|Year : 2016 | Volume
| Issue : 1 | Page : 126-133
Dexmedetomidine for heart rate control and renal protection in patients undergoing mitral valve replacement for tight mitral stenosis
Salah M Asida MD 1, Hatem S Mohamed2
1 Assistant Professor of Anaesthesia and Intensive Care, Qena Faculty of Medicine, South Valley University, Egypt
2 Lecturer of Anaesthesia and Intensive Care, Qena Faculty of Medicine, South Valley University, Egypt
|Date of Submission||07-Jun-2014|
|Date of Acceptance||19-Oct-2014|
|Date of Web Publication||17-Mar-2016|
Salah M Asida
Assistant Professor of Anaesthesia and Intensive Care, Qena Faculty of Medicine, South Valley University
Source of Support: None, Conflict of Interest: None
Dexmedetomidine (DXM) is an α2 adrenoceptor agonist that reduces the sympathetic outflow from the central nervous system resulting in bradycardia and hypotension.
We used this drug in this randomized controlled double-blind study to test its efficacy in controlling the heart rate and its safety regarding renal function in patients undergoing mitral valve replacement surgery.
Patients and methods
A total of 70 patients scheduled for mitral valve replacement were randomly allocated into two groups: in group D, 35 patients received DXM 1 μg/kg bolus dose over 10 min followed by an infusion of 0.5 μg/kg/h. In group C, 35 patients received saline bolus and infusion by the same method instead of DXM. The heart rate was measured at induction of anesthesia, after the end of bolus infusion, at skin incision, and every 10 min till the start of the cardiopulmonary bypass. We also measured the urine interleukin-18 level during the first 12 h of surgery and serum creatinine and blood urea for 3 days postoperatively.
The mean heart rate was significantly lower after bolus infusion, at skin incision, at 10 and 30 min, and just before bypass in the DXM group. Also, the urine output was higher in the DXM group during surgery and on the first postoperative day of surgery. No significant difference was found regarding other parameters of renal functions.
DXM can be used effectively in reducing the heart rate in patients undergoing mitral valve replacement surgery and was associated with an increase in the urinary output, and it did not alter the renal function in this cohort of patients.
Keywords: dexmedetomidine; mitral stenosis; mitral valve replacement
|How to cite this article:|
Asida SM, Mohamed HS. Dexmedetomidine for heart rate control and renal protection in patients undergoing mitral valve replacement for tight mitral stenosis. Ain-Shams J Anaesthesiol 2016;9:126-33
|How to cite this URL:|
Asida SM, Mohamed HS. Dexmedetomidine for heart rate control and renal protection in patients undergoing mitral valve replacement for tight mitral stenosis. Ain-Shams J Anaesthesiol [serial online] 2016 [cited 2019 Jun 25];9:126-33. Available from: http://www.asja.eg.net/text.asp?2016/9/1/126/178892
| Introduction|| |
The incidence of cases of mitral valve replacement surgery is increasing in our department's list of anesthesia for cardiac surgery. During the anesthetic management of these cases, tachycardia is detrimental as it causes pulmonary congestion and reduces the diastolic filling time necessary for coronary filling and left ventricular filling and also reduces the left atrial end-diastolic volume and pressure.
We considered two drugs to maintain a heart rate that ensures sufficient time for left atrial and left ventricular filling, hence ensuring normal cardiac output and arterial blood pressure during induction and maintenance of anesthesia for cases of mitral stenosis: esmolol, with its negative inotropic effect, and dexmedetomidine (DXM), the α2 adrenergic agonist. As esmolol has a negative inotropic effect and a short duration of action, we studied the effect of using DXM on the heart rate during anesthesia for mitral valve replacement due to mitral stenosis aiming at finding a suitable alternative to esmolol if it failed to decrease the heart rate.
