risk index. The new score performance was further compared with other measures of glucose variability (coefficient of variation [CV] and standard deviation [SD]) and with a clinical risk index for babies II (CRIB-II) as a predictor of IVH event. The two cohorts were analyzed separately for internal validation of the method. RESULTS: The primary cohort consisted of 26 neonates (gestational age 30 [28, 31] weeks; BW1275 g[1090, 1750]). Controls (n = 23) exhibited higher CLAIR index than cases (P = 0.004). A cut-off of 0.69 for the new CLAIR index allowed a 100% sensitivity and an 83% specificity for IVH prediction. The CLAIR index was the sole significant predictor for IVH (P = 0.003) when compared with clinical variables, CV, SD, and CRIB-II. In a subgroup analysis in very low-birth-weight infants, the CLAIR index was the sole variable significantly associated with IVH (P = 0.009). Analysis on the secondary cohort (five cases and 16 controls) confirmed a higher CLAIR index in the controls (P = 0.008), in the absence of a difference for CV, SD, and CRIB-II between the two groups. CONCLUSION: CGM, combined with the AI-algorithm, provides a high-sensitivity index for risk detection of IVH that reflects the glycemic impairment preceding IVH.

Short-Term Adverse Outcomes Associated With Hypoglycemia in Critically Ill Children.

OBJECTIVES: Previous studies report worse short-term outcomes with hypoglycemia in critically ill children. These studies relied on intermittent blood glucose measurements, which may have introduced detection bias. We analyzed data from the Heart And Lung Failure-Pediatric INsulin Titration trial to determine the association of hypoglycemia with adverse short-term outcomes in critically ill children. DESIGN: Nested case-control study. SETTING: Thirty-five PICUs. A computerized algorithm that guided the timing of blood glucose measurements and titration of insulin infusion, continuous glucose monitors, and standardized glucose infusion rates were used to minimize hypoglycemia. PATIENTS: Nondiabetic children with cardiovascular and/or respiratory failure and hyperglycemia. Cases were children with any hypoglycemia (blood glucose < 60 mg/dL), whereas controls were children without hypoglycemia. Each case was matched with up to four unique controls according to age group, study day, and severity of illness. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 112 (16.0%) of 698 children who received the Heart And Lung Failure-Pediatric INsulin Titration protocol developed hypoglycemia, including 25 (3.6%) who developed severe hypoglycemia (blood glucose < 40 mg/dL). Of these, 110 cases were matched to 427 controls. Hypoglycemia was associated with fewer ICU-free days (median, 15.3 vs 20.2 d; p = 0.04) and fewer hospital-free days (0 vs 7 d; p = 0.01) through day 28. Ventilator-free days through day 28 and mortality at 28 and 90 days did not differ between groups. More children with insulin-induced versus noninsulin-induced hypoglycemia had zero ICU-free days (35.8% vs 20.9%; p = 0.008). Outcomes did not differ between children with severe versus nonsevere hypoglycemia or those with recurrent versus isolated hypoglycemia. CONCLUSIONS: When a computerized algorithm, continuous glucose monitors and standardized glucose infusion rates were used to manage hyperglycemia in critically ill children with cardiovascular and/or respiratory failure, severe hypoglycemia (blood glucose < 40 mg/dL) was uncommon, but any hypoglycemia (blood glucose < 60 mg/dL) remained common and was associated with worse short-term outcomes.

Adjusting Insulin Delivery to Activity (AIDA) clinical trial: Effects of activity-based insulin profiles on glucose control in children with type 1 diabetes.

