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Strict Glycemic Targets Need Not Be So Strict: A More Permissive Glycemic Range for Critically Ill Children

^a Departments of Pediatrics
^b Cardiovascular Surgery
^c Anesthesiology and Critical Care, Driscoll Children's Hospital, Corpus Christi, Texas
^d Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas

	ABSTRACT

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OBJECTIVE. The goal was to determine whether a more permissive glycemic target would be associated with a decreased incidence of hypoglycemia but not increased mortality rates in critically ill pediatric patients.

METHODS. This retrospective study evaluated clinical and laboratory data for 177 patients who underwent 211 consecutive surgical procedures for repair or palliation of congenital heart defects at Driscoll Children's Hospital. To establish the relationship between postoperative glycemia and subsequent morbidity and mortality rates, patients were stratified into 4 groups according to their median glucose levels, that is, euglycemia (60–125 mg/dL, 3.3–6.9 mmol/L), mild hyperglycemia (126–139 mg/dL, 6.9–7.7 mmol/L), moderate hyperglycemia (140–179 mg/dL, 7.7–9.9 mmol/L), or severe hyperglycemia (180 mg/dL, 9.9 mmol/L). Postoperative outcomes for those groups also were compared with outcomes for a more permissive glycemic target group (90–140 mg/dL, 5–7.7 mmol/L).

RESULTS. The peak and mean blood glucose measurements and duration of hyperglycemia were not different for survivors and nonsurvivors in the first 24 hours after surgery. Nonsurvivors had higher peak glucose levels (389.3 ± 162 mg/dL vs 274.4 ± 106.3 mg/dL, 21.4 ± 8.9 mmol/L vs 15.1 ± 5.9 mmol/L) and longer duration of hyperglycemia (3.06 ± 1.67 days vs 2.11 ± 0.92 days) during the first 5 postoperative days, compared with survivors. Mortality rates were significantly higher for the moderate (38.8%) and severe (58.3%) hyperglycemia groups, compared with the euglycemia (6.02%) and permissive target (4.69%) groups. The incidence of hypoglycemia was significantly higher in the euglycemia group (31.8%), compared with the permissive target group (17.18%).

CONCLUSIONS. Postoperative hyperglycemia is associated with increased morbidity and mortality rates in children after surgical repair of congenital heart defects. A more permissive glycemic target is associated with a lower incidence of hypoglycemia but not increased mortality rates in these patients.

Key Words: hyperglycemia • hypoglycemia • congenital heart defects • postoperative care • children • intensive care • mortality • morbidity

Abbreviations: RACHS-1—Risk Adjustment for Congenital Heart Surgery • CPB—cardiopulmonary bypass

Hyperglycemia occurs frequently in ICUs and has been strongly associated with increased morbidity and mortality rates in both children^1–3 and adults.^4–6 Strict glycemic control with insulin administration was shown to reduce morbidity and mortality rates significantly for adult patients admitted to a surgical ICU.⁵ The same strategy was shown to reduce morbidity but not mortality rates for patients admitted to a medical ICU.⁷

We showed previously that the duration of hyperglycemia in children after surgical repair or palliation of congenital heart defects was associated strongly and independently with increased morbidity and mortality rates.⁸ We also reported that the mortality rate was higher among patients with severe hyperglycemia, compared with those with moderate or mild hyperglycemia.⁸ Although tight glycemic control has been associated with improved outcomes in the adult population, its role for pediatric patients has not been studied adequately. It is very likely, however, that the glycemic control targets used for critically ill adult patients would not be appropriate for the entire pediatric age range.

There is concern that glycemic control, aiming at avoiding hyperglycemia while maintaining a strict euglycemic target, could place patients at increased risk for hypoglycemia. In fact, a recent clinical trial of intensive insulin therapy for adult patients with severe sepsis had to be stopped prematurely because of the high rate of severe hypoglycemia in patients assigned to the intensive insulin treatment group.⁹ As many institutions begin to evaluate glycemic control strategies for use in the PICU, concerns regarding the occurrence of inadvertent hypoglycemia and how to avoid it should be central to the planning of any study protocol, particularly when the potentially dire effects of hypoglycemia on the developing brain of neonates and infants are considered.^10,11 We hypothesized that a more permissive glycemic target would be associated with a decreased incidence of hypoglycemia but not with an increased mortality rate for critically ill pediatric patients after surgical repair or palliation of congenital heart defects.