DXM is an α2 adrenoceptor agonist that reduces the sympathetic outflow from the central nervous system, thus keeping the blood pressure and the heart rate stable during the induction and the maintenance of anesthesia. It is approved by the FDA for short-term sedation and anxiolysis during mechanical ventilation in the ICU (the elimination half life is 2 h). It also has an analgesic effect that can reduce anesthetic requirements and postoperative analgesic requirements , . Moreover, DXM is thought to produce renal-protective effects through α2 adrenoceptor stimulation, including the inhibition of renin release, an increased glomerular filtration rate, and increased secretion of sodium and water  . Acute kidney injury (AKI) is a recognized complication of cardiac surgery and is usually associated with a high mortality  . The pathogenesis of AKI is multifactorial and includes hemodynamic, inflammatory, and nephrotoxic factors  . As cardiac surgery is associated with the activation of the sympathetic nervous system, DXM-induced sympatholysis may attenuate these harmful hemodynamic effects, preventing AKI. The primary end point of this randomized controlled study was to evaluate the safety and the efficacy of DXM infusion in controlling the heart rate (a primary outcome variable) and protecting renal function [assessed by the urine output (UOP), urine interleukin (IL)-18, serum creatinine, and creatinine clearance as secondary outcome variables] during anesthesia for mitral valve replacement for tight mitral stenosis.
| Patients and methods|| |
This randomized controlled double-blind study has been performed in the Department of Anesthesia of Qena University Hospital from December 2011 to December 2013. The study was registered in the Australian New Zealand Clinical Trials Registry (ANZCTR) and the allocated number is ACTRN12613000495729. The web address of the trial is http://www.ANZCTR.org.au/ACTRN12613000495729.aspx.
We enrolled patients between 18 and 60 years of age, ASA III physical status, admitted to the Cardiothoracic Surgery Department of Qena University Hospital for mitral valve replacement with a mitral valve orifice area of 1 cm or less (tight mitral stenosis) with no other respiratory, hepatic, or renal dysfunction and normal blood coagulation parameters. We excluded patients with persistent atrial fibrillation, an ejection fraction less than 45%, BMI more than 30, preoperative use of clonidine or α-methyl-dopa, preoperative left bundle branch block, and uncontrolled diabetes mellitus.
In total, 89 patients were recruited for the study; of them nine were excluded as they did not meet the study inclusion criteria. We allocated 80 patients randomly into the two groups. Of the 42 patients in the DXM group, seven patients did not receive DXM due to the occurrence of dysrhythmia during the induction of anesthesia; the remaining 35 patients were followed up and their data were analyzed [Figure 1].
In group C, in whom saline was given instead of DXM, 38 patients were studied; three cases were excluded again due to dysrhythmia, and the remaining 35 patients were followed and their data were analyzed [Figure 1]. Generating the allocation sequence and enrolling and assigning patients into each group was concealed from the drug administrator using closed opaque envelopes and was performed according to a computer-generated allocation software (GraphPad Software; GraphPad Software Inc., San Diego, California, USA) into two groups: the control group (group C) included 35 patients and the DXM group (group D) included 35 patients.
All patients were managed according to the same anesthesia protocol. At the preoperative holding room, an intravenous line was established in the forearm of the patient. About 1-2 mg midazolam was given and an arterial cannula was inserted (under local anesthesia) in the left radial artery near the wrist joint by a complete aseptic technique and connected to the invasive blood pressure module of the monitor (Nihon Kohden, Japan) for invasive blood pressure monitoring. Five-lead ECG electrodes were attached to the back of the patient, and BIS electrodes (GE, USA) were attached to the forehead. A pulse-oximetry probe and a noninvasive blood pressure cuff were also attached. The nasopharyngeal temperature probe was inserted after tracheal intubation and internal jugular vein cannulation. The central venous line used was a two-port catheter; hence, we usually insert a 14-G external jugular cannula as an additional venous line. An uretheral catheter was inserted after the induction of anesthesia. All probes were attached securely and fixed in position before the patient was covered by sterile surgery drapes.
Induction of anesthesia was performed by the intravenous administration of 1-2 mg/kg propofol 1%, 5-10 μg/kg fentanyl, and atracurium 0.5 mg/kg to facilitate tracheal intubation. After tracheal intubation, an infusion of fentanyl 1 μg/kg/h was started in all patients in the two groups (using syringe pump) through a peripheral vein.
