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 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 6  |  Issue : 3  |  Page : 321-329

Effect of premedication with clonidine, midazolam, and dexmedetomidine on stress response and sedation in pediatric congenital cardiac surgeries


1 Department of Anasthesia and Surgical Intensive Care, Faculty of Medicine, Alexandria University, Alexandria, Egypt
2 Department of Clinical and Chemical Pathology, Faculty of Medicine, Alexandria University, Alexandria, Egypt

Date of Submission17-Jul-2018
Date of Acceptance09-Jun-2019
Date of Web Publication29-Aug-2019

Correspondence Address:
Ayman M Maaly
PhD. Lecturer of Anaesthesia and Surgical Intensive Care, Department of Anasthesia and
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/roaic.roaic_60_18

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  Abstract 

Background Children undergoing cardiac surgery experience a substantial stress response mediated by the release of stress hormones and cytokines. Providing sedation and blunting stress response by one drug in a single oral dose and excellent oral bioavailability of clonidine prompted us to study its efficacy as premedication in pediatric patients and compare it with both oral midazolam, a gold standard premedication in pediatric patient, and oral dexmedetomidine, as a newer α2 receptor agonist.
Aim To compare the effect of premedication with three drugs (clonidine, midazolam and dexmedetomidine) in pediatric congenital cardiac surgeries including their effect on the stress response during surgery.
Patients and methods Patients were categorized into three groups (30 patients each): group clonidine (C) received oral clonidine at a dose of 4 µg/kg, group midazolam (M) received oral midazolam at a dose of 0.5 mg/kg, whereas group dexmedetomidine (Dx) received oral dexmedetomidine at a dose of 1 μg/kg. All the drugs were mixed with equal volume of 5% dextrose.
Results The bispectral index measurements in group Dx became significantly lower at 15 min and 30 min compared with the other two groups. Then, significantly lower bispectral index measurements were observed in group C compared with groups M and Dx at 45 min and afterward. The serum cortisol and catecholamines levels in group C became significantly lower than that in groups M and Dx after intravenous cannulation, after sternotomy, and at the end of surgery.
Conclusion Clonidine, as a preanesthetic drug in congenital heart surgery, is effective in decreasing stress response and achieving adequate level of sedation till the end of surgery. Oral dexmedetomidine has faster onset compared with midazolam in reaching the adequate level of sedation.

Keywords: bispectral index, clonidine, dexmedetomidine, stress response


How to cite this article:
Maaly AM, Hashem AM, El Neily DA, Hamouda SA, Abdel-Razek A. Effect of premedication with clonidine, midazolam, and dexmedetomidine on stress response and sedation in pediatric congenital cardiac surgeries. Res Opin Anesth Intensive Care 2019;6:321-9

How to cite this URL:
Maaly AM, Hashem AM, El Neily DA, Hamouda SA, Abdel-Razek A. Effect of premedication with clonidine, midazolam, and dexmedetomidine on stress response and sedation in pediatric congenital cardiac surgeries. Res Opin Anesth Intensive Care [serial online] 2019 [cited 2019 Nov 18];6:321-9. Available from: http://www.roaic.eg.net/text.asp?2019/6/3/321/265734


  Introduction Top


Congenital heart disease is relatively common, affecting between 4 and 14 individuals in every 1000 live births [1]. Approximately one-third of the affected children require surgery during early childhood. Induction of anesthesia is a stressful and anxiety-provoking experience for children undergoing surgery. Sedation allows for a comfortable and cooperative patient, decreases the levels of anxiety and stress, reduces insomnia and the risk of awareness during stressful interventions, and normalizes metabolism and hemodynamics. Moreover, sedation is often used to facilitate mechanical ventilation, to suppress gag reflexes related to the tubing system, and to treat self-destructive agitation [2].

Inadequate sedation usually produces sudden changes in the level of consciousness because of stress. These changes result in inadequate ventilation, hypertension, tachycardia, and discomfort, all of which have adverse consequences on the outcome of the patients [3],[4].

