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Effect of Dexmedetomidine Infusion on Hemodynamics and Stress Responses in Pediatric Cardiac Surgery: A Randomized Trial


1 Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, IR Iran
2 Iran University of Medical Sciences, Tehran, IR Iran
3 Hasheminejad Kidney Center, Iran University of Medical Sciences, Tehran, IR Iran
4 Kerman University of Medical Sciences, Kerman, IR Iran
*Corresponding author: Mitra Chitsazan, Rajaie Cardiovascular Medical and Research Center, Vali-Asr St., Niayesh Blvd, Tehran, IR Iran. Tel: +98-9122210385, Fax: +98-2122055594, E-mail: mitra.chitsazan66@yahoo.com.
Research in Cardiovascular Medicine. 6(1): e35016 , DOI: 10.5812/cardiovascmed.35016
Article Type: Research Article; Received: Nov 26, 2015; Revised: Dec 16, 2015; Accepted: Dec 21, 2015; epub: Jul 2, 2016; collection: Jan 2017

Abstract


Background: Infants and children compared with adults have intensified stress responses that lead to increased morbidity and mortality. Stress control reduces the incidence of complications and improves recovery. In clinical and experimental studies, dexmedetomidine reduces the inflammatory and neuroendocrine responses.

Objectives: This prospective randomized double-blinded clinical trial was conducted to assess the role of dexmedetomidine in reducing stress responses.

Materials and Methods: According to convenient sampling method, 40 patients in two groups (case under treatment with dexmedetomidine and control, each including 20 patients) were selected from whom admitted for open heart surgery. Anesthesia was induced and maintained by fentanyl and midazolam. After central venous and arterial catheter insertion, patients were randomly allocated into one of two equal groups (n = 20 each). In the dexmedetomidine group, patients received an initial loading dose (0.5 μg/kg) during 10 minutes immediately followed by a continuous infusion of 0.5 μg/kg. In the control group, normal saline solution with similar volume was infused.

Results: Changes in heart rate, systolic and diastolic blood pressures and central venous pressure before administration of dexmedetomidine, in 10, 20 and 30 minutes after the operation, after skin incision, after sternotomy, after separation from the pump and at the end of procedure showed no significant difference between the two groups (P = 0.860, 0.067, 0.888 and 0.482, respectively). Changes in lactate, interleukin 6, tumor necrosis factor, C-reactive protein concentrations before administration of dexmedetomidine, after separation of pump and 24 hours after intensive care unit entrance showed no significant difference between the two groups (P = 0.525, 0.767, 0.868 and 0.840, respectively).

Conclusions: According to our findings, using dexmedetomidine as an adjuvant anesthetic medication with initial loading dose of 0.5 μg/kg and maintenance dose of 0.5 μg /kg in pediatric heart surgeries is a safe choice. However, further studies are needed to clarify the role of dexmedetomidine to reduce stress responses.

Keywords: Dexmedetomidine; Open Heart Surgery; Stress

1. Background


Stress response defined as chemical and metabolic changes occurs after injury or trauma. It is initiated by hypothalamus, pituitary gland and adrenal gland (HPA) axis. The HPA axis comprises the system of feedback interactions between hypothalamus, pituitary gland and adrenal glands (1, 2). Surgery as a stressor causes increased activity of this pathway and initiates stress response. Many immunological, hematological and inflammatory mediators are involved.


The response affects different hormones, including C-reactive protein (CRP), cortisol, catecholamines and activation of complement system, migration of leukocytes into damaged areas of operation, release of cytokines such as interleukins, tumor necrosis factor and other cellular products such as superoxide radicals, proteases and growth factors (3, 4).


Inflammation cascade is necessary to regenerate tissue and infection control, but uncontrolled systemic inflammatory response could lead to complications in the elderly, children and patients with other comorbidities (5, 6). Infants and children compared with adults have intensified stress responses that lead to increased morbidity and mortality.


Therefore, stress control reduces the incidence of complications and improves recovery (5, 7). Controlling anesthesia during the operation could be effective directly through stimulation of immune mechanisms or indirectly by reducing the impact of stress responses.