	METHODS

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This study was conducted with patients admitted to a 20-bed, multidisciplinary PICU in a university-affiliated, tertiary care, freestanding, children's hospital staffed 24 hours per day by board-certified pediatric intensivists. The PICU has 1100 admissions per year, with cardiac patients generally representing 60% of this total.

This study was approved by the institutional review board with a waiver of informed consent requirements. We conducted a retrospective chart review of a continuous sample of patients who underwent repair or palliation of congenital heart defects between February 20, 2006, and January 1, 2007, at Driscoll Children's Hospital. Patients were excluded from the study if they had a history of preoperative necrotizing enterocolitis, active preoperative infections, preoperative renal or hepatic dysfunction, need for preoperative extracorporeal life support, or a preexisting diagnosis of diabetes mellitus.

Patients were classified into risk categories according to the consensus-based, Risk Adjustment for Congenital Heart Surgery (RACHS-1) method.¹² Operative data obtained from the anesthesia and operating room records included cardiopulmonary bypass (CPB) time and cross-clamp time. Deep hypothermic cardiac arrest during cardiac surgery is not used at our institution. Most patients requiring CPB are treated with high flows, and the core temperature is allowed to drift to 26°C to 30°C. Patients undergoing stage I palliation of hypoplastic left heart syndrome receive cephalad perfusion with flows of 50 to 60 mL/kg per minute at the surgeon's discretion during critical portions of the operation, with the remainder of the case being performed with full CPB. Cerebral perfusion and oxygenation during CPB are guided by cerebral near-infrared spectroscopy. We use modified ultrafiltration in all CPB cases.

Variables related to the hospital course included the PICU and hospital lengths of stay and indicators of morbidity and in-hospital death. Indicators of morbidity included markers of renal and hepatic dysfunction, occurrence of a new infection, adverse central nervous system events such as hemorrhage, stroke, or seizures, need for extracorporeal life support in the postoperative period, and use of dialysis. We arbitrarily defined renal dysfunction as serum creatinine levels of >1.4 mg/dL (>123.2 µmol/L) and hepatic dysfunction as any 2 of the following: aspartate aminotransferase level of >200 U/L, alanine aminotransferase level of >200 U/L, or ammonia level of >80 mmol/L. We defined combined morbidity as the occurrence of an individual morbidity or any permutation of the aforementioned morbidities in a single subject.

All laboratory data for the first 5 postoperative days were extracted from the hospital's computerized laboratory information system onto case-specific spreadsheets. Arterial blood gas and glucose measurements were not strictly scheduled. The routine practice in our unit is to measure arterial blood gas values (including electrolyte, ionized calcium, glucose, and lactate levels) every hour during the first 6 hours after surgery or longer, if necessary, until clinical stability is achieved. Beyond the most critical, initial, postoperative period, arterial blood sampling is performed every 2 hours until significant weaning of vasoactive and inotropic support is accomplished, followed by sampling every 4 to 6 hours until the patient is extubated or the arterial catheter is discontinued.

Inotropic and vasoactive drug usage and dosages were obtained hourly for the first 24 hours and were used to derive an inotropic score (dopamine dose [µg/kg per minute] + dobutamine dose [µg/kg per minute] + [100 x epinephrine dose [µg/kg per minute]] + [100 x norepinephrine dose [µg/kg per minute]]).¹³ The occurrence of nosocomial infections was tracked by using criteria based on National Nosocomial Infections Surveillance System methods.^14,15 All cultures from blood, urine, and tracheal aspirate samples were investigated and correlated with the clinical record. Only positive cultures that were not deemed to be contaminants and resulted in an intervention (ie, the start or change of antimicrobial therapy) were taken into account.

