|Year : 2013 | Volume
| Issue : 1 | Page : 7-12
Does dexmedetomidine affect renal outcome in patients with renal impairment undergoing CABG?
Maged Salah1, Tarek El-Tawil2, Sherif Nasr2, Tarek Nosser2
1 Department of Anesthesia and Intensive Care, Cairo University, Cairo, Egypt
2 Department of Cardiothoracic Surgery, Faculty of Medicine, Cairo University, Cairo, Egypt
|Date of Submission||16-Aug-2012|
|Date of Acceptance||01-Oct-2012|
|Date of Web Publication||26-Jun-2014|
MD, Department of Anesthesia and Intensive Care, Faculty of Medicine, Cairo University, 11431 Cairo
Source of Support: None, Conflict of Interest: None
Dexmedetomidine, a centrally acting α2-adrenoceptor agonist, has been used as an adjunct to anesthesia and in sedation because of its efficient sympatholytic, analgesic, and anxiolytic properties. Recently, several studies have focused on the potential neuroprotective and renoprotective effects of dexmedetomidine in patients undergoing different surgical procedures.
Coronary artery bypass grafting (CABG) with cardiopulmonary bypass is associated with a high incidence of perioperative renal dysfunction that is believed to be caused partly by the increased sympathetic nervous system activity leading to compromised hemodynamics and attenuated renal function.
Aim of the work
To test the hypothesis that dexmedetomidine would exert a renal protective effect and prevent the development of acute kidney injury in patients with mild to moderate renal dysfunction undergoing elective CABG during the early postoperative days.
A double-blind randomized placebo-controlled study was carried out. Eighty adult patients with mild to moderate renal impairment (serum creatinine between 1.5–2 mg/dl) and scheduled for elective CABG with cardiopulmonary bypass were randomly allocated to either dexmedetomidine infusion or placebo infusion groups. Infusion was started after induction of anesthesia and continued until the end of surgery. The primary outcome variables measured for assessment of renal functions included serum creatinine, creatinine clearance, and urinary output in the 72 h postoperatively.
No significant difference was detected for any indicators of renal function between both groups, except for an increase in urinary output in the dexmedetomidine infusion group in the first 24 h after surgery (P=0.007).
The use of dexmedetomidine infusion did not alter renal function in terms of serum creatinine or creatinine clearance but was associated with an increase in urinary output in the first 24 h.
Keywords: acute kidney injury, cardiopulmonary bypass, dexmedetomidine
|How to cite this article:|
Salah M, El-Tawil T, Nasr S, Nosser T. Does dexmedetomidine affect renal outcome in patients with renal impairment undergoing CABG?. Egypt J Cardiothorac Anesth 2013;7:7-12
|How to cite this URL:|
Salah M, El-Tawil T, Nasr S, Nosser T. Does dexmedetomidine affect renal outcome in patients with renal impairment undergoing CABG?. Egypt J Cardiothorac Anesth [serial online] 2013 [cited 2020 Jun 2];7:7-12. Available from: http://www.ejca.eg.net/text.asp?2013/7/1/7/135456
| Introduction|| |
Dexmedetomidine is a centrally acting α2-adrenoceptor agonist that has sedative, analgesic, and sympatholytic effects that blunt many of the cardiovascular responses in the perioperative period 1–3.
Many studies have explored the potential protective effects of dexmedetomidine on different organs and systems against variable surgical and anesthetic challenges 4–11.
Patients undergoing coronary artery bypass grafting (CABG) are more likely to have preoperative renal dysfunction because of a high prevalence of diabetes, hypertension, and contrast-induced nephropathy. In addition, these patients are at a higher risk of developing acute kidney injury (AKI) that could be attributed to multiple intraoperative factors such as hypoperfusion secondary to hemodynamic instability, release of inflammatory mediators during cardiopulmonary bypass (CPB), or exposure to nephrotoxins 12,13.
Dexmedetomidine, through its sympatholytic activity, decreases rennin release and increases the glomerular filtration rate, resulting in increased sodium and water excretion. Such effects are hypothesized to decrease the incidence and severity of AKI 14–16.