A soluset containing 100 ml saline only (in the control group) or containing DXM 0.5 μg/kg in 100 ml saline (Precedex, 200 μg/2 ml ampoule; Hospira, USA) (in the DXM group) as a bolus dose was prepared for infusion by an anesthesiologist and administered to the patient by another anesthesiologist who was blinded to the nature of the infusion drugs in the soluset over 10 min. This was followed by another infusion of 0.5 ml/kg/h of either saline or DXM (0.5 μg/kg/h prepared as 50 μg DXM diluted in 50 ml saline) using a syringe pump by the same blinding method.
Isoflurane was used for the maintenance of anesthesia, and its concentration was adjusted to maintain adequate depth of anesthesia (average BIS) and a stable blood pressure. Additional doses of atracurium were given as indicated by a peripheral nerve stimulator. Ringer lactate infusion was given intravenously, and the rate was adjusted according to blood pressure and central venous pressure measurements. The UOP was watched and recorded. All drugs and infusions were stopped when the cardiopulmonary bypass was started (except for the DXM infusion to assess its effect on renal functions).
Through a median sternotomy, cardiopulmonary bypass (CPB) was instituted through cannulation of the ascending aorta and the right atrium with two-stage venous cannulae, at moderate hypothermia (30-34°C), using a membrane oxygenator and a nonpulsatile flow. Anticoagulation for CPB was started with intravenous sodium heparin (300 μg/kg) and continued by intermittent repetition so as to keep the activated clotting time (ACT) more than 480 s. The system was prefilled with 1500 ml of lactated ringer solution, sodium bicarbonate, mannitol (0.5-1 g/kg), and heparin. Myocardial protection was achieved initially with antegrade cold blood crystalloid cardioplegia (at 4°C). After application of an aortic cross-clamp and ice topical cooling, the cardioplegia administration was repeated every 20 min. The left ventricle was vented through the aortic root. During CPB, the hematocrite was maintained between 20 and 25% and the perfusion pressure was maintained at 60-70 mmHg. All patients were rewarmed to 37°C just before the cross-clamp was removed. Heparin anticoagulation was reversed by intravenous protamine sulfate (heparin: protamine, 1: 1.3) after the patient was weaned off CPB. Serum potassium levels were optimized to 4-4.5 mEq/l throughout the surgery to prevent arrhythmia induced by hypokalemia or hyperkalemia. Substitution of blood and fluids during and after CPB was guided by the mean arterial blood pressure and the hematocrite. The initial rhythm after the release of the aortic cross-clamp was noted, and if the heart rate was less than 50 beats/min, epicardial pacing was initiated. If the patient had ventricular fibrillation or ventricular tachycardia, this was also treated with internal defibrillation in a stepwise manner, increasing the energy up to 50 J. Persistent dysrhythmia, bradycardia (<50 beats/min), and hypotension were treated with an appropriate antiarrhythmic drug, atropine for bradycardia, and/or vasopressor, and if not corrected, the patient was excluded from the study [Figure 1].
We recorded the heart rate (a primary outcome variable) using ECG and pulse oximetry, systolic, diastolic, and mean blood pressures just before the induction of anesthesia, after the end of the DXM (or saline) bolus, at skin incision, and every 10 min until the initiation of the cardiopulmonary bypass. We also recorded isoflurane requirements, BIS recordings, the duration of bypass, the total intraoperative analgesic consumption, and possible side effects. The UOP was monitored during surgery and through the rest of the day of surgery (all urine passed during the 90 h after catheter insertion was measured and recorded).
Renal function monitoring also included measurement of blood urea, serum creatinine, and creatinine clearance [estimated using the formula: creatinine clearance (ml/min) = (140 - age × weight (kg)/72 × serum creatinine (mg/dl)]. The values were recorded on the first postoperative day (24 h after transfer to the ICU) and 3 and 5 days after transfer to the ICU; urine samples were taken for analysis by enzyme-linked immunosorbent assay for IL-18 preoperatively (baseline) and at 2, 6, and 12 h after CPB (secondary outcome variables).
Patients were followed up for a month after surgery for possible complications, whether renal, respiratory, neurological, or surgical problems, as outpatients if they were discharged from the hospital and managed as necessary.
