|Year : 2014 | Volume
| Issue : 3 | Page : 297-303
Evaluation of the value of dexmedetomidine infusion in the improvement of renal function in preeclamptic patient with early renal impairment using cystatin C, a sensitive renal marker
Hatem Saied, Amr Sobhy, Aassem Mohram
Department of Anesthesiology, Intensive Care, and Pain Management, Faculty of Medicine, Ain-Shams University, Cairo, Egypt
|Date of Submission||20-Jun-2013|
|Date of Acceptance||04-Nov-2013|
|Date of Web Publication||27-Aug-2014|
Department of Anesthesiology, Intensive Care and Pain Management, Faculty of Medicine, Ain-Shams University,11566 Cairo
Source of Support: None, Conflict of Interest: None
Preeclampsia is characterized by the development of hypertension and proteinuria after 20 weeks of gestation. Altered renal function is an essential component of its pathophysiology. Serum cystatin C level is a better marker of glomerular filtration rate (GFR) than serum creatinine particularly for individuals with small to moderate decreases in GFR. Dexmedetomidine has great α2 selectivity and low placental transfer with anxiolytic, anesthetic, hypnotic, and analgesic properties. α2-Adrenoceptor activation produces renal-protective effects including inhibition of renin release, increased GFR, and increased secretion of sodium and water.
Patients and methods
The study included 60 American Society of Anesthesiology II-III patients, 19-40 years of age, proved to have mild preeclampsia with early renal impairment. They were randomly divided into two groups. The dexmedetomidine infusion group (Dexa group) that included 30 patients who received dexmedetomidine infusion (n = 30), whereas the control group (Cont group) (n = 30) were treated by conventional treatment according to the Obstetric ICU Protocol of Ain-Shams University Hospitals. For each patient, the following data were collected: age, gestational age, body weight, height, hemodynamic changes, fetal heart rate, urine output, and renal function as detected by sensitive renal marker cystatin C and also by serum creatinine, blood urea nitrogen (BUN), and then estimation of GFR.
There was statistically significant decrease in blood pressures (systolic blood pressure, diastolic blood pressure, and mean arterial blood pressure) in the Dexa group 10 min after dexmedetomidine infusion and after comparing subsequent measures to baseline value (T0 ) and also when compared with corresponding values in the Cont group. In addition, the Dexa group showed statistically significant increase in urine output 2 h after dexmedetomidine infusion in comparison with the baseline values and with the Cont group, denoting improvement in urine output. Patients in the Dexa group showed a statistically significant decrease in serum cystatin C and increase in estimated glomerular filtration rate (eGFR) based on cystatin C after 2 h of sympathetic block by epidural activation in comparison with baseline value and when compared with the Cont group, denoting marked improvement in GFR. Measurement of urine protein/creatinine ratio, serum creatinine, BUN, and eGFR based on serum creatinine showed no significant difference in both groups whether comparing to baseline of the same group or comparing both groups together.
Continuous infusion of dexmedetomidine 0.4 mcg/kg/h showed marked benefit improving renal function and better control of blood pressure in preeclamptic patients with early renal impairment detected by sensitive renal marker cystatin C.
Keywords: cystatin C, Dexmedetomidine, glomerular filtration rate, preeclampsia, renal impairment
|How to cite this article:|
Saied H, Sobhy A, Mohram A. Evaluation of the value of dexmedetomidine infusion in the improvement of renal function in preeclamptic patient with early renal impairment using cystatin C, a sensitive renal marker. Ain-Shams J Anaesthesiol 2014;7:297-303
|How to cite this URL:|
Saied H, Sobhy A, Mohram A. Evaluation of the value of dexmedetomidine infusion in the improvement of renal function in preeclamptic patient with early renal impairment using cystatin C, a sensitive renal marker. Ain-Shams J Anaesthesiol [serial online] 2014 [cited 2021 Apr 23];7:297-303. Available from: http://www.asja.eg.net/text.asp?2014/7/3/297/139550
| Introduction|| |
Preeclampsia is a pregnancy-specific, multisystem disorder that is characterized by the development of hypertension and proteinuria after 20 weeks of gestation. The disorder complicates ˜5-7% of pregnancies and is one of the leading causes of maternal and fetal morbidity and mortality .
