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PEDIATRIC ANESTHESIA

The Use of Dexmedetomidine in Pediatric Cardiac Surgery

Ahmed M. Mukhtar, MD^*, Eman M. Obayah, MD, and Amira M. Hassona

From the Departments of Anesthesia and Intensive Care and Biochemitry, Cairo Uniersity, Egypt.

Address correspondence and reprint requests to Ahmed M. Mukhtar, MD, Faculty of Medicine, Cairo University, 2 Zaafran St from Ahmed Kamel St behind Giza Governate Alharam, Cairo, Egypt. Address e-mail to Ahmed3m2003{at}yahoo.com.

	Abstract

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We tested dexmedetomidine, an ₂ agonist, for its ability to decrease heart rate, arterial blood pressure, and neuroendocrinal responses during pediatric cardiac surgery. In a randomized, placebo-controlled study, 30 pediatric patients undergoing open heart surgery were randomly assigned to one of two equal groups. The control group received saline, whereas the treatment group (DEX group) received an initial bolus dose of dexmedetomidine (0.5 µg/kg) over 10 min, followed immediately by a continuous infusion of 0.5 µg · kg^–1 · h^–1. Arterial blood pressure, heart rate, and sequential concentrations of circulating cortisol, epinephrine, norepinephrine, and blood glucose were measured. Relative to baseline, arterial blood pressure and heart rate decreased significantly after the administration of dexmedetomidine through skin incision. In the control group, patients' heart rate and arterial blood pressure measures increased after skin incision until the end of bypass (P < 0.05). In both groups, plasma cortisol, epinephrine, norepinephrine, and blood glucose increased significantly relative to baseline, after sternotomy, and after bypass. However, the values were significantly higher in the control group compared with the DEX group (P < 0.05). In conclusion, intraoperative dexmedetomidine infusion attenuated the hemodynamic and neuroendocrinal response to surgical trauma and cardiopulmonary bypass in pediatric patients undergoing corrective surgery for congenital heart disease.

	Introduction

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The stress response is the term given to the hormonal and metabolic changes that occur after injury or trauma. This is part of a systemic reaction to injury that encompasses a wide range of endocrinological, immunological, and hematological effects. It is initiated by neuronal activation of the hypothalamo-pituitary-adrenal axis (1). The stress response to surgery is characterized by increased secretion of pituitary hormones and activation of the sympathetic nervous system (2,3). Attenuation of the cardiovascular, neuroendocrine, and inflammatory responses to surgery may improve outcome by beneficial effects on organ function (1,4).

Dexmedetomidine is a highly specific, potent, and selective ² adrenoceptor agonist (5). It has a relatively high ratio of ²/¹ activity (1620:1 as compared to 220:1 for clonidine) (6) and is therefore considered a full agonist of the ² receptor. This ratio ensures that its potent action is selective for the central nervous system, without unwanted cardiovascular effects from ¹ receptor activation (6). Dexmedetomidine has activity at the imidazoline receptors involved in central arterial blood pressure control (7,8). It causes a dose-dependent decrease in mean arterial blood pressure (MAP) and heart rate (HR) (9) and a reduction in sympathetic nervous system activity (9,10). Dexmedetomidine is an imidazole compound, and therefore, it has the potential to exert similar inhibitory effects to etomidate on cortisol synthesis (11).

This is the first study to report the sympatholytic effects of a continuous intraoperative infusion of dexmedetomidine on cardiovascular function and stress hormones (cortisol and catecholamine) in pediatric cardiac surgery patients. The hypothesis that dexmedetomidine would attenuate the increase in HR, MAP, and plasma catecholamine concentrations in pediatric patients undergoing corrective surgery for congenital heart disease was investigated.

	METHODS

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After approval of the local Ethics Committee and obtaining written informed consent from the guardians of all patients, the study was designed to include 30 patients, aged 1–6 yr, scheduled for congenital heart disease repair surgery using cardiopulmonary bypass (CPB) between January 2004 and September 2004. Patients undergoing re-operations, deep hypothermia, those with low cardiac output, and those with nonpalpable peripheral pulses before surgery (e.g., accompanying coarctation of the aorta) were excluded from the study.

Anesthesia was induced with fentanyl 10 µg/kg and midazolam 0.1 mg/kg. Pancuronium 0.15 mg/kg was administered to facilitate endotracheal intubation and was repeated during surgery as required to maintain muscle relaxation. Anesthesia was maintained using isoflurane 0.3%–1.5% in an oxygen-air mixture (1:1 ratio). The concentration of isoflurane was titrated to maintain MAP and HR in the range of 80% and 120% of baseline values. Mechanical ventilation was provided by a Narkomed anesthesia machine (North American Dräger, Telford, PA) using a tidal volume of 10 mL/kg with the respiratory rate adjusted according to age, aiming to maintain Paco₂ between 30 and 35 mm Hg. All patients received 10 mL/kg of lactated Ringer's crystalloid solution before initiating CPB.

