OVERVIEW: What every practitioner needs to know

Are you sure your patient has hyperglycemia associated with critical illness? What are the typical findings for this disease?

Normal blood glucose levels in children may vary slightly with each hospital’s central laboratory but can safely be considered to be 70-126 mg/dL. Hyperglycemia, therefore, is a random blood glucose level greater than 126 mg/dL. Although the neonatal fasting blood glucose concentration can be as low as 50 mg/dL during the first 24 hours after birth, any blood glucose level less than 60 mg/dL after 24 hours of age should be treated with intravenous or enteral glucose.

Significant hyperglycemia may be present with or without glucosuria, as the renal threshold for spilling glucose into the urine is approximately 180 mg/dL. Until that point, hyperglycemia may have deleterious effects without discernible symptoms. In a sick child, any blood glucose level greater than 140 mg/dL should be followed regularly, and treatment should be considered when it exceeds 180 mg/dL.

What other disease/condition shares some of these symptoms?

Relative insulin deficiency: Type 1 or type 2 diabetes

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Insulin resistance: Glucocorticoid therapy, asparaginase

Excessive glucose delivery: Intravenous fluids with glucose infusion rate beyond 10-12 mg/kg/min

What caused this disease to develop at this time?

The cause of hyperglycemia in the pediatric critically ill population is multifactorial and likely related to the endogenous counterregulatory hormone and inflammatory responses to the cause of the illness (e.g., sepsis, trauma, respiratory failure), insulin resistance, use of catecholamine infusions and glucocorticoids for vasoactive support and to reverse inflammation, and reliance on carbohydrate-rich parenteral nutrition during the intensive care unit (ICU) stay.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

The most reliable blood glucose sample is one that is drawn from an arterial line after a suitable amount of waste has been removed from the line so that there is no dilution by the infusing fluid. New devices are available that allow for closed system removal of dilute blood to allow for an accurate blood draw, and then the dilute blood is returned to the patient.

If arterial blood is not available, venous blood from a central line is also reliable, and peripheral venous blood may also be acceptable. Capillary blood measurements must be interpreted with caution if the patient is receiving vasopressors, is poorly perfused, or has significant peripheral edema.

Several instruments are available for measurement of glucose concentration and are listed in order of decreasing accuracy: serum measurement by hospital central laboratory, blood gas analyzer, bedside glucose meter. A diagnosis of stress hyperglycemia may be made if two serial random blood glucose measurements are greater than 140 mg/dL.

Would imaging studies be helpful? If so, which ones?

Imaging studies are not useful.

If you are able to confirm that the patient has this disease, what treatment should be initiated?

Insulin infusion algorithms to treat stress hyperglycemia in the pediatric ICU are difficult to implement, depending on the therapeutic target. There are no published algorithms for children. There are several clinical trials under way, each of which uses a unique algorithm with dosing recommendations that may or may not take into account all key aspects of dosing decision making, including patient size, insulin sensitivity, glucose concentration, and glucose rate of change.

Some algorithms also use a continuous glucose monitoring device that can act as an additional warning system for hypoglycemia. These algorithms are in use within the research realm and are not currently available for clinical use.

Because of the risk of hypoglycemia and in light of the recent publication of the NICE-SUGAR trial with greater than 6000 adults studied, the glucose target range in the general pediatric ICU population should be 140-180 mg/dL. With a target in that range, insulin may be safely initiated once the glucose level exceeds 180 mg/dL at 0.01 units/kg/h intravenously and adjusted in 0.01-0.02 units/kg/h increments to achieve blood glucose concentrations in the target range.

While insulin is infusing, glucose should be monitored at a minimum of every 2 hours. If a dosing change has been made, a blood glucose determination should be repeated 1 hour later.

Particular care must be paid to the concomittant infusion rate of dextrose or carbohydrate in parenteral and enteral routes, for if insulin is dosed with such an infusion on board, and the infusion is decreased, hypoglycemia can quickly ensue.

What are the adverse effects associated with each treatment option??

The primary risk of treatment of hyperglycemia in critical illness is hypoglcyemia and associated neurologic injury. Insulin infusion should be halted for any blood glucose concentration less than 80 mg/dL, and rescue dextrose therapy should be given for a blood glucose concentration less than 70 mg/dL.

Insulin-induced hypoglycemia may be particularly harmful because high insulin concentrations suppress lipolysis and ketogenesis. Therefore, there can be no alternative fuel mobilized for the brain or other tissues when significant doses of insulin are being infused. It is for this reason that extreme care ought to be taken when considering therapy in a young child with a central nervous system still under development.

What are the possible outcomes of this disease?

Hyperglycemia in critical illness has been shown in several retrospective studies to be associated with increased mortality, longer length of ventilation and hospital stay, increased nosocomial infection rate, and increased rates of transfusion and renal replacement therapy. However, the causative link has not yet been definitively made.

What causes this disease and how frequent is it?

In nondiabetic patients in the pediatric ICU, the prevalence of hyperglycemia during the first 24 hours depends on the cutoff. In one representative study with 942 subjects, maximum blood glucose values were greater than120 mg/dL in 70% of patients, greater than 150 mg/dL in 50% of patients, and greater than 200 mg/dL in 26% of patients. There are no known genetic risk factors for hyperglycemia. Conversely, in patients with critical illness hyperglycemia there is no known increased risk of developing diabetes later in life.