For the purpose of this study, we considered hyperglycemia a blood glucose measurement of 126 mg/dL (6.9 mmol/L).¹⁶ After our initial analysis of hyperglycemia and death, we stratified patients according to median blood glucose measurements, in a euglycemia group (60–125 mg/dL, 3.3–6.9 mmol/L), a mild hyperglycemia group (126–139 mg/dL, 6.9–7.7 mmol/L), a moderate hyperglycemia group (140–179 mg/dL, 7.7–9.9 mmol/L), and a severe hyperglycemia group (180 mg/dL, 9.9 mmol/L). Data obtained from the analysis of these subgroups led us to the choice of a more permissive glycemic target of 90 to 140 mg/dL (5–7.7 mmol/L, permissive target group). We defined the duration of hyperglycemia as the number of days with 1 blood glucose measurement of 126 mg/dL (6.9 mmol/L). We arbitrarily defined hypoglycemia as a glucose level of <60 mg/dL (<3.3 mmol/L), because this is the value below which counter-regulatory hormonal responses to hypoglycemia are triggered^17,18 and transient neurocognitive dysfunction can be observed.¹⁹

Data are presented as means and SDs and medians and interquartile ranges for normally and nonnormally distributed continuous variables, respectively, and as percentages for categorical variables. Categorical variables were analyzed with the ² test or Fisher's exact test, with the Bonferroni correction applied for multiple comparisons, as indicated. Normally distributed continuous variables were analyzed with Student's t test. Nonnormally distributed continuous data were analyzed with the Mann-Whitney rank-sum test. Statistical significance was taken at P < .05. Analyses were performed with dedicated statistical software (SigmaStat 2.03; SPSS, Chicago, IL).

	RESULTS

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A cohort of 177 unique patients met eligibility criteria for inclusion in the study, for a total of 211 surgical procedures, consisting of 46 univentricular repairs (21.8%) and 165 biventricular repairs (78.2%). The age on the day of surgery for patients included in the study ranged from 0 to 21 years. Among the neonates, 18 patients were considered premature, with 4 patients having gestational ages of 29 to 33 weeks and 14 patients having gestational ages of 34 to 37 weeks. Additional characteristics of our patients are shown in Table 1. Fifteen patients (7.1%) died before hospital discharge. Fifty-four patients underwent surgery during the neonatal period, and 5 of those patients (9.3%) did not survive to hospital discharge. As expected, nonsurvivors had significantly lower age and weight, higher RACHS-1 score, and longer PICU length of stay, compared with survivors (Table 1).

View larger version (12K): [in this window] [in a new window]   FIGURE 1 Morbidity rates (A) and mortality rates (B) for the various groups, based on median blood glucose levels during postoperative days 2 to 5, that is, euglycemia (60–125 mg/dL, 3.3–6.9 mmol/L), mild hyperglycemia (126–139 mg/dL, 6.9–7.7 mmol/L), moderate hyperglycemia (140–179 mg/dL, 7.7–9.9 mmol/L), severe hyperglycemia (180 mg/dL, 9.9 mmol/L), or permissive glycemic target (90–140 mg/dL, 5–7.7 mmol/L). a, P < .0125 by 2 test with Bonferroni correction. Morbidity was defined as the occurrence of any of the following: renal or hepatic dysfunction, new infection, intracranial hemorrhage, stroke, or seizures, need for extracorporeal life support in the postoperative period, or use of dialysis.

View larger version (11K): [in this window] [in a new window]   FIGURE 2 Incidence of hypoglycemia during the postoperative period for the various groups, based on median blood glucose levels, that is, euglycemia (60–125 mg/dL, 3.3–6.9 mmol/L), mild hyperglycemia (126–139 mg/dL, 6.9–7.7 mmol/L), moderate hyperglycemia (140–179 mg/dL, 7.7–9.9 mmol/L), severe hyperglycemia (180 mg/dL, 9.9 mmol/L), or permissive glycemic target (90–140 mg/dL, 5–7.7 mmol/L). a, P < .0125 by 2 test with Bonferroni correction.