Ethical approval for this study was provided by the Ethical Committee of Qena University Hospitals, Qena, Egypt (Chairperson Prof Ahmad Abolyosr). Written informed consent was obtained from every patient who participated in the study.
GraphPad Instat 3.0 was used  to estimate a sample size of 33 cases for each group (completed to 35 cases) to be sufficient for 80% power to detect a difference of 20% in the heart rate. A difference of 14 beats/min was detected in the mean heart rate considering 65-85 beats/min as an average rate between the two groups on the basis of previously published data , at a 95% significance level (GraphPad Software). The χ2 -test was used for analysis of nonparametric data between the two groups and the McNemar test for analysis within each group. The unpaired t-test was used for analysis of parametric data between the two groups, whereas the paired t-test was used for the analysis of parametric data within each group. Data are expressed as mean ± SD (for parametric data), and a P value less than 0.05 was considered to be statistically significant.
| Results|| |
This study included 70 patients divided into two groups, admitted to the Cardiothoracic Surgery Department of Qena University Hospital for mitral valve replacement surgery. Group D (35 patients) received DXM bolus followed by the infusion in addition to fentanyl infusion. Group C (35 patients) received fentanyl infusion and saline (placebo) bolus, and then the infusion.
We found no significant difference between the two groups regarding patients' characteristics and the preoperative data concerning the mitral valve area, the pulmonary artery pressure, and the ejection fraction. Preoperative laboratory data were also comparable [Table 1].
Cardiorespiratory data showed a significant difference in the mean heart rate at skin incision, after bolus infusion, at 10 and 30 min, and just before CPB, being lower in the DXM group [Table 2].
The mean arterial blood pressure was found to be statistically lower in the DXM group at 10 and 30 min after skin incision [Table 3]. The mean systolic blood pressure was found to be statistically lower 30 min after skin incision in the DXM group [Figure 2]. The mean diastolic blood pressure was also found to be statistically lower in the DXM group at 20 and 30 min after skin incision [Figure 3].
|Figure 2: Changes in the mean systolic blood pressure (mmHg). Data are presented as mean ± SD. C, control group (placebo); D, dexmedetomidine group|
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|Figure 3: Changes in the mean diastolic blood pressure. Data are presented as mean ± SD. C, control group (placebo); D, dexmedetomidine group|
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Intraoperative data were recorded till the end of operation, and patients were followed up for a month after surgery. We found a statistically significant difference between the two groups, with the isoflurane concentration being lower in the DXM group. PO 2 values in blood gas analysis series were statistically (although not clinically) lower in the DXM group. We recorded one case of pneumothorax in the DXM group and two cases in the control group C (placebo group). We also recorded two cases of postoperative bleeding in the DXM group compared with one case in the placebo group (group C). Neurological deficits in the form of transient motor weakness occurred in two cases in the DXM group and in one case in the control group (group C). Other intraoperative data showed no significant difference between the two groups [Table 4].
In the DXM group, UOP values during surgery were significantly higher in the DXM group compared with the control group. Also, UOP values were significantly higher in the first 24 h of surgery in the DXM group compared with the control group [Table 5].
Regarding serum creatinine, there were no significant differences between both groups preoperatively and on the first, the third, and the fifth postoperative days. Also, each group showed no significant differences between the preoperative values, and the values on the first, the third, and the fifth postoperative days [Table 5].
The IL-18 level in the urine was lower in the DXM group than in the control group although there was no statistically significant difference between both groups at all measurement points [Table 5].
Preoperative creatinine clearance values showed no significant difference between both groups. Also, the values were comparable in both groups on the first, the third, and the fifth postoperative days. There were no significant differences between the preoperative values and the postoperative values in both groups [Table 5].
| Discussion|| |
The results of our study showed that the mean heart rate (primary outcome variable) was lower in the DXM group at skin incision, after bolus infusion, and at 10 and 30 min after skin incision [Table 2]. This means that DXM added to fentanyl maintains a controlled heart rate in the pre-bypass period more efficiently than fentanyl alone. We also found that blood pressure changes (systolic, diastolic) were lower in the DXM group than in the fentanyl-only group. Also, the results of this study show that DXM did not affect renal functions. However, the UOP was higher in the DXM group than in the control group (secondary outcome).