What complications might you expect from the disease or treatment of the disease?

See section on adverse efffects.

Are additional laboratory studies available; even some that are not widely available?

There are no known predictors of critical illness hyperglycemia or its severity. Plasma insulin concentrations are not useful in making the diagnosis or managing the disorder.

How can this disease be prevented?

There are no known approaches to prevent hyperglycemia in critical illness. There is evidence to suggest that enteral nutrition will produce fewer blood glucose perturbations than will parenteral nutrition and should be favored when the clinical management allows.

What is the evidence?

The following articles discuss pediatric retrospective data.

Polito, A, Thiagarajan, RR, Laussen, PC. “Association between intraoperative and early postoperative glucose levels and adverse outcomes after complex congenital heart surgery”. Circulation. vol. 118. 2008. pp. 2235-42.

Faustino, EV, Apkon, M. “Persistent hyperglycemia in critically ill children [see comment]”. J Pediatr. vol. 146. 2005. pp. 30-4.

Faustino, EV, Bogue, CW. “Relationship between hypoglycemia and mortality in critically ill children”. Pediatr Crit Care Med. vol. 11. 2010. pp. 690-8.

Hirshberg, E, Larsen, G, Van Duker, H. “Alterations in glucose homeostasis in the pediatric intensive care unit: hyperglycemia and glucose variability are associated with increased mortality and morbidity”. Pediatr Crit Care Med. vol. 9. 2008. pp. 361-6.

Srinivasan, V, Spinella, PC, Drott, HR. “Association of timing, duration, and intensity of hyperglycemia with intensive care unit mortality in critically ill children”. Pediatr Crit Care Med. vol. 5. 2004. pp. 329

Wintergerst, KA, Buckingham, B, Gandrud, L. “Association of hypoglycemia, hyperglycemia, and glucose variability with morbidity and death in the pediatric intensive care unit”. Pediatrics. vol. 118. 2006. pp. 173-9.

The following article discusses pediatric pivotal trials.

Vlasselaers, D, Milants, I, Desmet, L. “Intensive insulin therapy for patients in paediatric intensive care: a prospective, randomised controlled study”. Lancet. vol. 373. 2009. pp. 547-56.

The following articles discuss continuous glucose monitoring in the pediatric ICU.

Piper, HG, Alexander, JA, Shukla, A. “Real-time continuous glucose monitoring in pediatric cardiac surgery patients”. Pediatrics. vol. 118. 2006. pp. 1176-84.

Steil, GM, Langer, M, Jaeger, K. “Value of continuous glucose monitoring for minimizing severe hypoglycemia during tight glycemic control”. Pediatr Crit Care Med. vol. 12. 2011. pp. 643-8.

The following articles discuss glucose algorithms to guide tight glycemic control in children.

Wintergerst, KA, Deiss, D, Buckingham, B. “Glucose control in pediatric intensive care unit patients using an insulin-glucose algorithm”. Diabetes Technol Ther. vol. 9. 2007. pp. 211-22.

Steil, GM DD, Shih, J, Buckingham, B. “Intensive care unit insulin delivery algorithms: why so many? How to choose?”. J Diabetes Sci Technol. vol. 3. 2009. pp. 125-40.

The following article discusses adult retropective data.

Marik, PE, Raghavan, M. “Stress-hyperglycemia, insulin and immunomodulation in sepsis”. Intensive Care Med. vol. 30. 2004. pp. 748-56.

The following articles discuss adult pivotal trials.

Van den Berghe, G, Wouters, P, Weekers, F. “Intensive insulin therapy in the critically ill patients”. N Engl J Med. vol. 345. 2001. pp. 1359-67.

Van den Berghe, G, Wilmer, A, Hermans, G. “Intensive insulin therapy in the medical ICU”. N Engl J Med. vol. 354. 2006. pp. 449-61.

Finfer, S, Chittock, DR, Su, SY. “Intensive versus conventional glucose control in critically ill patients”. N Engl J Med. vol. 360. 2009. pp. 1283-97.

Ongoing controversies regarding etiology, diagnosis, treatment

There is ongoing debate in this field both for adults and children given the conflicting data published over the past 10 years in retrospective, cohort, and prospective randomized controlled trials. Although the benefits of tight glycemic control are evident in several trials, the potential harm of hypoglycemia is also becoming more evident.

The only published trial in pediatrics at present showed a reduction in mortality but also an unacceptably high rate of severe hypoglcyemia (<40 mg/dL) of 25% in all children treated and in 44% of those younger than 1 year of age. As a result, even though benefit was demonstrated, it was at an unacceptable cost and is not ready for widespread implementation.

In the adult world, the largest trial to date, NICE-SUGAR, with more than 6000 subjects demonstrated no benefit in the 80-110 mg/dL group, but a mortality reduction in the 140-180 mg/dL group. There are several ongoing trials in pediatrics that will likely shed much light on whether this therapy is warranted given the risk, and how much risk can be mitigated using advanced but widely available technologies such as continuous glucose monitoring.