BACKGROUND: Increased daytime activity in children with type I diabetes mellitus (T1DM) is associated with increased risk of hypoglycemia. OBJECTIVE: To determine whether an automated weekly review of accelerometer, continuous glucose monitoring (CGM), and insulin pump data, could be used to identify children with increased risk of nighttime hypoglycemia and preemptively adjust the nighttime basal insulin profile according to daytime activity. RESEARCH AND DESIGN METHODS: Clinical trial of children with T1DM on insulin pump and CGM therapy. Subjects at risk of nighttime hypoglycemia were identified from regression analysis of daytime step count vs nighttime nadir glucose. If the regression slope was significantly different from zero (P < 0.05) subjects were managed with different algorithm derived nighttime basal insulin profiles following high and low activity days. RESULTS: Twenty children (median age: 12; range: 7-17 years) were enrolled. Regression slopes were significant in 10 children. In these children, baseline nighttime nadir glucose level was lower following high activity days (120 [110-139] vs 152 [130-162] mg/dL, P = 0.004). Use of activity-based nighttime basal profiles produced similar nighttime nadir glucose levels following high and low activity days (136 [123-175] vs 140 [108-180] mg/dL, P = 0.73) with fewer nighttime interventions to correct hypoglycemia (0 [0-0.16] vs 0.15 [0.13-0.22] per night, P = 0.008). CONCLUSION: Children with lower nighttime glucose levels following high daytime activity can be identified using step count data obtained from readily available accelerometers and the nighttime glucose control improved using different activity-based basal profiles.

Procedural Pain during Insertion of a Continuous Glucose Monitoring Device in Preterm Infants.

Procedural pain was compared between the insertion of a continuous glucose monitoring sensor and heel stick using the Premature Infant Pain Profile in a single-blinded controlled trial in preterm infants (≤32 weeks of gestation or birth weight ≤1500 g) (ClinicalTrials.govNCT02583776). Continuous glucose monitoring insertion was associated with lower pain scores compared with the heel stick.

Continuous Glucose Monitoring in Very Preterm Infants: A Randomized Controlled Trial.

BACKGROUND AND OBJECTIVES: Impaired glucose control in very preterm infants is associated with increased morbidity, mortality, and poor neurologic outcome. Strategies based on insulin titration have been unsuccessful in achieving euglycemia in absence of an increase in hypoglycemia and mortality. We sought to assess whether glucose administration guided by continuous glucose monitoring (CGM) is more effective than standard of care blood glucose monitoring in maintaining euglycemia in very preterm infants. METHODS: Fifty newborns ≤32 weeks' gestation or with birth weight ≤1500 g were randomly assigned (1:1) within 48-hours from birth to receive computer-guided glucose infusion rate (GIR) with or without CGM. In the unblinded CGM group, the GIR adjustments were driven by CGM and rate of glucose change, whereas in the blinded CGM group the GIR was adjusted by using standard of care glucometer on the basis of blood glucose determinations. Primary outcome was percentage of time spent in euglycemic range (72-144 mg/dL). Secondary outcomes were percentage of time spent in mild (47-71 mg/dL) and severe (<47 mg/dL) hypoglycemia; percentage of time in mild (145-180 mg/dL) and severe (>180 mg/dL) hyperglycemia; and glucose variability. RESULTS: Neonates in the unblinded CGM group had a greater percentage of time spent in euglycemic range (median, 84% vs 68%, P < .001) and decreased time spent in mild (P = .04) and severe (P = .007) hypoglycemia and in severe hyperglycemia (P = .04) compared with the blinded CGM group. Use of CGM also decreased glycemic variability (SD: 21.6 ± 5.4 mg/dL vs 27 ± 7.2 mg/dL, P = .01; coefficient of variation: 22.8% ± 4.2% vs 27.9% ± 5.0%; P < .001). CONCLUSIONS: CGM-guided glucose titration can successfully increase the time spent in euglycemic range, reduce hypoglycemia, and minimize glycemic variability in preterm infants during the first week of life.

Tight Glycemic Control in Critically Ill Children.