	DISCUSSION

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Our study included a broad cohort of patients spanning the entire pediatric age range and exposed to the entire spectrum of cardiac surgical procedures. The mean RACHS-1 score for our sample was 2.74, and the observed 7.1% mortality rate was in line with the predicted mortality rates between 3.8% (RACHS-1 category 2) and 9.5% (RACHS-1 category 3).¹²

We observed a high prevalence of hyperglycemia in our study, with 98% of patients exhibiting 1 glucose measurement above 125 mg/dL (6.9 mmol/L) and 78% of patients having 1 measurement over 200 mg/dL (11 mmol/L). These values are somewhat higher than the 75% to 86% prevalence of hyperglycemia observed in studies involving general PICU samples that included large proportions of nonsurgical patients.^1,2,26 Our study, however, included patients at high risk for developing hyperglycemia because of exposure to corticosteroids, CPB, inotropic or vasoactive medications, and the stress of surgery.

Despite the high prevalence of hyperglycemia in our cohort, the use of insulin therapy was relatively low (7.1%), which was very similar to the 6% use of insulin for critically ill children reported by Srinivasan et al.¹ In our study, insulin use was significantly more frequent in nonsurvivors than in survivors. The small number of patients treated with insulin precluded any meaningful posthoc analysis of this finding, However, we speculate that, because insulin administration was initiated not according to protocol but according to attending physician preference, insulin could have been used more frequently in a sicker subset of patients with severe hyperglycemia of prolonged duration, with a higher risk of death.

Although strict glycemic control in the early phase of surgical stress seems to be important for adult diabetic patients undergoing cardiac surgery,²⁷ intraoperative hyperglycemia has not been associated with worse neurodevelopmental outcomes for infants in long-term follow-up monitoring.²⁸ Furthermore, a recent study of infants <6 months of age who underwent repair of congenital heart defects with CPB showed a lack of correlation between postoperative hyperglycemia and adverse neurodevelopmental outcomes assessed at 1 year of age.²⁹ That study excluded higher-risk patients with multiple congenital anomalies, patients with recognizable genetic or phenotypic syndromes, patients undergoing univentricular repairs, children from non–English-speaking families, patients with a need for repeated operations under CPB, and patients with >1 episode of deep hypothermic cardiac arrest.²⁹ It would be interesting to see whether the same findings would be applicable to a broader sample, such as ours, and whether they would persist at longer-term follow-up evaluations, when more-sophisticated neurocognitive testing could be performed. Our data indicated that hyperglycemia on the first postoperative day was not associated with poor outcomes. Only the duration and intensity of hyperglycemia for the entire 5-day period were associated with increased mortality rates, confirming the observations of Yates et al.³⁰ for infants after cardiac surgery.

Insulin therapy with the goal of obtaining strict glycemic control has now become ubiquitous in many adult ICUs. Whether the potential advantage of strict glycemic control is the result of avoidance of hyperglycemia or is related directly to the effects of insulin administration, such as promotion of anabolism and correction of relative insulin deficiency, has been the source of controversy.¹ However, an interesting prospective observational study attempting to correlate insulin administration with outcomes for critically ill adult patients suggested that mortality benefits were attributable to glycemic control rather than the infused insulin dose.³¹ In addition, target blood glucose levels of <145 mg/dL seemed to be associated with a survival benefit in adults.³²

As strict glycemic control strategies invariably begin to permeate into pediatric critical care practice, we must clearly understand the risks and benefits of such strategies and realize that a definitive study showing the benefits of strict glycemic control in the pediatric population is still lacking. Because of the normal biovariability of blood glucose levels over time, the occurrence of inadvertent hypoglycemia in patients undergoing strict glycemic control within a narrow euglycemic target is of significant concern, especially when we consider that its symptoms may be difficult to recognize in critically ill patients, who often are sedated and under neuromuscular blockade. A recent clinical trial involving critically ill adults with sepsis had to be terminated prematurely because of the high incidence of hypoglycemic events in the intensive insulin therapy group.⁹ Hypoglycemia can have serious repercussions, particularly in the developing brain,^10,11 and has been associated with increased morbidity and mortality rates in pediatric patients.² The elevated incidence of natural hypoglycemia in our sample (22.7%) and its association with increased mortality rates underscore the notion that allowing patients to drift into the hypoglycemic range should be unacceptable, especially if the hypoglycemia is iatrogenic while patients are undergoing insulin therapy to achieve a strict glycemic target.