After insertion of a central venous and an arterial catheter, patients were randomly allocated into one of two equal groups (n = 15 each). In the DEX group, patients received an initial bolus dose of dexmedetomidine (0.5 µg/kg) over 10 min, followed immediately by a continuous infusion of 0.5 µg · kg^–1 · h^–1. The infusion was continued throughout the operation and was discontinued at the end of CPB. A similar volume of normal saline was given in the control group.

Hemodynamic variables (HR, systolic blood pressure, and diastolic blood pressure) were recorded at baseline (after the anesthetic induction and before the administration of the study drug), at 5, 10, and 15 min after the administration of the study drug, after skin incisions, after sternotomy, and after termination of CPB. Blood samples were obtained from the arterial catheter for assessment of plasma cortisol, epinephrine, norepinephrine, and blood glucose measurements. Samples were obtained at baseline, after sternotomy, and after termination of CPB.

In all patients, a median sternotomy was performed. CPB was initiated after standard aorta-bicaval cannulation. A membrane oxygenator (Minimax Plus; Medtronic Inc., Anaheim, CA) and a nonpulsatile roller pump (model 10.10.00; Stôckert Instruments, Munich, Germany) were used. Venting of the left heart was performed with a left atrial vent inserted through a small incision at the interatrial septum. Priming fluids consisted of lactated Ringer's solution supplemented with heparin. Fresh whole blood was added to the priming solution in appropriate amounts to achieve a hematocrit of 20%–22% during CPB. Moderate hypothermia (26°C–28°C) was used during CPB.

Sodium nitroprusside infusion was initiated during the rewarming period, and its rate of infusion was titrated to keep MAP between 50 and 60 mm Hg in the rewarming period. Total bypass time, aortic cross-clamping time, and the dose of vasodilators (sodium nitroprusside) required at weaning off CPB were noted and recorded. Atropine requirement during surgery for treatment of possible bradycardia (decrease in HR > 30% of baseline) was also noted and recorded.

All of the following chemicals were obtained from Sigma (St. Louis, MO): diammonium hydrogen orthophosphate, heptane sulfuric acid, EDTA, dihydroxybenzylamine (internal standard), noradrenaline, adrenaline, acetonitrite, boric acid, and phosphoric acid.

Blood samples (10 mL) were collected into tubes containing heparin as an anticoagulant and transported to the laboratory on ice within 30 min. Samples were centrifuged at 3500 rpm for 10 min. Plasma was stored as aliquots at –80°C. The assay was by high-performance liquid chromatography with an electrochemical detector.

The system used was the GBC system (GBC Scientific equipment Bty Ltd., Victoria, Australia), (pum LC 1150, electrochemical detector CLC 100) equipped with phenomenex (USA, UK) phenosphere ODS analytical column (150 mm x 4.6 mm ID; 5-µm particle size). Electrochemical detection was achieved using an USA Coulochem II (ESA Analytical, Huntingdon. Cambridgeshire, United Kingdom) fitted with a guard cell and a 50 II analytical cell. Oxidation of the analyte was performed at +500 mV in the guard cell followed by a successively higher reduction potential of –100 mV and –300 mV in the analytical cell and sensitivity at 20 nA. The mobile phase consisted of 125 mmol/L of diammonium hydrogen orthophosphate containing 101 mg of heptane sulfuric and 73 mg of EDTA adjusted to a flow rate of 1 mL/min (isocratic mode). The peak of catecholamines was identified according to the retention time of the standard (12).

The plasma cortisol level was determined by a microtiter strip enzyme-linked immunosorbent assay (ELISA) kit (13), and blood glucose levels were determined with the enzymatic colorimetric method. Interassay and intraassay coefficient of variability for each assay were as follows: norepinephrine 4.6% (inter) and 4% (intra), epinephrine 4.2% and 4%, and cortisol 7.1% and 4.3%.

Power analysis was performed on norepinephrine because it was the main outcome variable in the present study. Student's t-test for independent samples was chosen to perform the power analysis, the -error level was fixed at 0.05, and the sample size was 30 participants divided equally into two groups. We tried multiple combinations of the assumed population standard deviation and effect size to make the power 80%. The final result was that the present study can be 80% powerful in detecting an effect size of 20 U when the assumed population standard deviation value was 19. Data were presented as mean (sd). Statistical analysis was performed using Statistica version 5.0 (StatSoft, Tulsa, OK). Fitting of data to a normal distribution model was tested using the Kolmogorov-Smirnov test. Repeated measures were compared between the groups using two-way analysis of variance with post hoc Scheffé test. Other variables were compared using two-tailed unpaired Student's t-test. Gender was compared using ² test. P value was considered statistically significant if <0.05.