Altered renal function is an essential component of the pathophysiological process in preeclampsia, and close monitoring of renal function is essential to ascertain the optimal time for delivery to avoid renal damage .
Glomerular filtration rate (GFR) is a representative index of renal function. Although inulin clearance measurement is the gold standard for estimating GFR, it is cumbersome and serum creatinine of an endogenous filtration marker has been widely used in clinical practice. However, when serum creatinine determinations are used to estimate GFR, it should be borne in mind that they are influenced by age, sex, muscle mass, and protein intake and that they show low sensitivity for the detection of early renal dysfunction .
Cystatin C is a low molecular weight (13 kDa) protein with 120 amino acids that functions as cysteine protease inhibitor. It is produced by all nucleated cells at a constant rate and is freely filtered and catabolized in the proximal tubules without being secreted. For this reason, its serum concentration is determined by glomerular filtration, and thus is used as a marker of GFR .
Various cross-sectional studies have shown that cystatin C has greater sensitivity to detect reduced GFR than creatinine and other low molecular weight proteins. Of note, serum cystatin C concentration increases already with mildly reduced GFR of 70-90 ml/min - that is, in the 'creatinine-blind range' .
Increased activity of the sympathoadrenal system has been implicated in the genesis and maintenance of elevated blood pressure, and vasoconstriction in various vessels such as the uterine artery has been observed in preeclampsia and eclampsia; there were reports that eclamptic and preeclamptic plasma has an excitotoxic effect on the sympathetic nerve by axoplasmic membrane depolarization, thus increasing noradrenaline secretion .
Dexmedetomidine is a short-acting agent with greater α2 selectivity and has significantly less placental transfer with anxiolytic, anesthetic, hypnotic, and analgesic properties. α-Agonists promote sedation by stimulating the locus caeruleus, a part of the brain stem involved in the sleep-wake cycle. Sedation is caused by inhibition of the sympathetic vasomotor center of the brain .
It is quickly distributed into tissues with a distribution half-life of ˜6 min. It is metabolized in the liver to practically inactive products, mainly glucuronides, with a mean elimination half-life of 2-2.5 h .
In fact, α2-adrenoceptor activation does produce some potential renal-protective effects including inhibition of renin release, increased glomerular filtration, and increased secretion of sodium and water; this mechanism is supported by the observation that dexmedetomidine decreases the renal cortical release of norepinephrine .
Dexmedetomidine has been successfully used as an adjunct to unsatisfactory analgesia by systemic opioids in laboring parturients who could not benefit from epidural analgesia. It provides maternal hemodynamic stability, anxiolysis, and stimulation of uterine contractions. It is retained in the placental tissue and passes less readily into the fetal circulation than clonidine because of high lipophilicity, and thereby has less susceptibility to cause fetal bradycardia.
The literature describes that, as dexmedetomidine has a high placental retention, it does not cross the placenta to reach the fetus .
The purpose of this study was to evaluate the value of dexmedetomidine infusion in the improvement of renal function in preeclamptic patient with early renal impairment using cystatin C, a sensitive renal marker.
| Patients and methods|| |
The study was conducted at Obstetric ICU of Ain-Shams University Hospitals during the period from October 2011 to March 2013. The study protocol was approved by 'research and ethics committee' of Anesthesia and Intensive Care Department, Ain-Shams University. Informative consent was obtained from all patients or from their legal guardians before enrolling in the study.
With respect to sample size calculation, it was calculated using PS (version 3.0.43, Department of Biostatistics, Vanderbilt University, located in Nashville, United States) with the following parameters: urine output used as the primary goal where power of the study was 80%, SD was ±2, mean was 20, and a error was 0.05.
Sixty pregnant women were enrolled in the study, with a range of age between 19 and 40 years. All patients were with American Society of Anesthesiology physical status of II or III and were proved to have mild preeclampsia with early renal impairment. Preeclamptic patients were defined as hypertension [systolic blood pressure (SBP)≥140 mmHg and/or diastolic blood pressure (DBP)≥90 mmHg] accompanied by proteinuria first detected after 20 weeks gestation. Proteinuria is defined as at least 300 mg protein in 24 h urine collection [or ≥1+ dipstick (30 mg/dl) in a single urine sample].