We hypothesized that dexmetomidine would improve renal outcome in patients with mild to moderate renal dysfunction undergoing elective CABG during the early postoperative days.
| Materials and methods|| |
After ethical and institutional committee approval and after obtaining written informed consent, 80 adult patients with mild to moderate renal impairment and scheduled for elective CABG surgery with CPB were enrolled in this prospective double-blind randomized study to compare the effects of a continuous infusion of dexmedetomidine versus placebo. Adult patients scheduled for elective CABG with serum creatinine level between 1.5 and 2.0 mg/dl and creatinine clearance less than 60 ml/min despite maximal medical treatment were included in the study. Patients who underwent urgent surgery, combined CABG and valve surgery, with ejection fraction less than 45%, hemodynamic instability, using mechanical support devices, with uncontrolled arrhythmias, under treatment with α2 blockers, with uncontrolled type 1 diabetes, morbid obesity, a history of severe drug allergy, liver disease, and diuretic therapy were excluded. Exclusion after enrollment applies for those patients who require reoperation for bleeding or graft revision, had postoperative myocardial dysfunction or intra-aortic balloon pump, and had prolonged ventilation more than 24 h. Those excluded patients received the standard level of care appropriate for their medical or surgical condition; however, their data were not included in the study. The decision on postrandomization exclusions was made without possible bias and was achieved by an investigator blinded to allocation.
Patients were allocated randomly by sealed envelopes to one of two equal groups (40 patients each): group A (Dex group) and group B (placebo group). Randomization was performed by independent personnel. Nurses who did not participate in the study prepared drugs according to the table of randomization. The anesthesiologist was supplied with indistinguishable, foil-covered 50 ml syringes of either 0.9% saline or dexmedetomidine with a number code given by the independent personnel. All patients, investigators, anesthesiologists, and intensivists were blinded to the infusion administered. Drug administration and data collection were carried out by investigators in a double-blind manner.
All patients were administered lorazepam 3 mg and ranitidine 150 mg orally 12 and 2 h before surgery, respectively. Upon arrival to the OR, patients were administered midazolam 3–5 mg (intravenous push), arterial cannulation was performed under local anesthesia, followed by induction of anesthesia using fentanyl 3–5 mcg/kg, propofol 1–1.5 mg/kg, and pancuronium 0.1 mg/kg. Anesthesia was maintained using propofol infusion (50–150 mcg/kg/min), fentanyl 1–2 mcg/kg increments, and isoflurane 1–2%. Muscle relaxation was maintained by pancuronium 0.025 mg/kg every 50–60 min. A urinary catheter was inserted after induction of anesthesia and urinary output was monitored. Fluid infusion was started at a rate of 4 ml/kg/h of Ringer’s acetated solution.
After induction of anesthesia, the infusion of dexmedetomidine or placebo (plain normal saline 0.9%) was started. Dexmedetomidine (Precedex; Hospira Inc., Lake Forest, Illinois, USA) was started at a dose 1 mcg/kg bolus, followed by a continuous infusion of 0.5 mcg/kg/h until skin closure. Dose calculation was performed by investigators assuming all syringes contained dexmedetomidine.
CABG was performed using normothermic CPB (35–37πC), with warm antegrade blood cardioplegia administered at 20 min intervals. The cardiopulmonary bypass circuit was primed with acetated Ringer’s solution (20–25 ml/kg) with 100 ml of mannitol 20%; the pump flow was maintained at 2.5 l/min/m2 to achieve a mean arterial blood pressure of 70–90 mmHg. Anesthesia and muscle relaxation were maintained on CPB by propofol 100–200 mcg/kg/min and pancuronium. After weaning from CPB, anesthesia was maintained using isoflurane and pancuronium.
Hemodynamic stability was maintained until skin closure. Hemodynamic targets were maintenance of the mean arterial blood pressure between 80 and 90 mmHg and central venous pressure between 8 and 10 mmHg and heart rate between 60 and 90 bpm. Target hemodynamics were maintained with volume boluses (Ringer’s acetate 200 ml), vasopressors (phenylepherine, nor-epinephrine), inotropic agents (calcium chloride, epinephrine, dobutamine), vasodilators (glyceryltrinitrate), and β-blockers as necessary in terms of patient hemodynamic derangement.