Midazolam, a γ-amino-butyric acid receptor inhibitor, is the most commonly used sedative drug for premedication in children. It provides effective sedation, anxiolysis, and varying degrees of anterograde amnesia; however, adverse effects such as postoperative behavioral changes, hiccups, and paradoxical hyperactive reactions have been observed [5],[6],[7],[8].

Clonidine is an α2 agonist that has emerged as a potential alternative to midazolam as premedication in pediatric patients. Dexmedetomidine is a newer potent α2 agonist that provides the same beneficial effects as clonidine, but with a higher potency and shorter duration of action [9].

Accurate assessment of the depth of sedation requires a tool that is reliable and valid but also easy to use in a clinical setting. The bispectral index (BIS) monitor is an FDA-approved monitor that has been used in clinical practice since 1997. It gathers processed EEG parameters to provide a numeric measure of the hypnotic effect of anesthetic or sedative drugs on brain activity. According to the manufacturer, a BIS score of more than 90 indicates an awake patient; 71–90, mild to moderate sedation; 61–70, deep sedation; and 40–60, general anesthesia [10].

The stress response to surgery is a major neuroendocrine and cytokine response to surgical trauma, characterized by increases in catecholamine and steroid hormones, with predictable metabolic consequences. This stress response has been considered as a homeostatic defense mechanism, important for the body for adaptation and developing resistance to the noxious insults. Such exaggerated physiological changes in patients with coexisting diseases are always life threatening. If the stress response is prolonged, the continuous hypermetabolic state may result in exhaustion of essential components of the body causing loss of weight, fatigue, decreased resistance, delayed ambulation, and increased morbidity and mortality [11],[12].

Patients undergoing cardiac surgery experience a substantial stress response mediated by the release of stress hormones and cytokines. Cardiopulmonary bypass (CPB) accentuates this response because of the activation of the immune system by direct contact of the blood to foreign surfaces of the CPB circuit, ischemia–reperfusion injury, and systemic endotoxemia owing to translocation of endotoxin from the gut [13].

The prospects of sedation and blunting stress response provided by one drug in single oral dose and excellent oral bioavailability of clonidine prompted us to study its efficacy as premedication in pediatric patients and compare it with oral midazolam, a gold standard premedication, in pediatric patients, and also comparing its effect with dexmedetomidine, a newer α2 receptor agonist [14].


  Aim Top


The study was conducted to compare the effect of premedication with three drugs (clonidine, midazolam and dexmedetomidine) in pediatric congenital cardiac surgeries including their effect on the stress response during surgery.


  Patients and methods Top


Patients were categorized into three groups (30 patients each): group clonidine (C) received oral clonidine at a dose of 4 µg/kg, group midazolam (M) received oral midazolam at a dose of 0.5 mg/kg, whereas group dexmedetomidine (Dx) received oral dexmedetomidine at a dose of 1 μg/kg. All the drugs were mixed with equal volume of 5% dextrose.

Preoperative evaluation included detailed medical and surgical history, complete clinical examination, routine laboratory investigations, chest radiography, ECG, echocardiography, and cardiac catheterization when needed.

The sedative drugs used were as follows:
  1. Crushed tablets of 100 µg clonidine (one tablet) were dissolved into 5 ml 0.9% NaCl to get a concentration of 20 µg/ml.
  2. One milliliter of parenteral form of dexmedetomidine (100 μg) was dissolved into 5 ml 0.9% NaCl to get a concentration of 20 µg/ml.
  3. One milliliter of parentral form of midazolam (5 mg) was used as such.
  4. Each drug was mixed with equal volume of 5% dextrose and was administered using a 5-ml syringe [14],[15],[16],[17].
  5. The premedication was given by the researcher in the preoperative holding area in the presence of one parent.


Monitoring: patients were monitored by BIS index and multichannel monitor (Drager PM-9000; Infinity® Acute Care System; Drägerwerk AG & Co. KGaA. Lübeck, Germany) for ECG monitoring [heart rate (HR) and rhythm], invasive mean arterial blood pressure (mmHg), oxygen saturation percentage (SpO2%) by pulse oximetry, and respiratory rate (cycles/min).