In clinical and experimental studies, dexmedetomidine reduces inflammatory and neuroendocrine responses. Dexmedetomidine is a selective alpha-2 adrenoceptor agonist with high specificity which means the ratio of 1 α . 2 α is high (8, 9). The high ratio indicates effects on the central nervous system without unwanted cardiovascular side effects (9). The drug has sedative, anxiolytic and analgesic effects (10). Dexmedetomidine affects the central nervous system associated with a decrease in mean arterial blood pressure and heart rate. Dexmedetomidine reduces the need for other anesthetic drugs during the operation, hemodynamic stability and provides sedation in recovery phase (11, 12).

2. Objectives


This prospective randomized double-blinded clinical trial was conducted to assess the role of dexmedetomidine in reducing stress responses.

3. Materials and Methods


This prospective randomized double-blinded clinical trial was conducted from January 2012 to May 2013 and approved by the ethics committee of Rajaie cardiovascular, medical and research center. A written informed consent was obtained from guardians of all patients.


All patients aged 6 months to 6 years with congenital heart defects undergoing open heart surgery were eligible if they had body weight below 25 kg, estimated pump time of at least an hour and a maximum of three hours, estimated operation duration of at least four hours and maximum of 5 hours. Patients were excluded if they had Re-do heart surgery, deep hypothermia, low cardiac output, known allergy to dexmedetomidine or had received dexmedetomidine during one week before surgery.


Anesthesia was induced by 10 - 15 μg/kg fentanyl and 0.1 mg/kg midazolam. Then, anesthesia was maintained by 5 μg/kg/h fentanyl and 1mg/kg/min midazolam. All patients received 10 mL/kg of ringer lactate solution before the operation. After central venous and arterial catheters insertion, using computer-generated random number list, patients were randomly allocated 1:1 into one of the two groups (each n = 20): In the dexmedetomidine group (n = 20), patients received an initial loading dose of dexmedetomidine (0.5 μg .kg) during 10 minute, immediately followed by a continuous infusion of 0.5 μg/kg dexmedetomidine. In the control group (n = 20), normal saline solution with similar volumes was infused.


Heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP) and central venous pressure (CVP) were recorded after induction of anesthesia, before administration of dexmedetomidine, after the first dose, after skin incision, after sternotomy and after termination of operation.


To evaluate plasma lactate, interleukin-6 (IL-6) and tumor necrosis factor (TNF) blood samples were taken from arterial catheter. The samples were obtained before dexmedetomidine injection, after termination of operation and 24 hours later in ICU.


During the operation, fresh whole blood was used to keep hematocrit at 25% - 30%.


During the operation, moderate hypothermia (32 - 30°C) was used. Mean Arterial Pressure (MAP) was maintained between 40 and 70 mmHg. Total bypass time and aortic cross-clamping time recorded.


During cardiopulmonary bypass, hypotension and hypertension were treated by phenylephrine and nitroglycerine.

4. Results


Forty patients including 16 (40%) males were randomized into the study. Demographic data were compared between the two groups (Table 1).


Table 1.
Demographic Dataa

Changes in heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP) and central venous pressure (CVP) before administration of dexmedetomidine, in 10, 20 and 30 minutes after the initial dose, after the operation, after skin incision, after sternotomy, after separation from the pump and at the end of procedure in the two groups are shown in Figure 1 (P = 0.860, 0.067, 0.888 and 0.482; respectively).


Figure 1.
A, changes in heart rate; B, systolic blood pressure; C, diastolic blood pressure; D, central venous pressure in the Two Groups

Changes in lactate, IL-6, TNF and CRP concentrations before administration of dexmedetomidine, after separation of pump and 24 hours after ICU entrance in the two groups are illustrated in Table 2 (P = 0.525, 0.767, 0.868 and 0.840, respectively).


Table 2.
Comparing Lactate, IL-6 and TNF at Different Times Between the Two Groups

Changes in laboratory measurements before administration of dexmedetomidine, after separation of pump and 24 hours after ICU entrance in the two groups are shown in Table 3.


