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 .).

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.

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.

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.

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.

Tight glycemic control versus standard care after pediatric cardiac surgery.

BACKGROUND: In some studies, tight glycemic control with insulin improved outcomes in adults undergoing cardiac surgery, but these benefits are unproven in critically ill children at risk for hyperinsulinemic hypoglycemia. We tested the hypothesis that tight glycemic control reduces morbidity after pediatric cardiac surgery. METHODS: In this two-center, prospective, randomized trial, we enrolled 980 children, 0 to 36 months of age, undergoing surgery with cardiopulmonary bypass. Patients were randomly assigned to either tight glycemic control (with the use of an insulin-dosing algorithm targeting a blood glucose level of 80 to 110 mg per deciliter [4.4 to 6.1 mmol per liter]) or standard care in the cardiac intensive care unit (ICU). Continuous glucose monitoring was used to guide the frequency of blood glucose measurement and to detect impending hypoglycemia. The primary outcome was the rate of health care-associated infections in the cardiac ICU. Secondary outcomes included mortality, length of stay, organ failure, and hypoglycemia. RESULTS: A total of 444 of the 490 children assigned to tight glycemic control (91%) received insulin versus 9 of 490 children assigned to standard care (2%). Although normoglycemia was achieved earlier with tight glycemic control than with standard care (6 hours vs. 16 hours, P<0.001) and was maintained for a greater proportion of the critical illness period (50% vs. 33%, P<0.001), tight glycemic control was not associated with a significantly decreased rate of health care-associated infections (8.6 vs. 9.9 per 1000 patient-days, P=0.67). Secondary outcomes did not differ significantly between groups, and tight glycemic control did not benefit high-risk subgroups. Only 3% of the patients assigned to tight glycemic control had severe hypoglycemia (blood glucose <40 mg per deciliter [2.2 mmol per liter]). CONCLUSIONS: Tight glycemic control can be achieved with a low hypoglycemia rate after cardiac surgery in children, but it does not significantly change the infection rate, mortality, length of stay, or measures of organ failure, as compared with standard care. (Funded by the National Heart, Lung, and Blood Institute and others; SPECS ClinicalTrials.gov number, NCT00443599.).

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.

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.

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.

Design and rationale of safe pediatric euglycemia after cardiac surgery: a randomized controlled trial of tight glycemic control after pediatric cardiac surgery.

OBJECTIVES: To describe the design of a clinical trial testing the hypothesis that children randomized to tight glycemic control with intensive insulin therapy after cardiac surgery will have improved clinical outcomes compared to children randomized to conventional blood glucose management. DESIGN: Two-center, randomized controlled trial. SETTING: Cardiac ICUs at two large academic pediatric centers. PATIENTS: Children from birth to those aged 36 months recovering in the cardiac ICU after surgery with cardiopulmonary bypass. INTERVENTIONS: Subjects in the tight glycemic control (intervention) group receive an intravenous insulin infusion titrated to achieve normoglycemia (target blood glucose range of 80-110 mg/dL; 4.4-6.1 mmol/L). The intervention begins at admission to the cardiac ICU from the operating room and terminates when the patient is ready for discharge from the ICU. Continuous glucose monitoring is performed during insulin infusion to minimize the risks of hypoglycemia. The standard care group has no target blood glucose range. MEASUREMENTS AND MAIN RESULTS: The primary outcome is the development of any nosocomial infection (bloodstream, urinary tract, and surgical site infection or nosocomial pneumonia). Secondary outcomes include mortality, measures of cardiorespiratory function and recovery, laboratory indices of nutritional balance, immunologic, endocrinologic, and neurologic function, cardiac ICU and hospital length of stay, and neurodevelopmental outcome at 1 and 3 yrs of age. A total of 980 subjects will be enrolled (490 in each treatment arm) for sufficient power to show a 50% reduction in the prevalence of the primary outcome. CONCLUSIONS: Pediatric cardiac surgery patients may recognize great benefit from tight glycemic control in the postoperative period, particularly with regard to reduction of nosocomial infections. The Safe Pediatric Euglycemia after Cardiac Surgery trial is designed to provide an unbiased answer to the question of whether this therapy is indeed beneficial and to define the associated risks of therapy.

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.

Cardiovascular effects of dexmedetomidine sedation in children.