BACKGROUND: In multicenter studies, tight glycemic control targeting a normal blood glucose level has not been shown to improve outcomes in critically ill adults or children after cardiac surgery. Studies involving critically ill children who have not undergone cardiac surgery are lacking. METHODS: In a 35-center trial, we randomly assigned critically ill children with confirmed hyperglycemia (excluding patients who had undergone cardiac surgery) to one of two ranges of glycemic control: 80 to 110 mg per deciliter (4.4 to 6.1 mmol per liter; lower-target group) or 150 to 180 mg per deciliter (8.3 to 10.0 mmol per liter; higher-target group). Clinicians were guided by continuous glucose monitoring and explicit methods for insulin adjustment. The primary outcome was the number of intensive care unit (ICU)-free days to day 28. RESULTS: The trial was stopped early, on the recommendation of the data and safety monitoring board, owing to a low likelihood of benefit and evidence of the possibility of harm. Of 713 patients, 360 were randomly assigned to the lower-target group and 353 to the higher-target group. In the intention-to-treat analysis, the median number of ICU-free days did not differ significantly between the lower-target group and the higher-target group (19.4 days [interquartile range {IQR}, 0 to 24.2] and 19.4 days [IQR, 6.7 to 23.9], respectively; P=0.58). In per-protocol analyses, the median time-weighted average glucose level was significantly lower in the lower-target group (109 mg per deciliter [IQR, 102 to 118]; 6.1 mmol per liter [IQR, 5.7 to 6.6]) than in the higher-target group (123 mg per deciliter [IQR, 108 to 142]; 6.8 mmol per liter [IQR, 6.0 to 7.9]; P<0.001). Patients in the lower-target group also had higher rates of health care-associated infections than those in the higher-target group (12 of 349 patients [3.4%] vs. 4 of 349 [1.1%], P=0.04), as well as higher rates of severe hypoglycemia, defined as a blood glucose level below 40 mg per deciliter (2.2 mmol per liter) (18 patients [5.2%] vs. 7 [2.0%], P=0.03). No significant differences were observed in mortality, severity of organ dysfunction, or the number of ventilator-free days. CONCLUSIONS: Critically ill children with hyperglycemia did not benefit from tight glycemic control targeted to a blood glucose level of 80 to 110 mg per deciliter, as compared with a level of 150 to 180 mg per deciliter. (Funded by the National Heart, Lung, and Blood Institute and others; HALF-PINT ClinicalTrials.gov number, NCT01565941 .).

Optimized Mealtime Insulin Dosing for Fat and Protein in Type 1 Diabetes: Application of a Model-Based Approach to Derive Insulin Doses for Open-Loop Diabetes Management.

OBJECTIVE: To determine insulin dose adjustments required for coverage of high-fat, high-protein (HFHP) meals in type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS: Ten adults with T1D received low-fat, low-protein (LFLP) and HFHP meals with identical carbohydrate content, covered with identical insulin doses. On subsequent occasions, subjects repeated the HFHP meal with an adaptive model-predictive insulin bolus until target postprandial glycemic control was achieved. RESULTS: With the same insulin dose, the HFHP increased the glucose incremental area under the curve over twofold (13,320 ± 2,960 vs. 27,092 ± 1,709 mg/dL ⋅ min; P = 0.0013). To achieve target glucose control following the HFHP, 65% more insulin was required (range 17%-124%) with a 30%/70% split over 2.4 h. CONCLUSIONS: This study demonstrates that insulin dose calculations need to consider meal composition in addition to carbohydrate content and provides the foundation for new insulin-dosing algorithms to cover meals of varying macronutrient composition.

Bolus Estimation--Rethinking the Effect of Meal Fat Content.

BACKGROUND: Traditionally, insulin bolus calculations for managing postprandial glucose levels in individuals with type 1 diabetes rely solely on the carbohydrate content of a meal. However, recent studies have reported that other macronutrients in a meal can alter the insulin required for good postprandial control. Specifically, studies have shown that high-fat (HF) meals require more insulin than low-fat (LF) meals with identical carbohydrate content. Our objective was to assess the mechanisms underlying the higher insulin requirement observed in one of these studies. MATERIALS AND METHODS: We used a combination of previously validated metabolic models to fit data from a study comparing HF and LF dinners with identical carbohydrate content in seven subjects with type 1 diabetes. For each subject and dinner type, we estimated the model parameters representing the time of peak meal-glucose appearance (τ(m)), insulin sensitivity (S(I)), the net hepatic glucose balance, and the glucose effect at zero insulin in four time windows (dinner, early night, late night, and breakfast) and assessed the differences in model parameters via paired Wilcoxon signed-rank tests. RESULTS: During the HF meal, the τ(m) was significantly delayed (mean and standard error [SE]: 102 [14] min vs. 71 [4] min; P = 0.02), and S(I) was significantly lower (7.25 × 10(-4) [1.29 × 10(-4)] mL/µU/min vs. 8.72 × 10(-4) [1.08 × 10(-4)] mL/µU/min; P = 0.02). CONCLUSIONS: In addition to considering the putative delay in gastric emptying associated with HF meals, we suggest that clinicians reviewing patient records consider that the fat content of these meals may alter S(I).