Anesthesia:
  1. General anesthesia was induced with fentanyl 5 µg/kg and diprivan 2% titrated till BIS score became 40–60.
  2. Rocuronium 0.6–0.9 mg/kg was administered to facilitate endotracheal intubation and was repeated every 30 min during surgery as required to ensure muscle relaxation (0.2–0.3 mg/kg).
  3. Endotracheal intubation was done using an ETT of appropriate size.
  4. Anesthesia was maintained using 1–2% sevoflurane in an oxygen-air mixture (1 : 1 ratio) before skin incision and during arterial and central venous cannulation. The concentration of sevoflurane was titrated to maintain mean arterial pressure and HR in the range of ±20% baseline values and adequate anesthetic depth as measured by BIS [18].
  5. Mechanical ventilation was provided by a Drager anesthesia machine (North American Dräger, Telford, Pennsylvania, USA) using pressure controlled ventilation to achieve normal minute volume ventilation with normocapnea as measured by end-tidal CO2.
  6. Cannulation of the radial or femoral artery was done using cannula of appropriate size for invasive blood pressure monitoring guided by ultrasound.
  7. Appropriate size of central venous pressure (CVP) catheter was inserted (5 Fr) in the right internal jugular vein under complete aseptic technique with ultrasound guidance.
  8. All patients received 10–20 ml/kg of lactated Ringer’s solution before initiating the CPB to keep normal CVP to ensure adequate intravascular volume.
  9. Intravenous heparin was given at a dose of 300–500 IU/kg in CVP 3–5 min before arterial (aortic) cannulation.
  10. CPB was initiated after aorto-bicaval cannulation, and cold cardioplegia (15 ml/kg) was administered into the aortic root and repeated every 20 min. The patients were cooled to 28–30°C or even less.
  11. 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.
  12. The mean arterial pressure was maintained between 50 and 60 mmHg during CPB [18].


Measurements:
  1. Demographic data included age, sex, and weight.
  2. Hemodynamics included HR (beats/min), mean arterial blood pressure (mmHg), SpO2% and respiratory rate (cycles/min).
  3. Degree of sedation was measure by BIS measurement [17].
    • Timing of assessment of the hemodynamic variables and BIS measurements was as follows:
      1. At baseline: on admission to the preoperative holding area.
      2. Every 15 min for 45 min in the preoperative holding area.
      3. On arrival to the operating room (OR) after connecting the patient to the multichannel monitor and BIS.
      4. After application of the O2 face mask.
      5. After peripheral intravenous cannulation.
      6. After intubation.
      7. After sternotomy.
  4. Stress response to sternotomy


Serum cortisol and catecholamines levels were measured at baseline (6 a.m. in the ward on the day before surgery), immediately after cannulation, immediately after sternotomy, and at the end of surgery before the patient was discharged to ICU.

Statistical analysis

Data were fed to the computer and analyzed using IBM SPSS software package version 20.0 (SPSS Inc., Chicago, Illinois, USA) [19]. Qualitative data were described using number and percent. Quantitative data were described using range (minimum and maximum), arithmetic mean, and SD.

χ2-Test was used for categorical variables, to compare between different groups. The distributions of quantitative variables were tested for normality using Kolmogorov–Smirnov test. When it revealed normal distribution, parametric tests were applied. If the data were abnormally distributed, nonparametric tests were used. Significance of the obtained results was judged at the 5% level.


  Results Top


The age of the patients ranged between 4 and 10 years. There was no statistically significant difference among the three groups regarding age, sex, or weight ([Table 1]).
Table 1 Comparison among the three studied groups according to demographic data

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There was no statistically significant difference in the mean HR among the three studied groups before sedation. At 15 min after sedation, the mean HR in group Dx became significantly lower than its values in the other two groups (P=0.012). At 30 min, the mean HR in group Dx continued to be significantly lower than its values in the other two groups (P=0.004). On the contrary, the mean HR in group M became significantly lower than its value in group C (P=0.046).