BACKGROUND: Dexmedetomidine (DEX) affects heart rate (HR), mean arterial blood pressure, cardiac index (CI), stroke index (SI), and systemic vascular resistance index (SVRI) in adults. In this study we sought to determine whether similar effects occur in children undergoing DEX sedation. METHODS: Hemodynamic changes in children were followed during IV DEX sedation for radiological procedures. One group of 8 patients (DEX-brief) received a bolus (2 mcg/kg bolus over 10 minutes) and completed the procedure within 10 minutes. The second group of 9 patients (DEX-prolong) received the bolus plus additional DEX as needed to maintain sedation for procedures lasting longer than 10 minutes (additional 1 mcg/kg/hr infusion with second bolus if needed). CI, SI, and SVRI were measured using a continuous noninvasive cardiac output monitor. Changes in hemodynamic variables at minutes 10, 20, and discharge (time at which patient achieved Aldrete Score ≥9) were compared to baseline by repeated measures ANOVA with effect sizes reported as mean [95% confidence interval]. RESULTS: Data were obtained during 8 DEX-brief and 9 DEX-prolong procedures. In DEX-brief, HR and CI decreased (18.9 [2.3 to 35.5] bpm and 0.74 [0.15 to 1.33] L/min/m(2); respectively) at T1. There was no change in any other hemodynamic variables and all hemodynamic variables returned to baseline at recovery. In DEX-prolong, both HR and CI remained decreased (24.0 [8.3 to 39.6] bpm, 1.51 [0.95 to 2.06] L/min/m(2); respectively) at recovery. In addition, SI was decreased (8.01 [1.71 to 14.31] mL/m(2)) and SVRI was increased (776.0 [271.9 to 1280.4] dynes-sec/cm(5)/m(2)) at recovery in the DEX-prolong group. There were no significant changes in mean arterial blood pressure in either group. CONCLUSION: DEX decreases CI in children and has a cumulative effect. For patients undergoing prolonged procedures HR and CI remained decreased at the time of discharge together with a decrease in SI and an increase in SVRI.

Changes in cardiac output and stroke volume as measured by non-invasive CO monitoring in infants with RSV bronchiolitis.

OBJECTIVES: The primary aim of the study was to determine the changes, if any, in cardiac output (CO) and stroke volume (SV) in normal infants with RSV bronchiolitis. The secondary aim was to determine whether changes in CO (ΔCO) and SV (ΔSV) are associated with changes in respiratory rate (ΔRR). METHODS: Non-invasive CO recordings were obtained within 24 h of admission and discharge. Changes in CO, SV, and HR measurements were compared using paired t-tests. The effect of fluid boluses during the first 24 h (<60 or ≥60 cc/kg) on CO was assessed by 2 way ANOVA with time and group as main effect. The relationship between ΔRR and ΔCO or ΔSV was assessed by linear regression. Data is presented as Mean ± SEM and mean differences with 95 % confidence interval (p < 0.05 considered significant). RESULTS: 15 infants with RSV bronchiolitis were studied. CO (1.31 ± 0.13 to 1.11 ± 0.11 l/min (0.21 [0.04-0.37]) and SV (9.42 ± 1.10 to 7.75 ± 0.83 ml/beat (1.67 [0.21-3.12]) decreased significantly while HR (142.1 ± 4.0 to 145.2 ± 3.1 beats/min 3.0 [-5.3 to 11.3]) was unchanged. SV (p = 0.02) and CO (p = 0.04) significantly decreased only in the 7 infants that received ≥60 cc/kg. ΔRR correlated significantly with ΔCO (r (2) = 0.28, p = 0.04); but not with ΔSV (r (2) = 0.20, p = 0.09). CONCLUSIONS: ∆CO was related to ΔSV and not Δ HR. The ∆CO and ΔSV were affected by fluid boluses. ΔRR correlated with ΔCO. Non-invasive CO monitoring can trend CO and SV in infants with bronchiolitis during hospitalization.

Value of continuous glucose monitoring for minimizing severe hypoglycemia during tight glycemic control.

