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Anesth Analg 2004;99:1044-1048
© 2004 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000132550.59059.55

PEDIATRIC ANESTHESIA

Blood Glucose Control During Selective Arterial Stimulation and Venous Sampling for Localization of Focal Hyperinsulinism Lesions in Anesthetized Children

Giovanni Cucchiaro, MD, Scott D. Markowitz, MD, Robin Kaye, MD, N. Scott Adzick, Ronald S. Litman, DO, Charles A. Stanley, MD, and Mehernoor F. Watcha, MD

From The Children’s Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania.

Address correspondence and reprint requests to Giovanni Cucchiaro MD, Department of Anesthesiology and Critical Care Medicine, The Children’s Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Philadelphia, PA 19104. Address email to cucchiaro{at}email.chop.edu


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Surgical management of congenital hyperinsulinism is improved by accurate localization of small, focal dysregulated pancreatic lesions using the arterial stimulation and venous sampling (ASVS) test, which can demonstrate increased hepatic venous insulin concentrations after selective arterial injections of calcium. However, anesthesia-related increases in blood glucose can induce insulin secretion, making it difficult to interpret ASVS test data. In this retrospective study, we examined the effect of anesthetic interventions on blood glucose concentrations in 68 children undergoing ASVS testing. We considered only the glucose concentrations observed before calcium stimulation in the final analysis. The choice of drugs for induction (sevoflurane, propofol, or thiopentone), maintenance inhaled anesthetics (sevoflurane, desflurane, or isoflurane), and the use of caudal epidural bupivacaine were not associated with significant differences in the mean blood glucose concentration before ASVS. However, patients receiving remifentanil infusions had smaller mean glucose concentrations (80 ± 18 versus 100 ± 44 mg · dl–1, P = 0.01). These concentrations were also significantly smaller if tracheal intubation was delayed for at least 10 min after induction while patients received inhaled anesthetics via a face mask along with remifentanil infusions (79 ± 14 for delayed intubation versus 95 ± 39 mg · dl–1 for early intubation, respectively, P = 0.03). The percentage increase in glucose concentrations from preintubation values was significantly smaller in these subjects (3.7% ± 21.9% for delayed intubation versus 31.7% ± 60.4% for early intubation, P = 0.02). We conclude that the anesthetic management protocol for these patients should include the use of remifentanil infusions and the administration of inhaled anesthetics and remifentanil infusions for a minimum of 10 min to establish a deep plane of anesthesia before tracheal intubation.

IMPLICATIONS: The use of a remifentanil infusion and delayed tracheal intubation decrease intraoperative glucose concentrations during arterial stimulation and hepatic venous sampling for localization of focal hyperinsulinism lesions in children.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Congenital hyperinsulinism, the most frequent cause of persistent, severe hypoglycemia in infancy, is amenable to surgical resection of focal dysregulated pancreatic lesions. However, localization of such tumors is difficult if they are less than 2 cm in diameter (1–6). A sensitive technique for localization is the arterial stimulation and venous sampling (ASVS) test, in which blood samples are drawn from the right hepatic vein after selective injections of a rapid bolus of calcium gluconate in the arteries supplying various areas of the pancreas (7–10). The diagnosis is established if this is accompanied by a larger than two-fold increase in insulin concentrations in hepatic veins. If the increase is noted after injection in only one artery, the tumor is localized to the area supplied by that vessel (8,11,12). This test is performed with sedation in adults, but most pediatric patients require general anesthesia for successful completion of the procedure. Stress-related secretion of catecholamines during general anesthesia can cause a marked increase in blood glucose concentrations, which can induce insulin secretion from normal pancreatic tissue, making it difficult to interpret ASVS test data (13–15). Although deep anesthesia can minimize blood glucose changes, such techniques can prolong emergence and cause cardiovascular depression (13,16,17). This retrospective cohort study examined the effect of anesthetic-related factors on blood glucose concentrations in children undergoing ASVS testing, with the aim of using such data to devise an anesthetic management protocol for patients undergoing this procedure.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
After obtaining approval from our IRB, we extracted data from the medical records of 68 children who received general anesthesia for testing for congenital hyperinsulinism at The Children’s Hospital of Philadelphia between October, 1998 and November, 2003. The procedure involved advancing a diagnostic vascular catheter under fluoroscopic control from the right internal jugular vein into the right hepatic vein. Another catheter was inserted into the femoral artery and selectively advanced into the hepatic artery for a negative control and then serially into the gastroduodenal, superior mesenteric and splenic arteries, respectively. After contrast confirmation of catheter placement, a rapid bolus of calcium gluconate, 0.025 mEq · kg–1, was injected into the artery and serial samples of blood were drawn from the hepatic vein immediately before and 30, 60, 90, and 120 s after injection of calcium. Glucose and insulin concentrations were measured in these samples.