The mean HR in group C became significantly lower than that in groups M and Dx when recorded at 45 min, and afterward. When comparing the mean HR in group Dx with that in group M, it was significantly lower in group Dx at 45 min and afterward ([Figure 1]).
Figure 1 Comparison among the three studied groups regarding changes in the heart rate (beats/min). C, clonidine; M, midazolam; Dx, dexmedetomidine.

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There was no statistically significant difference regarding the mean arterial blood pressure (MABP) among the three studied groups before sedation. At 15 min after sedation, the MABP in group Dx became significantly lower than its values in the other two groups (P=0.043). At 30 min, the MABP in group Dx continued to be significantly lower than its values in the other two groups (P<0.001). On the contrary, the MABP in group M became significantly lower than its value in group C (P=0.036).

The MABP in group C became significantly lower than that in groups M and Dx at 45 min, and afterward. Moreover, it was significantly lower in group Dx when compared with group M at 45 min, and afterward ([Figure 2]).
Figure 2 Comparison among the three studied groups regarding changes in the mean arterial blood pressure (MABP) (mmHg). C, clonidine; M, midazolam; Dx, dexmedetomidine.

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Regarding the assessment of the level of sedation using BIS measurement, there was no statistically significant difference among the three studied groups at the basal measurement. The BIS measurements in group Dx became significantly lower at 15 and 30 min compared with the other two groups. Then, significantly lower BIS measurements were observed in group C compared with groups M and Dx at 45 min and afterward ([Figure 3]).
Figure 3 Comparison among the three studied groups regarding changes in the bispectral index (BIS) measurements. C, clonidine; M, midazolam; Dx, dexmedetomidine.

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Concerning changes in serum cortisol and catecholamines levels as markers of stress response, there was no statistically significant difference among the three studied groups before sedation (baseline), with P value of 0.181. Their serum levels in group C became significantly lower than that in groups M and Dx after intravenous cannulation, after sternotomy, and at the end of surgery. On the contrary, there was no significant difference between groups M and Dx regarding serum cortisol and catecholamines levels at all timings of measurement ([Figure 4] and [Figure 5]).
Figure 4 Comparison among the three studied groups regarding changes in serum cortisol level. C, clonidine; M, midazolam; Dx, dexmedetomidine.

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Figure 5 Comparison among the three studied groups regarding changes in serum noradrenaline level. C, clonidine; M, midazolam; Dx, dexmedetomidine.

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Correlation analysis was performed to explore the relation between BIS measurement and serum markers of stress response. Before sedation, significant positive correlations were revealed between BIS measurement and serum cortisol (r=0.113, P=0.005), serum adrenaline (r=0.104, P=0.026), serum noradrenaline level (r=0.281, P<0.001), and serum glucose level (r=0.273, P<0.001). Just after peripheral intravenous cannula insertion, significant positive correlations were revealed between BIS measurement and serum cortisol (r=0.562, P=0.017), serum adrenaline (r=0.734, P=0.001), serum noradrenaline level (r=0.614, P=0.003), and serum glucose level (r=0.082, P=0.04). After sternotomy, significant positive correlations were revealed between BIS measurement and serum cortisol (r=0.636, P<0.001), serum adrenaline (r=0.838, P<0.001), serum noradrenaline level (r=0.756, P<0.001), and serum glucose level (r=0.346, P<0.001; [Table 2]).
Table 2 Correlation between bispectral index measurement and serum markers of stress response for total sample (n=90)

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  Discussion Top


This study compared the effect of premedication with three drugs (clonidine, midazolam and dexmedetomidine) in pediatric congenital cardiac surgeries including their effect on the stress response during surgery. The study involved 90 children scheduled for congenital heart surgeries. The age of the patients in the three studied groups ranged between 4 and 10 years whereas the children’s weight ranged between 11 and 34 kg, with nonsignificant difference among the three groups regarding the patients’ ages, sex, or body weight.

