Michael S. D. Agus

Guidelines for the use of an insulin infusion for the management of hyperglycemia in critically ill patients.

Objective:To evaluate the literature and identify important aspects of insulin therapy that facilitate safe and effective infusion therapy for a defined glycemic end point. Methods:Where available, the literature was evaluated using Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) methodology to assess the impact of insulin infusions on outcome for general intensive care unit patients and those in specific subsets of neurologic injury, traumatic injury, and cardiovascular surgery. Elements that contribute to safe and effective insulin infusion therapy were determined through literature review and expert opinion. The majority of the literature supporting the use of insulin infusion therapy for critically ill patients lacks adequate strength to support more than weak recommendations, termed suggestions, such that the difference between desirable and undesirable effect of a given intervention is not always clear. Recommendations:The article is focused on a suggested glycemic control end point such that a blood glucose ≥150 mg/dL triggers interventions to maintain blood glucose below that level and absolutely <180 mg/dL. There is a slight reduction in mortality with this treatment end point for general intensive care unit patients and reductions in morbidity for perioperative patients, postoperative cardiac surgery patients, post-traumatic injury patients, and neurologic injury patients. We suggest that the insulin regimen and monitoring system be designed to avoid and detect hypoglycemia (blood glucose ⩽70 mg/dL) and to minimize glycemic variability.Important processes of care for insulin therapy include use of a reliable insulin infusion protocol, frequent blood glucose monitoring, and avoidance of finger-stick glucose testing through the use of arterial or venous glucose samples. The essential components of an insulin infusion system include use of a validated insulin titration program, availability of appropriate staffing resources, accurate monitoring technology, and standardized approaches to infusion preparation, provision of consistent carbohydrate calories and nutritional support, and dextrose replacement for hypoglycemia prevention and treatment. Quality improvement of glycemic management programs should include analysis of hypoglycemia rates, run charts of glucose values <150 and 180 mg/dL. The literature is inadequate to support recommendations regarding glycemic control in pediatric patients. Conclusions:While the benefits of tight glycemic control have not been definitive, there are patients who will receive insulin infusion therapy, and the suggestions in this article provide the structure for safe and effective use of this therapy.

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

OBJECTIVES. Given the demonstrated benefit of euglycemia in critically ill patients as well as the risk for hypoglycemia during insulin infusion in children, we sought to validate a subcutaneous sensor for real-time continuous glucose monitoring in pediatric patients during and after cardiac surgery. METHODS. Children up to 36 months of age who were undergoing cardiac bypass surgery were recruited. After anesthetic induction, a continuous glucose-monitoring system sensor (CGMS, Medtronic Minimed, Northridge, CA) was inserted subcutaneously. Sensors remained in place for up to 72 hours. Arterial blood glucose was measured intermittently in the central laboratory (Bayer Rapidlab 860, Tarrytown, NY). Sensor data, after prospective calibration with 6-hourly laboratory values using the proprietary Medtronic Minimed Guardian RT algorithm, were compared with all laboratory glucose values. Statistical analysis was performed 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 and 246 paired sensor and laboratory glucose values. Consensus error grid analysis demonstrated that 72.0% of sensor value comparisons were within zone A (no effect on clinical action), and 27.6% of comparisons were within zone B (altered clinical action of little or no effect on outcome), with a mean absolute relative deviation of 17.6% for all comparisons. One comparison (0.4%) was in zone C (altered clinical action likely to affect outcome). No significant correlations were found between sensor performance and body temperature, inotrope dose, or body-wall edema. All patients tolerated the sensors well without bleeding or tissue reaction. CONCLUSIONS. Guardian RT real-time subcutaneous blood glucose measurement is safe and potentially useful for continuous glucose monitoring in critically ill children. Subcutaneous sensors performed well in the setting of hypothermia, inotrope use, and edema. These sensors facilitate identifying and following the effects of interventions to control blood glucose.

Association Between Intraoperative and Early Postoperative Glucose Levels and Adverse Outcomes After Complex Congenital Heart Surgery