Impact of fat, protein, and glycemic index on postprandial glucose control in type 1 diabetes: implications for intensive diabetes management in the continuous glucose monitoring era.

BACKGROUND: Continuous glucose monitoring highlights the complexity of postprandial glucose patterns present in type 1 diabetes and points to the limitations of current approaches to mealtime insulin dosing based primarily on carbohydrate counting. METHODS: A systematic review of all relevant biomedical databases, including MEDLINE, Embase, CINAHL, and the Cochrane Central Register of Controlled Trials, was conducted to identify research on the effects of dietary fat, protein, and glycemic index (GI) on acute postprandial glucose control in type 1 diabetes and prandial insulin dosing strategies for these dietary factors. RESULTS: All studies examining the effect of fat (n = 7), protein (n = 7), and GI (n = 7) indicated that these dietary factors modify postprandial glycemia. Late postprandial hyperglycemia was the predominant effect of dietary fat; however, in some studies, glucose concentrations were reduced in the first 2-3 h, possibly due to delayed gastric emptying. Ten studies examining insulin bolus dose and delivery patterns required for high-fat and/or high-protein meals were identified. Because of methodological differences and limitations in experimental design, study findings were inconsistent regarding optimal bolus delivery pattern; however, the studies indicated that high-fat/protein meals require more insulin than lower-fat/protein meals with identical carbohydrate content. CONCLUSIONS: These studies have important implications for clinical practice and patient education and point to the need for research focused on the development of new insulin dosing algorithms based on meal composition rather than on carbohydrate content alone.

Tight glycemic control in the ICU - is the earth flat?

Tight glycemic control in the ICU has been shown to reduce mortality in some but not all prospective randomized control trials. Confounding the interpretation of these studies are differences in how the control was achieved and underlying incidence of hypoglycemia, which can be expected to be affected by the introduction of continuous glucose monitoring (CGM). In this issue of Critical Care, a consensus panel provides a list of the research priorities they believe are needed for CGM to become routine practice in the ICU. We reflect on these recommendations and consider the implications for using CGM today.

Tight glycemic control after pediatric cardiac surgery in high-risk patient populations: a secondary analysis of the safe pediatric euglycemia after cardiac surgery trial.

BACKGROUND: Our previous randomized, clinical trial showed that postoperative tight glycemic control (TGC) for children undergoing cardiac surgery did not reduce the rate of health care-associated infections compared with standard care (STD). Heterogeneity of treatment effect may exist within this population. METHODS AND RESULTS: We performed a post hoc exploratory analysis of 980 children from birth to 36 months of age at the time of cardiac surgery who were randomized to postoperative TGC or STD in the intensive care unit. Significant interactions were observed between treatment group and both neonate (age ≤30 days; P=0.03) and intraoperative glucocorticoid exposure (P=0.03) on the risk of infection. The rate and incidence of infections in subjects ≤60 days old were significantly increased in the TGC compared with the STD group (rate: 13.5 versus 3.7 infections per 1000 cardiac intensive care unit days, P=0.01; incidence: 13% versus 4%, P=0.02), whereas infections among those >60 days of age were significantly reduced in the TGC compared with the STD group (rate: 5.0 versus 14.1 infections per 1000 cardiac intensive care unit days, P=0.02; incidence: 2% versus 5%, P=0.03); the interaction of treatment group by age subgroup was highly significant (P=0.001). Multivariable logistic regression controlling for the main effects revealed that previous cardiac surgery, chromosomal anomaly, and delayed sternal closure were independently associated with increased risk of infection. CONCLUSIONS: This exploratory analysis demonstrated that TGC may lower the risk of infection in children >60 days of age at the time of cardiac surgery compared with children receiving STD. Meta-analyses of past and ongoing clinical trials are necessary to confirm these findings before clinical practice is altered. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00443599.