In this study, the HR and MABP were significantly lower in group Dx compared with group M at 30, 45 min, in the OR, after face mask application, after intravenous cannulation, after intubation, as well as after sternotomy.

These findings could be explained by a more rapid onset of midazolam and its shorter duration of action, so its hemodynamic effect subsided at 45 min and afterward. The median onset of action of dexmedetomidine is 25 min, with median duration of 85 min. Its median absolute bioavailability is 85%. Clonidine is absorbed after oral administration and reaches its peak plasma concentration within 60–90 min. It has a half-life of 9–12 h [20].

This result was in accordance with Sun et al. [21] who concluded in their meta-analysis of randomized controlled trials that dexmedetomidine premedication reduced significantly the MABP at 30 and 45 min following the administration of the drug compared with midazolam.

Similarly, Kamal et al. [22], reported that the mean arterial pressure and HR were significantly lower in children who received oral dexmedetomidine compared with those who received oral midazolam during the intraoperative and postoperative periods.

Assessment of the level of sedation in this study was done using BIS measurements. The BIS measurements in group Dx was significantly lower at 15 and 30 min compared with the other two groups. Afterward, significantly lower BIS measurements were observed in group C compared with groups M and Dx at 45 min, in the OR, after face mask application, after intravenous cannulation, after intubation, and after sternotomy.

These results are in agreement with previous studies. Mitra et al. [9] reported that the onset of sedation was significantly faster in midazolam group as compared with clonidine group in their study, but both groups achieved acceptable sedation levels at 30 min. This was consistent with other findings [5],[23] but faster compared with few other reports [24],[25],[26],[27].

On the contrary, Kamal et al. [22] studied the effect of oral dexmedetomidine versus oral midazolam as premedication in 60 pediatric patients, and there was no significant difference in the preoperative and postoperative levels of sedation between the two groups, but onset of sedation was significantly faster in group M (28.4±13.7 vs. 39.5±14.3 min; P<0.05).

Surgical procedures and CPB during cardiac surgery produce a neuroendocrine stress response that plays an important role in the pathogenesis of perioperative cardiac complications and increases morbidity and mortality. Blood levels of cortisol and catecholamines are regarded as predictors of this stress response [28].

In this study, serum cortisol and catecholamines levels in group C became significantly lower than that in groups M and Dx after intravenous cannulation, after sternotomy and at the end of surgery, without significant difference between groups M and Dx at all timings of measurement. These results were in concordance with previous studies which reported decreased cortisol and catecholamines release after oral clonidine administration [29],[30].

Significant positive correlations were revealed between BIS measurement and serum cortisol, adrenaline, noradrenaline, and glucose levels at all timings of measurement. Similar significant positive correlation was reported by Bauer et al. [31]. The potential benefit of individual titration of anesthetic drugs based on electroencephalographic monitoring is particularly obvious in patients who are at risk of adverse effects of inadequate anesthesia, most notably hemodynamic instability. Moreover, in the study by Miyawaki et al. [32], the depth of sedation indicated by the BIS value was significantly related to the serum cortisol level at 30 min after induction (r=0.840, P=0.0012).

Recently, dexmedetomidine has been increasingly used as an adjunct during cardiac surgery in both children and adults. Mukhtar et al. [33] reported that the use of dexmedetomidine in addition to low-dose fentanyl has resulted in lower levels of hormonal and metabolic stress markers when compared with low-dose fentanyl alone.


  Conclusion Top


The use of oral dexmedetomidine in congenital cardiac operations is a good choice as a premedication in decreasing the stress response and achieving a good level of sedation with faster onset compared with midazolam in reaching the adequate level of sedation. Clonidine, as a preanesthetic drug in congenital heart surgery, is effective in decreasing stress response and achieving adequate level of sedation till the end of surgery. BIS is a good choice for assessing the level of sedation preoperatively, intraoperatively, and postoperatively. Serum glucose level can be used as a surrogate to serum cortisol and catecholamines levels for monitoring stress response.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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