	RESULTS

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Thirty patients were randomized into the study, and they all completed the study. Demographic data were comparable between the two groups (Table 1).

Administration of dexmedetomidine resulted in a significant decrease in HR and MAP relative to baseline, starting after the administration of the drug and continuing to the time of the skin incision. In the control group, HR and MAP increased significantly relative to baseline, starting from skin incision and continuing until the end of the study. Patients in the control group had significantly more rapid HR and MAP levels relative to those in the DEX group after the administration of the drug and lasting for the rest of the study period (P < 0.05; Table 2).

End-tidal isoflurane concentration did not vary between groups throughout the study period (Table 2).

Plasma cortisol, epinephrine, norepinephrine, and blood glucose levels were comparable between groups at baseline. Although all aforementioned variables increased significantly relative to baseline in both groups after sternotomy and after bypass, their levels were significantly higher in the control group compared with the DEX group (P < 0.05; Figs. 1–4).

View larger version (20K): [in this window] [in a new window]   Figure 1. Random blood glucose. Columns are mean, and error bars are standard deviations. *P < 0.05 compared with control group; P < 0.05 compared with baseline in the same group.

View larger version (18K): [in this window] [in a new window]   Figure 2. Plasma cortisol level. Columns are mean, and error bars are standard deviations. *P < 0.05 compared with control group; P < 0.05 compared with baseline in the same group.

View larger version (23K): [in this window] [in a new window]   Figure 3. Plasma epinephrine level. Columns are mean, and error bars are standard deviations. *P < 0.05 compared with control group; P < 0.05 compared with baseline in the same group.

View larger version (22K): [in this window] [in a new window]   Figure 4. Plasma norepinephrine level. Columns are mean, and error bars are standard deviations. *P < 0.05 compared with control group; P < 0.05 compared with baseline in the same group.

	DISCUSSION

Top Abstract Introduction METHODS RESULTS DISCUSSION REFERENCES

 
The present study demonstrated that the use of dexmedetomidine in pediatric cardiac surgery results in decreasing HR and MAP, with a concomitant reduction in cortisol, catecholamines, and blood glucose levels as markers of stress response.

Few reports investigated the effect of dexmedetomidine infusion in pediatric patients undergoing noncardiac surgery (14) and there has been no report concerning using this drug in pediatric patients undergoing open heart surgery.

The hemodynamic effects of dexmedetomidine are predictable from the pharmacology of adrenoceptor agonists and have been confirmed from previous studies in volunteers (15). These hypotensive and bradycardic effects of dexmedetomidine are presumably mediated by the sympatholytic effect of dexmedetomidine, which is confirmed in our study by significant reductions of both epinephrine and norepinephrine in the DEX group compared with the placebo group. This partly explains why patients in the control group required more vasodilator than those in the DEX group. Our results are consistent with those of another study (16), which showed that dexmedetomidine infusion decreased the plasma level of catecholamine in healthy volunteers.

Activation of the hypothalamo-pituitary-adrenal axis and cortisol secretion associated with surgical trauma are very important perioperative stress responses. Dexmedetomidine was not found to affect the process of steroidogenesis, as proven by the work of Venn et al. (17), who demonstrated that dexmedetomidine did not affect the response to the adrenocorticotropic hormone stimulation test. However, patients receiving dexmedetomidine had significantly lower intraoperative cortisol levels as compared with those who did not receive the drug before surgery (18). This supports our findings that dexmedetomidine administration resulted in lower levels of stress response markers in this pediatric population.

Alpha-2 adrenoceptor agonists can cause hyperglycemia in humans (19,20). The mechanism is thought to involve postsynaptic ₂-adrenoceptor stimulation of pancreatic ß cells, which inhibits insulin release. Interestingly, we found that dexmedetomidine infusion did inhibit the hyperglycemic response to surgery and CPB significantly more than placebo, and this may reflect attenuation of sympathoadrenal response.

There are several limitations in the present study that should be considered. The most important is that it was performed in simple, relatively short procedures and in patients with relatively good cardiac function. Indeed patients with more complex cardiac lesions may be at high risk for developing significant bradycardia and hypotension that may need intervention when using dexmedetomidine.

We concluded that intraoperative dexmedetomidine infusion can be a useful adjuvant in pediatric cardiac anesthesia because it attenuates the hemodynamic and neuroendocrinal response of surgical trauma and CPB. Further studies are required to determine the safety and efficacy of using dexmedetomidine infusion in more complex pediatric cardiac procedures.

	Footnotes

 
Accepted for publication February 6, 2006.

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (13) Citing Articles via Google Scholar Google Scholar Articles by Mukhtar, A. M. Articles by Hassona, A. M. Search for Related Content PubMed PubMed Citation Articles by Mukhtar, A. M. Articles by Hassona, A. M. Related Collections Cardiovascular Anesthetic Techniques Pediatrics Pharmacology