Early renal impairment was defined by the RIFLE classification (when increased plasma creatinine ×1.5 or GFR decrease >25% of normal range for age or urine output <0.5 ml/kg/h×6 h). In addition, in this study we used urine output criteria, as serum creatinine was still normal.
After completion of the baseline laboratory work, patients were randomly allocated into one of the following two groups (30 patients each) using closed sealed envelope method of randomization:
Dexmedetomidine infusion group (the Dexa group): this included 30 patients who received dexmedetomidine infusion.
Control group (the Cont group): this included 30 patients who were treated by conventional treatment according to the Obstetric ICU Protocol of Ain-Shams University Hospitals.
Exclusion criteria for the study included: patient refusal to consent (obsolete), preexisting neurological disease or psychic patients, history of cardiac and respiratory system failure, coexisting renal or liver disease, eclamptic patients, and patients who terminate their pregnancy before 2 h (time needed to establish renal sympathetic block).
| Methods|| |
On arrival to the ICU (due to persistent oliguria over last 6 h), all patients were continuously monitored with electrocardiography, noninvasive blood pressure, and pulse oximetry; urinary catheter was inserted if not already present. An 18-G cannula was inserted in a peripheral vein and 500 ml Ringer's solution was given as loading over 15-20 min, followed by 1500 ml Ringer's solution over the next 2 h.
Baseline investigations were obtained, which included complete blood picture, bleeding time, clotting time, prothrombin time, INR, and liver function tests.
Renal assessment was performed utilizing the following: a urine protein-to-creatinine ratio, BUN, serum creatinine, serum cystatin C by ELISA, and GFR were estimated for each patient using the following equations:
Simplified Modification of Diet in Renal Disease equation:
eGFR (ml/min/1.37m 2 ) = 186.3 × [serum creatine (mg/dl] -1.154 [age(years] -0.203 ×(0.742). (1)
Equations estimating GFR based on cystatin C:
GFR = 76.6 × cystatin C(mg/l) -1.16 . (2)
A continuous infusion of dexmedetomidine 0.4 mcg/kg/h was infused for 30 patients through 18-G cannula using a syringe pump until 24 h after cesarean section and good hydration was provided by 2000 ml Ringer's solution over 2 h.
Thirty patients were treated by conventional treatment according to the Obstetric ICU Protocol of Ain-Shams University Hospitals.
Strict fluid balance was maintained with good hydration (2000 ml Ringer's solution over 2 h), control of blood pressure by nitroglycerin infusion as the first choice if needed (if SBP > 165 mmHg), and avoidance of nephrotoxic drugs with renal adjusted dose for the drugs known to be renally excreted.
For the next 2 h after initiation of the treatment in the two groups, the following data were collected:
All hemodynamic data were measured continually for clinical assessment; however, recordings for the study purpose were performed at designated time interval as shown in results.
Noninvasive blood pressure measurements were recorded every 5 min; heart rate was recorded every 5 min, and urine output was recorded every 30 min.
Fetal heart rate was monitored by electronic fetal monitoring continually for clinical assessment; however, recordings for the study purpose were performed at designated time interval as shown in results.
By the end of the 2 h, blood samples were obtained for assessment of renal function by a urine protein/creatinine ratio, BUN, serum creatinine, serum cystatin C by ELISA, and GFR, which was estimated for each patient using the previous equations.
Statistical analysis was performed using computer software statistical package for the social science (SPSS, version 17.0; SPSS Inc., Chicago, Illinois, USA).
Description of quantitative (numerical) variables was performed in the form of mean ± SD.
Description of qualitative (categorical) data was performed in the form of number of cases and percent. Error bars represent 95% confidence interval. Analysis of unpaired numerical variable was performed using the unpaired Student t-test, whereas analysis of paired numerical variables was performed using repeated measure general linear model analysis of variance.
Analysis of categorical data was performed using Fisher's exact test or the χ2 -test, whenever appropriate.
The significance level was set at P-value of 0.05 or less, and P-value of 0.01 or less was considered highly significant.
| Results|| |
With respect to age, gestational age, and body weight of patients, there were no statistically significant differences between both groups (P > 0.05) [Table 1].