Capillary blood for glucose determination was obtained by heel-stick until the central lines were placed. Blood samples were subsequently obtained from the arterial catheter. Systemic blood glucose concentrations were checked regularly (approximately every 10 to 15 min) from the time of anesthesia induction until completion of the ASVS test. However, in the data analysis we used only the concentrations from samples obtained before injecting calcium. Glucose concentrations were targeted to be maintained between 50 and 80 mg · dl–1 during the procedure (18). When blood glucose was persistently more than 80 mg · dl–1, patients received IV insulin lis-pro (Humalog®, Lilly, Indianapolis, IN), 0.01 U · kg–1. This form of insulin does not cross-react with the insulin assay and has a short half-life. A bolus of IV glucose, 0.25 gm · kg–1 (2 mL · kg–1 of 10% glucose) was administered for blood glucose concentrations <50 mg · dl–1.

We noted the time and details of any adjustment of glucose infusion rate and administration of insulin, along with all blood glucose concentrations. We determined the mean, peak, variance, and range (difference between the lowest and highest value) of blood glucose concentrations obtained after induction of general anesthesia for each patient. Demographic data, anesthetic drugs, doses, and anesthetic interventions were recorded along with the time of induction, tracheal intubation, start and completion of the procedure, time of tracheal extubation, and end of anesthesia.

We examined the effect of the following anesthetic-related factors on the mean, peak, range and variance of glucose concentrations obtained before injection of calcium.

  1. Induction anesthetics: inhaled (sevoflurane), IV (propofol, thiopental).
  2. Maintenance inhaled anesthetics: sevoflurane, isoflurane, or desflurane.
  3. Supplemental regional anesthesia with caudal bupivacaine.
  4. Continuous infusions of remifentanil.
  5. Time between induction and tracheal intubation. For statistical analysis, glucose concentrations were compared among patients who underwent tracheal intubation 10 min after induction versus earlier intubation. We chose a 10-min period because the hemodynamic and hormonal changes induced by intubation are usually observed within 3–10 min from intubation (19,20).

Data are presented as mean ± SD if normally distributed or as median with interquartile range (IQR) if not normally distributed. Normally distributed continuous variables were compared by Student’s t-test if only 2 groups were present, and by analysis of variance if more than 2 groups were present. If significant differences were noted in the analysis of variance test, intergroup comparisons were made using the Student-Newman-Keuls test. The corresponding nonparametric tests (Kruskal-Wallis and Mann-Whitney U-test) were used for data not normally distributed. {chi}2 tests with Yates’ continuity correction and Fisher’s exact tests were used for categorical data. P values <0.05 were considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Sixty-eight patients with histologically proven hyperinsulinism underwent selective ASVS testing between October, 1998 and November, 2003. There were 30 males and 38 females, median age 5.6 (IQR, 0.2–16.8) months and median weight 5.9 (IQR, 2.8–9.0) kg. The peak blood glucose concentrations associated with the use of specific anesthetic drugs are provided in Table 1. The choice of induction technique (IV or inhaled), induction anesthetic (propofol or thiopental), maintenance inhaled anesthetic (sevoflurane, isoflurane, or desflurane), drugs used for neuromuscular blockade (vecuronium or pancuronium), or bolus injections of opioids (morphine or fentanyl) did not result in significant differences in the mean, peak, range, or variance of glucose concentrations during ASVS testing (Table 1). The use of caudal regional anesthesia with bupivacaine for supplementing general anesthesia was not associated with a decrease in these glucose concentrations compared to the concentrations in patients receiving only general anesthesia.


View this table:
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  		Table 1. Peak Glucose Concentrations Associated with the Use of Specific Anesthetic Drugs
 
In patients who received remifentanil infusions, the initial rate was set at 1.0 µg · kg–1 · min–1 immediately after induction and then adjusted, based on the patients vital signs (arterial blood pressure and heart rate). The infusion rate of remifentanil ranged between 0.4 and 1.5 µg · kg–1 · min–1 during the procedure. Patients receiving remifentanil infusions had significantly smaller mean and peak glucose concentrations during the procedure (mean glucose, 80 ± 18 versus 100 ± 44 mg · dl–1, P = 0.01; peak glucose, 119 ± 38 versus 153 ± 80 mg · dl–1, P = 0.02 respectively). The mean, peak, and range of glucose concentrations were also significantly smaller in patients who received inhaled anesthetics via a face mask for a minimum of 10 min after induction of anesthesia before tracheal intubation was attempted. The mean glucose was 79 ± 14 versus 95 ± 39 mg · dl–1 (P = 0.03), peak glucose was 111 ± 27 versus 147 ± 72 mg · dl–1 (P = 0.01), and the range was 59 ± 28 versus 87 ± 63 mg · dl–1 (P = 0.03) for delayed versus early intubation, respectively. The percentage increase in glucose concentrations from preintubation concentrations was significantly smaller in these subjects (3.7% ± 21.9% for delayed intubation versus 31.7% ± 60.4% for early intubation, P = 0.02). In addition, the variance of glucose concentrations before ASVS was significantly smaller in children receiving remifentanil infusions and in those whose tracheal intubation was delayed.