In the current study, we found that a strict euglycemic target on postoperative days 2 to 5 was associated with a lower mortality rate, in comparison with hyperglycemic ranges. However, we also observed that those patients were at significantly increased risk of developing hypoglycemia sometime during the first 5 postoperative days. By identifying a more permissive glycemic target (90–140 mg/dL, 5–7.7 mmol/L) that is associated not only with a low mortality rate, comparable to that of the euglycemic group, but also with a lower likelihood of undesirable hypoglycemia, we may now have a safer range for the prospective evaluation of glycemic control strategies for critically ill children.

Our study has limitations inherent to its retrospective design. An important limitation is that we were unable to account for differences in carbohydrate administration during the entire postoperative period, including enteral feedings and glucose infusion from maintenance fluids or hyperalimentation. We recognize that a precise analysis of carbohydrate administration beyond the first 24 hours in the PICU would have been valuable in a study such as this. However, a concerted effort to estimate the daily carbohydrate load per patient proved unreliable beyond the first 24 hours, because intravenous fluids often were not the only source of glucose for a given patient; sources also included diluent for medications and partially consumed enteral nutrition. In addition, the timing and frequency of blood glucose measurements were not standardized in the postoperative period. Therefore, sicker patients were more likely to undergo more frequent laboratory testing, which could have resulted in a sampling bias. We attempted to minimize this bias by including a measurement of the number of days of hyperglycemia, defined as the number of postoperative days with 1 measurement beyond a certain hyperglycemic threshold. We recognize that this method does not differentiate a patient with multiple hyperglycemic measurements within a 24-hour period from another with only 1 episode of hyperglycemia within that period. However, this approach ensured a high sensitivity for including every observed episode of hyperglycemia in the analysis. If this had been a prospective study with blood glucose measurements performed at regular preset intervals, we could have analyzed the area under the blood glucose level curve, as a surrogate marker for the intensity and duration of hyperglycemia. However, it must be recognized that, even with frequent monitoring of blood glucose levels in critically ill children at regular intervals, the occurrence of hyperglycemia and hypoglycemia can be underestimated significantly,³³ which underscores the importance of applying more precise techniques, such as continuous blood glucose monitoring, in well-planned, prospective, outcome trials of glycemic control in children.^33,34 Finally, it is important to reiterate that our study does not imply a causal relationship between hyperglycemia or hypoglycemia and adverse outcomes but merely indicates associations between the duration of hyperglycemia or the occurrence of hypoglycemia and morbidity and mortality rates. The question of whether postoperative hyperglycemia and hypoglycemia influence pediatric outcomes directly or are mere epiphenomena can be answered only with a large, randomized, controlled trial of strict glycemic control.

	CONCLUSIONS

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The occurrence of hyperglycemia in the postoperative period is associated with increased morbidity and mortality rates in children after surgical repair or palliation of congenital heart defects. Postoperative hypoglycemia also is associated with an increased mortality rate in these children. A more permissive glycemic target (90–140 mg/dL, 5–7.7 mmol/L) is associated with a lower incidence of hypoglycemia without negatively affecting outcomes for these critically ill patients. Future clinical studies of strict glycemic control in critically ill children should consider this more permissive glycemic range as a desirable target, instead of the riskier euglycemic range.

	FOOTNOTES

 
Accepted Jun 4, 2008.

Address correspondence to Alexandre T. Rotta, MD, FCCM, FAAP, Department of Anesthesiology and Critical Care, Driscoll Children's Hospital, 3533 S. Alameda St, Corpus Christi, TX 78411. E-mail: alexrotta{at}stx.rr.com

The authors have indicated they have no financial relationships relevant to this article to disclose.

What's Known on This Subject Hyperglycemia and hypoglycemia occur frequently in PICUs and are associated with poor outcomes. Glycemic control to avoid hyperglycemia has been shown to reduce morbidity and mortality rates for adult patients but could increase the risk of hypoglycemia and adverse outcomes.

 

What This Study Adds We propose a more permissive glycemic target that is associated with a lower incidence of hypoglycemia without negatively affecting outcomes. Clinical studies of glycemic control in children should consider this more permissive target, instead of the riskier euglycemic range.