Regarding hemodynamic parameters
The baseline SBP, DBP, and mean arterial blood pressure (MAP) readings showed no statistically significant difference between both groups (P > 0.05).
The Dexa group showed decreases in SBP, DBP, and MAP values, starting 10 min after dexmedetomidine infusion when compared with baseline readings and was statistically highly significant (P <0.001). In contrast, there were no statistically significant changes in SBP, DBP, and MAP in the Cont group ([Table 2], [Table 3], [Table 4].
Regarding fetal heart rate monitoring
With respect to the fetal heart rate monitoring of babies, there were no statistically significant differences between both groups (P > 0.05) [Table 5].
Regarding urine output
(1) Although the baseline urine volume in both groups was oliguric as fulfilled by the admitting criteria in the study, there were no statistically significant differences between both groups (P > 0.05).
(2) The Dexa group showed increase urine output 1 h after dexmedetomidine infusion, and this increase was statistically significant in comparison with the Cont group and in comparison with baseline value (P < 0.05) [Table 6].
Regarding renal function
Patients in the Dexa group showed a statistically significant decrease in serum cystatin C and increase in estimated glomerular filtration rate (eGFR) based on cystatin C 2 h after dexmedetomidine infusion in comparison with baseline value and when compared with the Cont group, denoting marked improvement in GFR, whereas measurement of urine protein/creatinine ratio, serum creatinine, BUN, and eGFR based on serum creatinine showed no significant difference in both groups whether comparing with baseline of the same group or comparing both groups together. This reflects a delayed response for these parameters to early phase of renal injury, and hence a late diagnostic value ([Figure 1], [Figure 2], [Figure 3], [Figure 4] and [Table 7] and [Table 8]).
|Figure 1: Changes in blood urea nitrogen (mg/dl). Dexa group, dexmedetomidine infusion group; T0, on admission; T1, 2 h after dexmedetomi dine infusion.|
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|Figure 2: Changes in creatinine (mg/dl). Dexa group, dexmedetomidine infusion group; T0, on admission; T1, 2 h after dexmedetomi dine infusion.|
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|Figure 3: Changes in estimated glomerular fi ltration rate based on Modifi cation of Diet in Renal Disease (ml/min/1.73 m2). Dexa group, dexmedetomidine infusion group; T0, on admission; T1, 2 h after dexmedetomi dine infusion.|
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|Figure 4: Urine protein/creatinine ratio (mg/mg). Dexa group, dexmedetomidine infusion group; T0, on admission; T1, 2 h after dexmedetomi dine infusion.|
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|Table 8 Changes in estimated glomerular fi ltration rate based on cystatin C (ml/min/1.73 m2)|
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| Discussion|| |
In the present study, we traced the advantage of using dexmedetomidine infusion to improve renal function in preeclamptic patients with subclinical and clinical renal injury guided by the sensitive and specific renal marker cystatin C.
The Dexa group showed statistically significant increase in urine output (46.951 ± 9.942) after 2 h of dexmedetomidine infusion (T3 ) in comparison with baseline value (32.61 ± 10.04) at T0 and in comparison with the Cont group (38.963 ± 13.366), denoting improvement in urine output [Table 5]. This is in agreement with observation reported by Rouch et al.  who demonstrated the diuretic effect of dexmedetomidine by inhibiting osmotic water permeability in the rat cortical collecting duct, but Leino et al.  performed a double-blind, randomized, parallel-group study on 87 patients with normal renal function and scheduled for elective coronary artery bypass grafting (CABG) who were randomized to placebo or to infusion of dexmedetomidine to achieve a pseudo-steady-state plasma concentration of 0.60 ng/ml. The infusion was started after anesthesia induction and was continued until 4 h after surgery. The primary endpoint was creatinine clearance. Other variables included urinary creatinine and output, fractional sodium and potassium excretion, urinary potassium, sodium, and glucose, serum and urinary osmolality, and plasma catecholamine concentrations. The data were analyzed with repeated-measures analysis of variance or the Cochran-Mantel-Haenszel test. They concluded that use of intravenous dexmedetomidine did not alter renal function in this cohort of relatively low-risk elective CABG patients but was associated with an increase in urinary output; however, in this study they used creatinine clearance, which is a late diagnostic tool rather than cystatin C clearance.