OBJECTIVE: Tight glycemic control can potentially reduce morbidity and mortality in the intensive care unit but increases the risk of hypoglycemia. The most effective means to avoid hypoglycemia is to obtain frequent blood glucose samples, but this increases the burden to nursing staff. The objective of this study was to assess the ability of a real-time continuous glucose monitor to reduce hypoglycemia (blood glucose <60 mg/dL [3.3 mmol/L]) during standard care or tight glycemic control effected with a proportional integral derivative insulin titration algorithm. DESIGN: Real-time continuous glucose monitor profiles obtained from an ongoing prospective randomized trial of tight glycemic control were retrospectively analyzed to determine whether the continuous glucose measure had prevented instances of hypoglycemia. SETTING: Cardiac intensive care unit. PATIENTS: Children 3 yrs of age or younger undergoing cardiac surgery were studied. INTERVENTIONS: Intravenous insulin infusion and rescue glucose guided by the real-time continuous glucose monitor and the proportional integral derivative algorithm in the tight glycemic control arm (n = 155; target glucose 80-110 mg/dL [4.4-6.1 mmol/L]) and the real-time continuous glucose monitor in the standard care arm (n = 156). MEASUREMENTS AND MAIN RESULTS: No reduction in hypoglycemia was observed with real-time continuous glucose monitor alarms set at 60 mg/dL (3.3 mmol/L) (zero of 19 occurrences of blood glucose <60 mg/dL [3.3 mmol/L] detected); 18 of 40 subsequent incidences of hypoglycemia were detected after the alarm threshold was increased to 70 mg/dL (3.9 mmol/L). In the tight glycemic control arm, eight incidences were reduced in duration and an additional eight events were prevented with intravenous glucose. In the standard care arm, three of nine occurrences of hypoglycemia were detected with the duration reduced in all cases. On average, one to two false hypoglycemia alarms were observed in each patient. CONCLUSIONS: The real-time continuous glucose monitor in combination with proportional integral derivative control can reduce hypoglycemia during tight glycemic control. The real-time continuous glucose monitor can also reduce hypoglycemia during standard care. However, false alarms increase the overall nursing workload.

Non-invasive cardiac output and oxygen delivery measurement in an infant with critical anemia.

OBJECTIVE: To assess the combination of a non-invasive blood oxygen content (CaO(2)) monitor and a non-invasive cardiac output (CO) monitor to continuously measure oxygen delivery (DO(2); DO(2) = CaO(2) × CO). METHODS: DO(2) was assessed during blood transfusions in an infant with acute hemolytic anemia following admission (~48 h). CaO(2) was measured by Pulse Co-Oximetry, which also provides estimates of hemoglobin (Hgb) concentration and percent oxygen saturation. CO was measured by Electrical Velocimetry, which also provides an estimate of stroke volume (SV). Lactate levels, an indirect measure of adequate DO(2), were assessed during the initial 8 h following admission. RESULTS: Incremental blood transfusions during the first 36 h increased Hgb from 2.7 to 9.5 g/dL during which time heart rate (HR) normalized from 156 to 115 beats/min. Lactate levels decreased from 20 to 0.8 mmol/L in the first 7 h. Non-invasive Hgb and CaO(2) measurements were well correlated with invasive Hgb and CaO(2) measures (r (2) = 0.88; P = 0.019; r (2) = 0.86; P = 0.0074, respectively). CO decreased from 2.47 ± 0.06 to 1.28 ± 0.02 L/min and SV decreased from 15.9 ± 0.4 to 11.1 ± 0.2 mL/beat. Mean arterial blood pressure was stable throughout the admission with systemic vascular resistance increasing from 407.6 ± 15.2 to 887.7 ± 30.1 dynes-s/cm(5). DO(2) was estimated to increase from 120.2 ± 18.9 to 182.4 ± 5.6 mL O(2)/min. CONCLUSIONS: Non-invasive continuous CO and CaO(2) monitors are shown in this single case to provide continuous DO(2) measurement. The ability to assess DO(2) may improve hemodynamic monitoring during goal directed therapies.

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.

Is an automatic pump suspension feature safe for children with type 1 diabetes? An exploratory analysis with a closed-loop system.

OBJECTIVES: It has been proposed that the first step towards a closed-loop artificial pancreas might be to use a continuous glucose sensor to automatically suspend the basal insulin delivery based on projected low sensor glucose values. METHODS: We reviewed our recent experience with an artificial pancreas system, utilizing a proportional-integrative-derivative (PID) algorithm, in 17 adolescents with type 1 diabetes (T1D) to assess the safety and efficacy of this maneuver. RESULTS: During 34 h of closed-loop automated insulin delivery, 18 pump suspensions > or =60 min (90 +/- 18 min) occurred in eight subjects. Sensor glucose levels fell from 159 +/- 42 mg/dL to a nadir of 72 +/- 13 mg/dL. Corresponding plasma glucose levels fell from 168 +/- 51 to 72 +/- 16 mg/dL, with values <60 mg/dL recorded in only four of the 18 events. CONCLUSIONS: These data suggest that automatic pump suspension using the PID algorithm may be an effective means to prevent hypoglycemia in youth with T1D.

Critical illness hyperglycemia: is failure of the beta-cell to meet extreme insulin demand indicative of dysfunction?

In the recent study by Preissig and Rigby in Critical Care, the authors argue that critical illness hyperglycemia in children with both respiratory failure and cardiovascular failure is due to a primary failure of the beta-cell. However, alternative explanations that the failure is secondary to an increase in insulin resistance leading to beta-cell exhaustion, or a negative impact of exogenous glucocorticoid therapy, may be equally likely.

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.