Table 3.
Comparing Laboratory Values at Different Times Between the Two Groups

Blood products usage in ICU and duration of mechanical ventilation are compared in Table 4.


Table 4.
Blood Products Usage in Intensive Care Unit and Duration of Mechanical Ventilation

5. Discussion


The present study assessed the effect of dexmedetomidine in pediatric cardiac surgery on hemodynamic variables (HR, SBP, DBP, and CVP) and concentrations of different plasma components between the two groups.


Dexmedetomidine is a selective alpha-2 adrenoceptor agonist with high specificity, which means the ratio of 1 α / 2 α is high. It has also sedative, anxiolytic and analgesic effects. We used an initial loading dose (0.5 μg/kg) during 10 minutes and maintenance dose of 0.5 μg/kg.


Heart rate measurement in different times showed no significant difference between the two groups. However, heart rate in dexmedetomidine group increased with a significant difference comparing 30 minutes after administration, time of sternotomy and after separation of pump. SBP measurement in different times showed no significant difference between the two groups. Nevertheless, SBP in dexmedetomidine group showed significant difference (decreased BP) between 10 and 20 minutes after administration and also, between 30 minutes after administration and skin incision (increased BP). DBP measurement in different times showed no significant difference between the two groups. However, DBP in dexmedetomidine group showed significant difference comparing sternotomy and time of separation from pump. CVP measurement in different times showed no significant difference between the two groups. Although, CVP in dexmedetomidine group showed a significant difference comparing 10 and 20 minutes after administration (increased BP).


These findings are consistent with previous studies, which proved that dexmedetomidine causes heart rate and blood pressure changes and hemodynamic stability (13-16). In some studies about dexmedetomidine, hypotension and dose dependent bradycardia have been reported (4, 6, 17-20). Lactate concentration showed no significant difference in different times between the two groups, but there was a significant difference (increased concentration) in dexmedetomidine group before administration of loading dose and after separation from pump. No significant difference in IL-6 concentration between the two groups was observed. Findings about lactate and IL-6 in our study are not consistent with some other similar studies (20). Changes in CRP and TNF had no significant differences in our study. Although, TNF level in the both groups increased. In some other studies, no changes in TNF levels were reported, which is inconsistent with this study (21). Hb and hematocrit, BUN and Cr levels showed no significant differences. Hemodynamic effects of dexmedetomidine (including changes in BP and HR) are one major problem of this drug. In our study, none of these was observed; it might be due to dose protocol used in this study. Moreover, comparing placebo and dexmedetomidine groups, the latter caused more hemodynamic stability and less stress responses.


5.1. Study Limitations

The major limitation of our study was its relatively small sample size. Moreover, as the study population was pediatric patients, we had to start dexmedetomidine after induction of anesthesia and insertion of arterial lines. As a result, surgery stress responses have been started to an unavoidable degree by the time of dexmedetomidine administration. This may alter the effects of dexmedetomidine on stress responses.


5.2. Conclusions

According to our findings, using dexmedetomidine as an adjuvant anesthetic medication with initial loading dose of 0.5 μg/kg during 10 minutes and maintenance dose of 0.5 μg/kg in pediatric heart surgeries is safe. However, we could not show any beneficial effects of this medication on hemodynamic changes and stress responses. To further elucidate the role of dexmedetomidine in pediatric heart surgery, we suggest further studies with larger sample sizes and larger doses of dexmedetomidine.

Footnotes

Authors’ Contribution: Ziae Totonchi contributed to the study concept and design, data collection, critical revision and approval of the manuscript. Hengameh Rezvani, Masoud Ghorbanloo, Forouzan Yazdanian, Mohammad Mahdavi, Shirin Salajegheh and Mitra Chitsazan contributed to data collection, critical revision and approval of the manuscript. Nima Babaali contributed to the analysis and interpretation, statistics, drafting, critical revision and approval of the manuscript.

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Table 1.