The induction of anesthesia and the pre-bypass stage of cardiac surgery represents a critical time, especially for patients with tight mitral stenosis as it is usually associated with a high pulmonary artery pressure and the potential for pulmonary congestion and impaired gas exchange. The control of heart rate in this stage of operation is necessary to reduce pulmonary congestion and gives time for coronary perfusion, thus improving myocardial oxygenation, and reduces the work load on the heart and the oxygen demand. DXM is an α2 adrenoceptor agonist acting on presynaptic and postsynaptic locations in the central nervous system. Presynaptic activation inhibits the release of norepinephrine and prevents the propagation of pain signals. However, postsynaptic activation of these receptors, especially in the locus coeruleus, inhibits sympathetic activity and reduces the heart rate and the blood pressure, and hence, we tested this drug in this study. It is also responsible for the sedative and anxiolytic effects of this drug, contributing to its analgesic sparing effect  . After correction of the stenotic state of the mitral valve by a synthetic valve, the blood flow and the pressure gradient across the valve returns to near normal together with the pulmonary artery pressure, and hence, the heart rate should be in the normal range, obviating the need for this drug in the post-bypass stage of surgery; yet, we continued the drug infusion till the end of the operation to assess its analgesia sparing effect and its effect on renal functions.
There are many studies on the effect of DXM on the hemodynamics of patients (regarding heart rate and arterial blood pressure) ,,, ; Lawrence et al.  used DXM 2 μg/kg as a single preinduction intravenous dose for 50 patients undergoing minor orthopedic and general surgery. Anesthesia was maintained with nitrous oxide, oxygen, and fentanyl and supplemented with isoflurane. A statistically significant difference in the heart rate was found between the DXM group and the placebo group. In this study, the dose of DXM was double the dose we used in our study in which the bolus dose was followed by an infusion of DXM to ensure the maximum effect that can be sustained over the pre-bypass period.
Ruesch and Levy  reported that in 2002 they treated a case of persistent tachycardia with DXM during off-pump cardiac surgery. In this case report, they used DXM as a new (at that time) approach for the management of tachycardia after failure to do so using esmolol in incremental doses up to 200 mg. DXM was given after protamine administration as a loading dose of 1 μg/kg over 10 min followed by an infusion of 0.3 μg/kg/h. Within 15 min of infusion, the heart rate decreased to 80 beats/min and remained in that range till the end of the surgery. In our study, we used the same regime, but the infusion dose was increased to 0.5 μg/kg instead of 0.3 μg/kg. We achieved a lower range of heart rate of 45-65 beats/min than that reported in the case report. This case report showed that esmolol (perhaps due to its ceiling effect) was not reliable in controlling the heart rate for a relatively long duration, especially if the tachycardia was resistant and persistent.
A trial was conducted by Menda et al.  in 2010 to attenuate the hemodynamic response to endotracheal intubation in patients undergoing fast-track coronary artery bypass grating (CABG). They used DXM infusion at 1 μg/kg before the induction of anesthesia, which was induced by etomidate and low-dose fentanyl (5 μg/kg), followed by rocuronium 1 mg/kg to facilitate tracheal intubation. They reported that the heart rate and the arterial blood pressure were lower (60-70 beats/min) at all times in comparison with baseline values in the DXM group than in the placebo group (80-90 beats/min). This study showed that DXM is a reliable drug for short-term control of the heart rate (just during the induction of anesthesia), and we obtained further benefit of this criterion of DXM and prolonged its effect on the heart rate using both a bolus dose and an infusion to cover the pre-bypass period.