 

	REFERENCES

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1. Srinivasan V, Spinella PC, Drott HR, Roth CL, Helfaer MA, Nadkarni V. Association of timing, duration, and intensity of hyperglycemia with intensive care unit mortality in critically ill children. Pediatr Crit Care Med. 2004;5 (4):329 –336[CrossRef][Medline]
2. Wintergerst KA, Buckingham B, Gandrud L, Wong BJ, Kache S, Wilson DM. Association of hypoglycemia, hyperglycemia, and glucose variability with morbidity and death in the pediatric intensive care unit. Pediatrics. 2006;118 (1):173 –179[Abstract/Free Full Text]
3. Yung M, Wilkins B, Norton L, et al. Glucose control, organ failure, and mortality in pediatric intensive care. Pediatr Crit Care Med. 2008;9 (2):147 –152[CrossRef][ISI][Medline]
4. Sung J, Bochicchio GV, Joshi M, Bochicchio K, Tracy K, Scalea TM. Admission hyperglycemia is predictive of outcome in critically ill trauma patients. J Trauma. 2005;59 (1):80 –83[ISI][Medline]
5. Van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically ill patients. N Engl J Med. 2001;345 (19):1359 –1367[Abstract/Free Full Text]
6. Krinsley JS. Association between hyperglycemia and increased hospital mortality in a heterogeneous population of critically ill patients. Mayo Clin Proc. 2003;78 (12):1471 –1478[ISI][Medline]
7. Van den Berghe G, Wilmer A, Hermans G, et al. Intensive insulin therapy in the medical ICU. N Engl J Med. 2006;354 (5):449 –461[Abstract/Free Full Text]
8. Falcao G, Ulate K, Kouzekanani K, Bielefeld MR, Morales JM, Rotta AT. Impact of postoperative hyperglycemia following surgical repair of congenital cardiac defects. Pediatr Cardiol. 2008;29 (3):628 –636[CrossRef][ISI][Medline]
9. Brunkhorst FM, Engel C, Bloos F, et al. Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med. 2008;358 (2):125 –139[Abstract/Free Full Text]
10. Lucas A, Morley R, Cole TJ. Adverse neurodevelopmental outcome of moderate neonatal hypoglycaemia. BMJ. 1988;297 (6659):1304 –1308[ISI][Medline]
11. Yager JY. Hypoglycemic injury to the immature brain. Clin Perinatol. 2002;29 (4):651 –674[CrossRef][ISI][Medline]
12. Jenkins KJ, Gauvreau K, Newburger JW, Spray TL, Moller JH, Iezzoni LI. Consensus-based method for risk adjustment for surgery for congenital heart disease. J Thorac Cardiovasc Surg. 2002;123 (1):110 –118[Abstract/Free Full Text]
13. Wernovsky G, Wypij D, Jonas RA, et al. Postoperative course and hemodynamic profile after the arterial switch operation in neonates and infants: a comparison of low-flow cardiopulmonary bypass and circulatory arrest. Circulation. 1995;92 (8):2226 –2235[Medline]
14. Richards MJ, Edwards JR, Culver DH, Gaynes RP, National Nosocomial Infections Surveillance System. Nosocomial infections in pediatric intensive care units in the United States. Pediatrics. 1999;103 (4). Available at: www.pediatrics.org/cgi/content/full/103/4/e39
15. Brown RB, Stechenberg B, Sands M, Hosmer D, Ryczak M. Infections in a pediatric intensive care unit. Am J Dis Child. 1987;141 (3):267 –270[Abstract]
16. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2005;28 (suppl 1):S37 –S42[Free Full Text]
17. Fanelli C, Pampanelli S, Epifano L, et al. Relative roles of insulin and hypoglycaemia on induction of neuroendocrine responses to, symptoms of, and deterioration of cognitive function in hypoglycaemia in male and female humans. Diabetologia. 1994;37 (8):797 –807[ISI][Medline]
18. Amiel SA, Simonson DC, Tamborlane WV, DeFronzo RA, Sherwin RS. Rate of glucose fall does not affect counterregulatory hormone responses to hypoglycemia in normal and diabetic humans. Diabetes. 1987;36 (4):518 –522[CrossRef][ISI][Medline]