Urine protein/creatinine ratio was estimated to confirm proteinuria; we found in this study no significant difference in urine protein/creatinine ratio in both groups whether comparing with baseline of the same group or comparing both groups together.
It was expected, as the morphological changes of preeclamptic nephropathy (responsible for protinurea) begin to resolve 48 h following delivery, and complete resolution is common by 4-6 weeks postpartum; the current results are in agreement with the work by Cτtι et al.  who performed a systematic review of the literature extracted from 13 studies concerning the spot protein/creatinine ratio (1214 women with primarily gestational hypertension); they concluded that the spot protein/creatinine ratio is a reasonable 'rule-out' test for detecting proteinuria of 0.3 g/day or more in hypertensive pregnancy.
Regarding serum creatinine, BUN, and eGFR based on serum creatinine, we found in this study that there were no statistically significant differences in serum creatinine, BUN, and eGFR based on serum creatinine in both groups whether comparing with baseline of the same group or comparing both groups together. This reflects a delayed response for these parameters to early phase of renal injury, and hence a late diagnostic value ([Figure 1], [Figure 2], [Figure 3], whereas serum cystatin C results of this study showed no statistically significant difference between both groups at the baseline value (1.624 ± 0.32 and 1.57 ± 0.342 for the Dexa group and the Cont group, respectively); however, in both groups, high than normal range values (0.7 ± 0.2) denoted early renal injury, despite normal serum creatinine in both groups (0.920 ± 0.3334, 1.083 ± 0.308) [Table 6].
Later, patients of the Dexa group showed a statistically significant decrease in serum cystatin C (0.874 ± 0.128) and increase in eGFR based on cystatin C (92.053 ± 17.210) after 2 h of sympathetic block by epidural activation in comparison with baseline value (1.624 ± 0.32 and 46.12 ± 12.51, respectively) and in comparison with the Cont group (1.589 ± 0.412 and 48.56 ± 15.04, respectively), denoting marked improvement in GFR.
Many studies found that cystatin C is more specific and sensitive than creatinine, such as the study conducted by Strevens et al. ; they investigated the serum levels of creatinine, urate, and cystatin C in samples from 100 healthy women at term as well as in 45 samples of patients with preeclampsia. They found that the levels of all three components were significantly higher in samples from preeclamptic patients with the mean ± SD being 1.55 ± 0.29 versus 1.05 ± 0.19 mg/l for cystatin C, 70 ± 23 versus 56 ± 9.7 mmol/l for creatinine, and 413 ± 128 versus 305 ± 61 mmol/l for urate. They concluded that serum cystatin C has a superior diagnostic accuracy for preeclampsia compared with that of serum urate or serum creatinine.
Studies in humans and animals show that dexmedetomidine has high placental retention and increases the frequency and amplitude of uterine contractions directly and in a dose-dependent manner, suggesting advantages for use as an analgesic adjunct during labor .
Palanisamy et al.  reported the successful use of continuous-infusion dexmedetomidine as analgesic adjunct in intravenous patient-controlled analgesia (PCA) with fentanyl for labor in a patient with occult spina bifida.
Abu-Halaweh et al.  reported a case of an obese diabetic patient with severe eclampsia who rejected spinal analgesia for labor and received only dexmedetomidine, achieving mild pain scores and superficial sedation during the infusion, with no other side effects.
Mendoza Villa  published two case reports in Rev Colomb Anesthesiol, in which dexmedetomidine was used as an adjunct for labor analgesia along with remifentanil. Both patients underwent vaginal delivery, although the first patient had instrumentation. Babies were delivered with normal Apgar scores at 1 and 5 min.
In conclusion, the results of this study demonstrated that a continuous infusion of dexmedetomidine 0.4 mcg/kg/h showed marked benefit improving renal function and better control of blood pressure in preeclamptic patients with early renal impairment detected by sensitive renal marker cystatin C. This study opens the ground for intensive research for examination of the role of a continuous infusion of dexmedetomidine as a therapeutic tool for patients with established renal impairment.
| Acknowledgements|| |
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8]