Klamt et al.  studied the effect of DXM-fentanyl infusion on the blood pressure and the heart rate before surgical stimulation during cardiac surgery in children. They conducted the study on 32 children aged from 1 month to 10 years admitted to correct congenital cardiac defects, the children were divided into two groups. They administered in one group DXM as an intravenous infusion 1 μg/kg/h for an hour followed by half this dose for the rest of the surgery in addition to fentanyl 10 μg/kg and midazolam 0.2 mg/kg. The other group did not receive DXM. The infusions were started after the induction of anesthesia without bolus dose administration and maintained till the end of the surgery. No significant difference was found between the two groups regarding the heart rate and the arterial blood pressure. In this study, no bolus dose was given and the authors concluded that DXM is ineffective in reducing the heart rate and the arterial blood pressure in children without a bolus dose, which was omitted to avoid rapid hemodynamic changes as the cardiac output in children is heart rate dependent and the rapid reduction of heart rate can cause dangerous hypotension in these fragile patients.
Mukhtar et al.  conducted a similar study on children, but they started a bolus infusion of DXM 1 μg/kg followed by an infusion of 0.5 μg/kg/h. They reported that this regimen was effective in attenuating the hemodynamic response to surgery without any deleterious hemodynamic changes in patients older than 1 year of age with less complex cardiac defects. The difference between the study of Mukhtar and colleagues and that of Klamt and colleagues may be in the selection of patients as Mukhtar and colleagues studied older children with less complex cardiac problems, rendering them capable to cope with the effect of a bolus dose of DXM on the hemodynamics.
The results of this study showed that DXM did not alter renal functions. However, the UOP was higher in the DXM group than in the control group. This resulted in an increased hematocrite and improved oxygen-carrying capacity of the blood. It also aided in controlling the serum potassium and the pH of the blood, allowing smooth weaning from CPB. We could not find a significant difference in serum creatinine or blood urea between the DXM group and the control group possibly because these laboratory data are not early biomarkers of AKI, but at least it showed that no harm was caused from using DXM in these cases. Serum creatinine remains the most frequently used parameter in the diagnosis of AKI, although it is an insensitive and unreliable biomarker for short-term changes in kidney function, because patients take days to be affected by kidney injury. Therefore, there is a need for more sensitive and specific biomarkers that can diagnose AKI earlier, possibly indicate the cause, and rapidly measure the response to therapy. We measured urine levels of IL-18 as a biomarker of early kidney injury, and we found no significant increase in its urine level in both groups. Further follow-up of renal function was carried out by measuring serum creatinine and blood urea.
There are not many studies conducted on the renal-protective effects of DXM ,, ; Leino et al.  studied the renal effects of DXM during coronary artery bypass surgery. They scheduled 66 patients undergoing CABG surgery with normal renal function, and randomized them to receive placebo or an infusion of DXM to achieve a pseudo steady-state plasma concentration of 0.60 ng/ml. The infusion was started after anesthesia induction and continued until 4 h after surgery. They reported that no significant differences between groups were recorded for any indices of renal function except for a mean 74% increase in the urinary output with DXM in the first 4 h after the insertion of a urinary catheter (P < 0.001). This study supports our results as renal functions were not affected by the DXM infusion, although they did not use early biomarkers for the detection of AKI.
Ji et al.  published a retrospective study conducted on the effect of DXM in the post-bypass period on kidney function. They reported that post-bypass DXM use was associated with a significantly reduced incidence of total AKI, and also that post-bypass infusion of DXM was associated with significantly reduced incidences of complication and 30-day mortalities. They concluded that post-bypass DXM use is associated with a significant reduction in the incidence of AKI, especially mild AKI in patients with normal renal function preoperatively. These investigators examined the renal-protective effect of DXM in the post-bypass period and found a positive renal-protective effect of DXM on cardiac surgery patients, the results of which when correlated to our results will potentiate each other and encourage the use of DXM infusion to control the heart rate without harmful effects on renal functions.
We conclude that DXM can be used safely and effectively in controlling the heart rate and preserving renal functions in patients undergoing mitral valve replacement surgery due to tight mitral stenosis.
| Acknowledgements|| |
The authors express sincere gratitude to their colleague Prof. Abdelrahaman Abdelhameed, Head of the Clinical Pathology Department of Qena Faculty of Medicine, for his help in measuring renal functions of patients scheduled in this study.
This study was supported by the South Valley University.
Conflicts of interest
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]