Background— This study sought to determine whether associations exist between perioperative glucose exposure, prolonged hospitalization, and morbid events after complex congenital heart surgery. Methods and Results— Metrics of glucose control, including average, peak, minimum, and SD of glucose levels, and duration of hyperglycemia were determined intraoperatively and for 72 hours after surgery for 378 consecutive high-risk cardiac surgical patients. Multivariable regression analyses were used to determine relationships between these metrics of glucose control, hospital length of stay, and a composite morbidity-mortality outcome after controlling for multiple variables known to influence early outcomes after congenital heart surgery. Intraoperatively, a minimum glucose ≤75 mg/dL was associated with greater adjusted odds of reaching the composite morbidity-mortality end point (odds ratio [OR], 3.10; 95% confidence interval [CI], 1.49 to 6.48), but other metrics of glucose control were not associated with the composite end point or length of stay. Greater duration of hyperglycemia (glucose >126 mg/dL) during the 72 postoperative hours was associated with longer duration of hospitalization (P<0.001). In the 72 hours after surgery, average glucose <110 mg/dL (OR, 7.30; 95% CI, 1.95 to 27.25) or >143 mg/dL (OR, 5.21; 95% CI, 1.37 to 19.89), minimum glucose ≤75 mg/dL (OR, 2.85; 95% CI, 1.38 to 5.88), and peak glucose level ≥250 mg/dL (OR, 2.55; 95% CI, 1.20 to 5.43) were all associated with greater adjusted odds of reaching the composite morbidity-mortality end point. Conclusions— In children undergoing complex congenital heart surgery, the optimal postoperative glucose range may be 110 to 126 mg/dL. Randomized trials of strict glycemic control achieved with insulin infusions in this patient population are warranted.

Closed-Loop Insulin Therapy Improves Glycemic Control in Children Aged <7 Years: A randomized controlled trial

OBJECTIVE To assess the possibility of improving nocturnal glycemic control as well as meal glycemic response using closed-loop therapy in children aged <7 years. RESEARCH DESIGN AND METHODS This was a randomized controlled crossover trial comparing closed-loop with standard open-loop insulin pump therapy performed in an inpatient clinical research center. Ten subjects aged <7 years with type 1 diabetes for >6 months treated with insulin pump therapy were studied. Closed-loop therapy and standard open-loop therapy were compared from 10:00 p.m. to 12:00 p.m. on 2 consecutive days. The primary outcome was plasma glucose time in range (110–200 mg/dL) during the night (10:00 p.m.–8:00 a.m.). Secondary outcomes included peak postprandial glucose levels, incidence of hypoglycemia, degree of hyperglycemia, and prelunch glucose levels. RESULTS A trend toward a higher mean nocturnal time within target range was noted for closed- versus open-loop therapy, although not reaching statistical significance (5.3 vs. 3.2 h, P = 0.12). There was no difference in peak postprandial glucose or number of episodes of hypoglycemia. There was significant improvement in time spent >300 mg/dL overnight with closed-loop therapy (0.18 vs. 1.3 h, P = 0.035) and the total area under the curve of glucose >200 mg/dL (P = 0.049). Closed-loop therapy returned prelunch blood glucose closer to target (189 vs. 273 mg/dL on open loop, P = 0.009). CONCLUSIONS Closed-loop insulin delivery decreases the severity of overnight hyperglycemia without increasing the incidence of hypoglycemia. The therapy is better able to reestablish target glucose levels in advance of a subsequent meal. Younger children with type 1 diabetes may reap significant benefits from closed-loop therapy.

Nutritional support of the critically ill child.

The pediatric metabolic response to injury and operation is proportional to the degree of stress and causes an increase in the turnover of proteins, fats, and carbohydrates. Thereby, substrates are made readily available for the immune response and wound healing. Because this process requires energy, the resting energy expenditure of ill patients increases. Whole-body protein degradation rates are elevated out of proportion to synthetic rates, and negative protein balance also ensues. Neonates and children are particularly susceptible to the loss of lean body mass and its attendant increased morbidity and mortality caused by an intrinsic lack of endogenous stores and greater baseline requirements. An appropriately designed mixed fuel system of nutritional support replete in protein does not quell this metabolic response but can result in anabolism and continued growth in ill children. In addition, the use of adequate analgesia and anesthesia is a readily available and proven means of reducing the magnitude of the catabolism associated with operation and injury. Finally, as hormonal- and cytokine-mediated metabolic alterations are better understood, therapeutic interventions may become available to directly modulate the metabolic response to illness, thus potentially further improving clinical outcome in pediatric surgical patients.

Adrenal insufficiency in the critically ill neonate and child.

Purpose of review Adrenal insufficiency, common in critically ill patients of all ages, has recently gained prominence as a significant pathologic entity in pediatrics. This review describes the current diagnostic approach to detecting adrenal insufficiency and the clinical consequences in critically ill children and infants. It also discusses the current therapeutic approach to adrenal insufficiency in critically ill patients. Recent findings Relative adrenal insufficiency and its clinical implications have recently come into focus with observational studies demonstrating a high prevalence in pediatric septic shock patients and a significant associated morbidity. Neonatal studies have clarified diagnostic testing and defined clinical outcomes associated with adrenal insufficiency in preterm infants. Comparisons of bioavailable and total cortisol levels demonstrate the utility of total cortisol testing in pediatric septic shock patients. Summary Adrenal insufficiency contributes to morbidity in critically ill neonates and children. Diagnostic testing by adrenocorticotropin stimulation tests should be done in patients unresponsive to standard treatment of shock. Prospective, randomized clinical trials in critically ill neonates and children with adrenal insufficiency are required to determine if these populations will benefit from glucocorticoid replacement therapy.