Demographic Dataa

Dexmedetomidine Placebo P Value
Age, y 1.3 ± 9.1 0.4 ± 6.2 0.579
Sex 0.143
Male 10 (7.66) 6 (0.40)
Female 5 (3.33) 9 (0.60)
Weight, kg 8.3 ± 7.9 7.3 ± 8.10 0.423
Duration between loading dose and skin incision, min 9.6 ± 7.29 6.8 ± 0.38 0.700
Aortic cross clamp duration, min 4.27 ± 4.60 0.16 ± 3.49 0.198
Pump time, min 2.40 ± 8.89 6.29 ± 0.80 0.454
Operation time, min 1.93 ± 5.247 3.106 ± 5.239 0.827
Systolic Blood Pressure 01.14 ± 9.84 9.11 ± 8.83 0.824
Diastolic Blood Pressure 8.11 ± 3.49 9.7 ± 6.46 0.473
Heart rate, bpm 1.23 ± 7.122 2.21 ± 4.122 0.967
Central Venous Pressure, mmHg 7.2 ± 5.6 1.2 ± 9.6 0.617
a Values are expressed as mean ± SD or No. (%).

Table 2.

Comparing Lactate, IL-6 and TNF at Different Times Between the Two Groups

Dexmedetomidine Placebo P Value
Lactate
Before loading dose 9.0 ± 0.1 7.0 ± 0.1 0.982
After separation of pump 2.1 ± 5.2 2.1 ± 3.2 0.717
24 hours after ICU entrance 3.1 ± 4.1 3.0 ± 2.1 0.638
Interleukin-6
Before loading dose 7.5 ± 9.10 7.16 ± 7.14 0.852
After separation of pump 8.112 ± 1.47 8.45 ± 1.45 0.406
24 hours after ICU entrance 0.115 ± 5.48 8.82 ± 1.67 0.616
Tumor necrosis factor
Before loading dose 6.61 ± 7.36 0.17 ± 9.15 0.663
After separation of pump 5.61 ± 3.40 2.19 ± 7.19 0.589
24 hours after ICU entrance 4.59 ± 0.38 8.158 ± 8.68 0.282
C-Reactive protein
Before loading dose 3.13 ± 2.10 1.12 ± 2.9 0.574
After separation of pump 6.5 ± 7.3 7.2 ± 3.3 0.503
24 hours after ICU entrance 2.36 ± 3.47 8.30 ± 2.57 0.477

Table 3.

Comparing Laboratory Values at Different Times Between the Two Groups

Dexmedetomidine Placebo P Value
Hemoglobin
Before loading dose 8.2 ± 9.11 3.3 ± 6.12 0.289
After separation of pump 9.1 ± 2.10 4.1 ± 0.10 0.772
24 hours after ICU entrance 3.1 ± 0.12 4.8 ± 5.15 0.155
Hematocrit
Before loading dose 1.9 ± 1.38 6.9 ± 6.39 0.672
After separation of pump 1.6 ± 0.33 6.4 ± 4.32 0.764
24 hours after ICU entrance 3.4 ± 8.38 3.4 ± 8.38 0.989
Blood Urea Nitrogen
Before loading dose 0.5 ± 2.10 7.3 ± 2.11 0.540
After separation of pump 8.1 ± 9.9 1.3 ± 4.11 0.113
24 hours after ICU entrance 6.3 ± 8.11 7.5 ± 2.11 0.772
Creatinine
Before loading dose 13.0 ± 47.0 10.0 ± 50.0 0.471
After separation of pump 09.0 ± 45.0 09.0 ± 41.0 0.292
24 hours after ICU entrance 13.0 ± 43.0 17.0 ± 49.0 0.403

Table 4.

Blood Products Usage in Intensive Care Unit and Duration of Mechanical Ventilation

Dexmedetomidine Placebo P Value
Packed cell 2.77 ± 7.111 9.84 ± 1.88 0.558
Platelet 0 ± 0 0 ± 11 0.292
Fresh frozen plasma 0 ± 140 5.53 ± 90 0.465
Duration of mechanical ventilation 1.25 ± 6.18 4.6 ± 8.12 0.464

Figure 1.

A, changes in heart rate; B, systolic blood pressure; C, diastolic blood pressure; D, central venous pressure in the Two Groups