Urine output was maintained at a level greater than 1 ml/kg/h by maintaining hemodynamic stability as before. If urine output was less than 1 ml/kg/h before institution of CBP, 200 ml Ringer’s acetate solution was infused over 15 min to maintain central venous pressure 8–10 mmHg; if there was still no response, 5 mg boluses of frusemide were administered every 30 min. If urine output was less than 1 ml/kg/h after institution of CPB, pump flow was adjusted to maintain a mean pressure of 70–90 mmHg and if the response was not satisfactory, frusemide 10 mg boluses were administered every 30 min.
Assessment of renal function
The main target of the study was the assessment of renal function through creatinine clearance (primary outcome) and serum creatinine 24 h before the study and 24, 48, and 72 h after skin closure. Creatinine clearance was defined as urinary creatinine×urine output/serum creatinine. Urine output was checked every hour and recorded every 6 h.
Forty patients per treatment group were required to achieve an 80% power to detect a 36% difference between the treatment groups with a 5% type I error rate and assuming a standardized effect size (expected effect size divided by SD of the outcome variable) of 0.63.
Results of urine output, serum creatinine, and creatinine clearance were presented as mean±SD and analyzed using repeated-measures analysis of variance.
Assuming that the SDs of both groups remain constant and the mean correlation between the four measurement occasions of creatinine clearance remains at 0.5, estimation of the required sample size on the basis of a pooled SD of 24.47 ml/min in creatinine clearance from a previous study 17 indicated that a total sample size of 80 patients randomized to a balanced within-between (mixed repeated measures) design with an assumed α error probability of 0.05 and β error probability of 0.2 would allow detection of a between-factor effect size of 0.25, which translates into a mean difference of 12.24 ml/min between groups in creatinine clearance and represents the minimum detectable mean difference that can be found with this study by a power of 80%. In other words, if the real difference in population is that huge, there will be an 80% chance that this study will almost certainly detect a statistically significant difference. If it is accepted that differences in creatinine clearance of less than 15 ml/min are not considered clinically significant and may be attributed to measurement error, then this study yields convincing results. Statistical power calculations were carried out using the computer program G*Power 3 for Windows (Franz Faul, Universität Kiel, Germany).
| Results|| |
Eighty patients were included in the study in the period between 2009 and 2012 after excluding patients who did not fulfill the criteria. The study was completed until the inclusion of 40 patients in each group. Five patients were excluded from the study after randomization (three in the Dex group and two in the placebo group). Exclusion was because of reoperation and severe hemodynamic instability. The number of postrandomization exclusion patients was too small to affect the results.
Demographic data and preoperative status
There were no significant differences between two groups in the demographic data and baseline characteristics [Table 1].
|Table 1: Demographic data and preoperative hemodynamics and comorbidities|
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Operative and cardiopulmonary bypass data
There were no significant differences between the two groups in the operative time, number of grafts, CPB time, CPB perfusion pressure, and cross-clamp time [Table 2] and [Table 3].
|Table 3: Intraoperative and postoperative hemodynamics, fluid requirements, and blood losses|
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Intraoperative and postoperative hemodynamics
Mean arterial pressure
The mean arterial pressure showed no significant difference between the two groups at any evaluation time point. Heart rate, however, showed significantly less values in the dexmedetomidine infusion group both intraoperatively and postoperatively, except at the time following separation from CPB, where no significant difference exists between the dexmedetomidine and the placebo groups.
Significantly higher volumes of acetated Ringer’s solution were required to maintain hemodynamics of the patients in the dexmedetomidine group both intraoperatively and postoperatively compared with the patients in the placebo group. However, there was no significant difference in hydroxy-ethyl starch 6% volume in both groups intraoperatively and postoperatively.
No significant difference in blood loss was found between the two groups intraoperatively or postoperatively.