Cardiovascular Actions of Magnesium

Intracellular magnesium is an important modulator of calcium and potassium channels in cardiac myocytes. Hypomagnesemia is common in hospitalized patients and may contribute significantly to cardiac morbidity and mortality, particularly in states associated with myocardial ischemia. Therefore, it is important to maintain the plasma magnesium concentration within the normal range in asymptomatic patients and in patients with cardiac disease as prophylaxis against the occurrence of significant arrhythmias.

Intensive Care Unit Insulin Delivery Algorithms: Why So Many? How to Choose?

Objective: Studies showing improved outcomes with tight glycemic control in the intensive care unit (ICU) have resulted in a substantial number of new insulin delivery algorithms being proposed. The present study highlights mechanisms used in the better-known approaches, examines what might be critical differences among them, and uses systems theory to characterize the conditions under which each can be expected to perform best. Methods: Algorithm dose (ΔI/ΔG) and step (response to a persistent elevation in glucose) response curves were calculated for written instruction algorithms, developed at the Providence Heart and Vascular Institute (Portland [P] protocol), the University of Washington (UW), and Yale University (Y), together with similar curves for the Glucommander (GM) and proportional integral derivative (PID) computer algorithms. From the simulated curves, different mechanisms used to adjust insulin delivery were identified. Results: All algorithms increased insulin delivery in response to persistent hyperglycemia, but the mechanism used altered the algorithms sensitivity to glucose, or gain, in the GM, UW, and Y protocols, while leaving it unchanged for the P protocol and PID algorithm. Conclusions: The increase in insulin delivery in response to persistent hyperglycemia observed with all the algorithms can be expected to bring subjects who respond to insulin to targeted glucose ranges. However, because the PID and P protocols did not alter the insulin delivery response curves, these algorithms can be expected to take longer to achieve target glucose levels in individuals who are insulin resistant and/or are exposed to increased carbohydrate loads (e.g., glucose infusions). By contrast, the GM, UW, and Y algorithms can be expected to adapt to the insulin resistance such that the time to achieve target levels is unchanged if the time for insulin to act does not change. If the insulin resistance is accompanied by a longer time for insulin to act, the UW, Y, and GM algorithms may increase the risk of hypoglycemia. Under these conditions, the longer time required for the PID and P protocols to achieve a target glucose level may be a reasonable trade-off for no increase in the risk of hypoglycemia.

The Effect of Insulin Infusion Upon Protein Metabolism in Neonates on Extracorporeal Life Support

Objective:Critically ill neonates on extracorporeal life support (ECLS) demonstrate elevated rates of protein breakdown that, in turn, are associated with increased morbidity and mortality. This study sought to determine if the administration of the anabolic hormone insulin improved net protein balance in neonates on ECLS. Methods:Twelve parenterally fed neonates, on ECLS, were enrolled in a randomized, prospective, crossover trial. Subjects were administered a hyperinsulinemic euglycemic clamp and a control saline infusion. Protein metabolism was quantified using ring-D5-phenylyalanine and ring-D2-tyrosine stable isotopic infusions. Statistical comparisons were made by paired sample t tests (significance at P < 0.05). Results:Serum insulin concentration increased 20-fold during insulin infusion compared with saline infusion control (P < 0.0001). Protein breakdown was significantly decreased during insulin infusion compared with controls (7.98 ± 1.82 vs. 6.89 ± 1.03 g/kg per day; P < 0.05). Serum amino acid concentrations were significantly decreased by insulin infusion (28,450 ± 9270 vs. 20,830 ± 8110 μmol/L; P < 0.02). Insulin administration tended to decrease protein synthesis (9.58 ± 2.10 g/kg per day vs. 8.60 ± 1.20; P = 0.05). For the whole cohort, insulin only slightly improved net protein balance (protein synthesis minus protein breakdown) (1.60 ± 0.80 vs. 1.71 ± 0.89 g/kg per day; P = 0.08). In neonates receiving ≥2 g/kg per day of dietary amino acids insulin significantly improved net protein balance (2.17 ± 0.34 vs. 2.40 ± 0.26 g/kg per day; P < 0.01). Conclusions:Insulin effectively decreases protein breakdown in critically ill neonates on ECLS. However, this is associated with a significant reduction in plasma amino acids and a trend toward decreased protein synthesis. Insulin administration significantly improves net protein balance only in those ECLS neonates in whom adequate dietary protein is provided.

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.)