19. Ryan CM, Becker DJ. Hypoglycemia in children with type 1 diabetes mellitus: risk factors, cognitive function, and management. Endocrinol Metab Clin North Am. 1999;28 (4):883 –900[CrossRef][ISI][Medline]
20. Mizock BA. Alterations in carbohydrate metabolism during stress: a review of the literature. Am J Med. 1995;98 (1):75 –84[CrossRef][ISI][Medline]
21. Bochicchio GV, Sung J, Joshi M, et al. Persistent hyperglycemia is predictive of outcome in critically ill trauma patients. J Trauma. 2005;58 (5):921 –924[ISI][Medline]
22. Hall NJ, Peters M, Eaton S, Pierro A. Hyperglycemia is associated with increased morbidity and mortality rates in neonates with necrotizing enterocolitis. J Pediatr Surg. 2004;39 (6):898 –901[CrossRef][ISI][Medline]
23. Branco RG, Garcia PC, Piva JP, Casartelli CH, Seibel V, Tasker RC. Glucose level and risk of mortality in pediatric septic shock. Pediatr Crit Care Med. 2005;6 (4):470 –472[CrossRef][Medline]
24. Cochran A, Scaife ER, Hansen KW, Downey EC. Hyperglycemia and outcomes from pediatric traumatic brain injury. J Trauma. 2003;55 (6):1035 –1038[ISI][Medline]
25. Gore DC, Chinkes D, Heggers J, Herndon DN, Wolf SE, Desai M. Association of hyperglycemia with increased mortality after severe burn injury. J Trauma. 2001;51 (3):540 –544[ISI][Medline]
26. Faustino EV, Apkon M. Persistent hyperglycemia in critically ill children. J Pediatr. 2005;146 (1):30 –34[CrossRef][ISI][Medline]
27. Kersten JR, Warltier DC, Pagel PS. Aggressive control of intraoperative blood glucose concentration: a shifting paradigm? Anesthesiology. 2005;103 (4):677 –678[CrossRef][ISI][Medline]
28. de Ferranti S, Gauvreau K, Hickey PR, et al. Intraoperative hyperglycemia during infant cardiac surgery is not associated with adverse neurodevelopmental outcomes at 1, 4, and 8 years. Anesthesiology. 2004;100 (6):1345 –1352[CrossRef][ISI][Medline]
29. Ballweg JA, Wernovsky G, Ittenbach RF, et al. Hyperglycemia after infant cardiac surgery does not adversely impact neurodevelopmental outcome. Ann Thorac Surg. 2007;84 (6):2052 –2058[Abstract/Free Full Text]
30. Yates AR, Dyke PC II, Taeed R, et al. Hyperglycemia is a marker for poor outcome in the postoperative pediatric cardiac patient. Pediatr Crit Care Med. 2006;7 (4):351 –355[CrossRef][ISI][Medline]
31. Van den Berghe G, Wouters PJ, Bouillon R, et al. Outcome benefit of intensive insulin therapy in the critically ill: insulin dose versus glycemic control. Crit Care Med. 2003;31 (2):359 –366[CrossRef][ISI][Medline]
32. Finney SJ, Zekveld C, Elia A, Evans TW. Glucose control and mortality in critically ill patients. JAMA. 2003;290 (15):2041 –2047[Abstract/Free Full Text]
33. Allen HF, Rake A, Roy M, Brenner D, McKiernan CA. Prospective detection of hyperglycemia in critically ill children using continuous glucose monitoring. Pediatr Crit Care Med. 2008;9 (2):153 –158[CrossRef][ISI][Medline]
34. Srinivasan V. Hyperglycemia in the pediatric intensive care unit: a few steps closer to sweetening the pot. Pediatr Crit Care Med. 2008;9 (2):231 –232[CrossRef][ISI][Medline]

This Article Abstract Full Text (PDF) P3Rs: Submit a response Alert me when this article is cited Alert me when P3Rs are posted Alert me if a correction is posted Citation Map Services E-mail this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My File Cabinet Download to citation manager Citing Articles Citing Articles via CrossRef Google Scholar Articles by Ulate, K. P. Articles by Rotta, A. T. PubMed PubMed Citation Articles by Ulate, K. P. Articles by Rotta, A. T. Related Collections Nutrition & Metabolism

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