There was no significant difference in serum creatinine levels between the two groups at baseline, 24, 48, and 72 h postoperatively. There was a significant reduction in serum creatinine 24 h postoperatively compared with the baseline in both groups [Table 4].
|Table 4: Serum creatinine, creatinine clearance, and urine volume in Dex and placebo groups|
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In both groups, there was no statistically significant difference in creatinine clearance at any time point of comparison (baseline, 24, 48, and 72 h postoperatively). However, a significant increase in creatinine clearance at 24 h postoperatively was found in both groups compared with their own baseline values.
Urine output showed a significant increase in both groups (as compared with their own baseline); moreover, the increase in urine volume was significantly higher in the dexmedetomidine group compared with placebo. Apart from the first 24 h, no significant difference existed in urine volume between the two groups or within the same group compared with the baseline [Figure 1], [Figure 2] and [Figure 3].
|Figure 1: Serum creatinine in Dex and placebo groups. Dex, dexmedetomidine.|
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|Figure 2: Creatinine clearance in Dex and placebo groups. Dex, dexmedetomidine.|
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| Discussion|| |
Postoperative AKI is a common complication of CABG and has a clear negative impact on short-term (<30 day) morbidity and mortality. Hospital mortality of 40% and more have been reported in many series of patients, compared with rates of around 1% in patients without kidney insufficiency 18–21. Loef et al. 21 have reported a more than 10-fold increase in mortality with postoperative kidney insufficiency.
Holzmann et al. 19 showed that indices of clearance may be preferable to serum creatinine levels as an indicator of renal function. Other markers such as cystatin C or estimation of glomerular filtration rate may be an alternative means of monitoring renal function 21. In the present study, serum creatinine and creatinine clearance were determined but no statistically significant difference was found in the dexmedetomidine-treated and placebo-treated patients.
In the current study, there was a significant increase in the urinary output during the first 24 h postoperatively in dexmedetomidine-treated patients, whereas there was no significant dexmedetomidine-related benefit in terms of renal function in terms of serum creatinine and creatinine clearance. The confidence intervals for group differences in creatinine clearance show that our sample size was adequate for a negative conclusion. It should be noted that plasma dexmedetomidine concentration was not measured in the current study; thus, an interindividual variation in the plasma concentrations may exist.
Renal effects of α2-adrenergic agonists in clinical practice have not been fully studied till now. Pretreatment with clonidine has shown protective effects of renal function expressed as creatinine clearance after cardiac surgery. However, clonidine is a less selective α2-adrenergic agonist than dexmedetomidine and has a different pharmacodynamic profile 22.
The enhancement of urinary output with dexmedetomidine during the first 24 h after surgery is an advantage for dexmedetomidine, although it does not necessarily indicate a preserved renal function. Nevertheless, there was an increase in creatinine clearance from the baseline in both groups but there was no difference between groups, indicating that this difference is mostly not because of the drug effect. The increase observed in both groups in creatinine clearance might have been an artifact resulting from diurnal variation or hemodilution 23. Eventual problems in spontaneous voiding might also have resulted in systematic but likely similar underestimation of baseline creatinine clearance in both groups. Increased urine output is a well-known property of dexmedetomidine and was already observed earlier in patients undergoing CABG and recently in patients undergoing thoracotomy 9.
The diuretic action of dexmedetomidine also evident in the present study is consistent with sympatholysis-attenuated sodium reabsorption in tubular cells through α2-adrenergic action 24.
Dexmedetomidine-treated patients showed a more favorable hemodynamics intraoperatively in terms of less tachycardia and better control of the mean arterial blood pressure, a finding that is in agreement with the sympatholytic activity of the drug. A slower heart rate is unquestionably better in CABG patients by minimization of myocardial oxygen demand and consequently lower risk of perioperative myocardial ischemia or infarction. Such findings are in agreement with those of Willigers et al. 25, who described the beneficial indirect myocardial protective properties of dexmedetomidine through a central sympatholytic action in reducing heart rate and myocardial oxygen consumption. A recent research by Yoshitomi et al. 7 reported the direct protective effects of dexmedetomidine against myocardial ischemia–reperfusion injury in anesthetized pigs, but no further evidence supports this theory.
| Conclusion|| |
The use of dexmedetomidine infusion did not alter renal function in terms of serum creatinine or creatinine clearance, but was associated with an increase in urinary output in the first 24 h postoperatively.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4]