Cardiac output assessed by non-invasive monitoring is associated with ECG changes in children with critical asthma.

The primary aim of this study was to determine changes in CI and SI, if any, in children hospitalized with status asthmatics during the course of treatment as measured by non-invasive EC monitoring. The secondary aim was to determine if there is an association between Abnormal CI (defined as <5 or >95 % tile adjusted for age) and Abnormal ECG (defined as ST waves changes) Non-invasive cardiac output (CO) recordings were obtained daily from admission (Initial) to discharge (Final). Changes in CI and SI measurements were compared using paired t tests or 1-way ANOVA. The association between Abnormal CI on Initial CO recording and Abnormal ECG was analyzed by Fischer's exact test. Data are presented as mean ± SEM with mean differences reported with 95 % confidence interval; p < 0.05 was considered significant. Thirty-five children with critical asthma were analyzed. CI decreased from 6.2 ± 0.2 to 4.5 ± 0.1 [-1.6 (-0.04 to -0.37)] L/min/m(2) during hospitalization. There was no change in SI. There was a significant association between Abnormal Initial CI and Abnormal ECG (p = 0.02). In 11 children requiring prolonged hospitalization CI significantly decreased from 7.2 ± 0.5 to 4.0 ± 0.2 [-3.2 (-4.0 to -2.3)] L/min/m(2) and SI decreased from 51.2 ± 3.8 to 40.3 ± 2.0 [-11.0 (-17.6 to -4.4)] ml/beat/m(2) There was a significant decrease in CI in all children treated for critical asthma. In children that required a prolonged course of treatment, there was also a significant decrease in SI. Abnormal CI at Initial CO recording was associated with ST waves changes on ECG during hospitalization. Future studies are required to determine whether non-invasive CO monitoring can predict which patients are at risk for developing abnormal ECG.

Algorithms for a closed-loop artificial pancreas: the case for proportional-integral-derivative control.

Closed-loop insulin delivery continues to be one of most promising strategies for achieving near-normal control of blood glucose levels in individuals with diabetes. Of the many components that need to work well for the artificial pancreas to be advanced into routine use, the algorithm used to calculate insulin delivery has received a substantial amount of attention. Most of that attention has focused on the relative merits of proportional-integral-derivative versus model-predictive control. A meta-analysis of the clinical data obtained in studies performed to date with these approaches is conducted here, with the objective of determining if there is a trend for one approach to be performing better than the other approach. Challenges associated with implementing each approach are reviewed with the objective of determining how these approaches might be improved. Results of the meta-analysis, which focused predominantly on the breakfast meal response, suggest that to date, the two approaches have performed similarly. However, uncontrolled variables among the various studies, and the possibility that future improvements could still be effected in either approach, limit the validity of this conclusion. It is suggested that a more detailed examination of the challenges associated with implementing each approach be conducted.

The artificial pancreas: is it important to understand how the ß cell controls blood glucose?

It has been more than 7 years since the first fully automated closed-loop insulin delivery system that linked subcutaneous insulin delivery and glucose sensing was published. Since the initial report, the physiologic insulin delivery (PID) algorithm used to emulate the ß cell has been modified from the original proportional-integral-derivative terms needed to fit the ß cell's biphasic response to a hyperglycemic clamp to include terms emulating cephalic phase insulin release and the effect of insulin per se to inhibit insulin secretion. In this article, we compare the closed-loop glucose profiles obtained as each new term has been added, reassess the ability of the revised PID model to describe the ß cells' insulin response to a hyperglycemic clamp, and look for the first time at its ability to describe the response to a hypoglycemic clamp. We also consider changes that might be added to the model based on perfused pancreas data. We conclude that the changes introduced in the PID model have systematically improved the closed-loop meal response. We note that the changes made do not adversely affect the ability of the model to fit hyperglycemic clamp data but are necessary to fit the response to a hypoglycemic clamp. Finally, we note a number of ß cell characteristics observed in the perfused pancreas have not been included in the model. We suggest that continuing the effort to understand and incorporate aspects of how the ß cell achieves glucose control can provide valuable insights into how improvements in future artificial pancreas algorithms might be achieved.