There were no clinically important changes in blood pressure or heart rate requiring drug intervention therapy during ASVS testing in any patient. There were also no significant differences in the duration of the procedure, time from the start of induction to the first calcium stimulation test, or in the time from the end of the procedure to tracheal extubation in patients who did or did not receive remifentanil infusions during anesthesia.


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Blood glucose concentrations during anesthesia are of concern as both hyperglycemia and hypoglycemia can have deleterious effects (21,22). However, a tight control of postinduction blood glucose is even more critical for ASVS testing than for most other procedures, as significant variations in blood glucose could lead to alterations in insulin secretion, confounding the interpretation of insulin concentrations. Blood glucose concentrations during general anesthesia are influenced by a neurohormonal response to stress with an increased secretion of endogenous catecholamines with subsequent increase of plasma cortisol, glucagon, and glucose, along with hemodynamic changes of increased heart rate, arterial blood pressure, and cardiac output (22,23). We have shown in this study that the anesthetic technique can significantly influence blood glucose concentrations (hyperglycemia, specifically) in this group of patients.

We identified tracheal intubation as an event associated with a hyperglycemic stress response and found that two anesthetic interventions can ameliorate this response. These interventions are the use of remifentanil infusions and delaying tracheal intubation to establish a deeper level of anesthesia. We did not use a depth of anesthesia monitor such as the bispectral index to document this, as the validity of this device in the infant patient population has been questioned (24). However, there is evidence that larger concentrations of inhaled anesthetics are required to block stress responses (MAC-BAR) compared with movement responses (MAC) during surgery, at least in the adult population (25,26). The use of large concentrations of inhaled anesthetics or infusions with other less-expensive opioids (e.g., fentanyl or morphine) may have provided similar protection against hyperglycemic responses to tracheal intubation compared to remifentanil infusions, but this may have been associated with cardiorespiratory depression and prolonged emergence (27–29). The ASVS procedure took a mean of 164 ± 49 minutes, and the ultra-short action of remifentanil along with its steady context-sensitive half-life make it a useful drug in this situation (30). Patients who received remifentanil did not have a longer time from the end of the procedure to tracheal extubation.

In our study, the control of blood glucose in patients receiving isoflurane and remifentanil infusions was not improved by additional caudal epidural analgesia. This seems to contradict previous studies showing that epidural analgesia significantly reduces stress response to abdominal surgery (31,32). However, there is minimal surgical stimulation during ASVS. In addition, the procedure requires insertion of catheters in the neck, an area outside the limits of analgesia provided by caudal epidural analgesia. This may explain the failure of supplemental epidural analgesia in controlling hyperglycemia. It is our practice to use epidural analgesia in this patient population when they undergo subsequent pancreatectomy, a procedure with more surgical stimulation than ASVS.

This study may be criticized, as it used retrospective data. However, within these limitations, we can formulate an anesthetic management protocol for ASVS (Table 2). The key features of this protocol are the use of remifentanil infusions and continuation of controlled ventilation while delivering inhaled anesthetics via a face mask, during the remifentanil infusion, for a minimum of 10 minutes before attempting tracheal intubation. In conclusion, better control of blood glucose during ASVS testing may be achieved with the use of remifentanil infusions and delaying tracheal intubation until a deep plane of anesthesia is achieved. Close monitoring of blood glucose at regular intervals is mandatory in these patients to ensure a tight control of glucose concentrations with the avoidance of both hypoglycemia and hyperglycemia. However, if episodes of hyperglycemia occur, synthetic lis-pro insulin should be used, as this preparation does not cross-react with the insulin assay.


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  		Table 2. Anesthetic Management Protocol for Arterial Stimulation Venous Sampling Test
 

   Acknowledgments
 
Supported, in part, by National Institutes of Health grants RO1 DK 56268, MO1 RR 00240 and departmental sources.

We would like to acknowledge the assistance of Dr. Laura Myers, Dr. Juan Grimaldos, Katie Harris, Anil Rajendra, Catherine Cho, Rosetta Chiavacci, L. A. Wanner, Pooja Bhatia and many others at the Children’s Hospital of Philadelphia who made it possible for us to collect the data for this study.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. Aynsley-Green A, Hussain K, Hall J, et al. Practical management of hyperinsulinism in infancy. Arch Dis Child Fetal Neontal Ed 2000; 82: F98–107.
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Accepted for publication April 27, 2004.





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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press