Increasing use of hypertonic saline over mannitol in the treatment of symptomatic cerebral edema in pediatric diabetic ketoacidosis: an 11-year retrospective analysis of mortality*.

OBJECTIVES: Cerebral edema in diabetic ketoacidosis is a devastating complication with significant morbidity and mortality. This entity has traditionally been treated with mannitol, but use of 3% hypertonic saline has become an accepted alternative. We sought to assess if changes in the use of hyperosmolar therapies for treatment of cerebral edema in diabetic ketoacidosis may have influenced mortality over the last decade. DESIGN: Retrospective cohort study. SETTING: Patients discharged between 1999 and 2009 from 41 children's hospitals that provided data to the Pediatric Health Information System database. PATIENTS: A total of 43,107 children (age < 19) with diagnosis codes related to diabetic ketoacidosis were identified and further classified as having cerebral edema if treated with mannitol and/or 3% hypertonic saline. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Billing for 3% hypertonic saline and mannitol was quantified, and mortality associated with both diabetic ketoacidosis and cerebral edema in diabetic ketoacidosis was examined. Overall mortality in diabetic ketoacidosis was 0.25% and significantly decreased (p < 0.001) over the study period, whereas the frequency of treatment with hyperosmolar agents (3.8%) was unchanged. Use of mannitol as a sole agent decreased from 98% to 49%, 3% hypertonic saline as a sole agent increased from 2% to 39%, and combined therapy increased from 0% to 10%. Use of 3% hypertonic saline alone was associated with a higher mortality than mannitol alone (adjusted odds ratio, 2.71 [95% CI, 1.01-7.26]) in patients treated for cerebral edema. Similar results were obtained after adjustment for the propensity to receive hypertonic saline (adjusted odds ratio, 2.33 [95% CI, 1.07-5.07]) and in the subset of subjects receiving mechanical ventilation (adjusted odds ratio, 3.27 [95% CI, 1.12-9.60]). CONCLUSION: Hypertonic saline has replaced mannitol as the most commonly used agent at many institutions for treatment of cerebral edema in diabetic ketoacidosis. In our analysis, however, use of hypertonic saline as a sole agent was associated with an increased risk of mortality. Recognizing the limitations of administrative data, we conclude that equipoise regarding choice of therapy for treatment of cerebral edema in diabetic ketoacidosis should be maintained until a more definitive study is performed to guide therapy of this potentially lethal complication.

Cardiac parameters in children recovered from acute illness as measured by electrical cardiometry and comparisons to the literature.

Electrical cardiometry (EC) is a non-invasive cardiac output method that can assess cardiac index (CI) and stroke index (SI) but there are no reference values for children per se. The primary aim of this study was to develop reference values for clinical application. The secondary aim was to compare the EC measurements to published values. We performed a prospective observational study in patients (<21 years of age) without structural heart disease who had recovered from an acute illness. EC recordings in children that had normal heart rate and mean arterial blood pressure at discharge were eligible for analysis. The relationship of CI or SI and age in children was performed by regression analysis. Similar analysis was performed comparing measurements by EC to cardiac parameters values compiled from reference sources to assess bias in EC. Eighty-three children (2 weeks-21 years of age) were studied. There was a significant curvilinear relationship between CI or SI and age by EC (F-test, p < 0.05). Regression curves of cardiac parameters reported in the literature using 6 Fick's method, thermodilution, echocardiography and cardiac MRI were the same or higher than (0-19.6 %) values obtained with EC, with higher values being statistically significant (p < 0.05 all). There is a curvilinear relationship of CI or SI and age by EC in normal children. Cardiac parameters reported in the literature using alternative methods are different from those obtained with EC but are within acceptable ranges, with EC biased to underestimate CI. Adjustment of target value is required for EC goal-directed therapies.