|Year : 2016 | Volume
| Issue : 1 | Page : 19-23
Evaluating the effect of midodrine on renal resistance index in patients with liver cirrhosis and ascites
Hamdy M Moustafa1, Khaled Abdel-Azeem Eid1, Amro M Hassan1, Ahmed Abd-Elrady Ahmed2
1 Department of Tropical Medicine, Faculty of Medicine, Al-Azhar Assiut University, Assiut, Egypt
2 Department of Radiology, Faculty of Medicine, Al-Azhar Assiut University, Assiut, Egypt
|Date of Submission||11-Nov-2015|
|Date of Acceptance||15-Dec-2015|
|Date of Web Publication||18-Apr-2016|
Hamdy M Moustafa
Gastroenterology and Hepatology, Tropical Medicine Department, Faculty of Medicine, Al-Azhar University, Assiut, Postal Code: 71111
Source of Support: None, Conflict of Interest: None
Portal hypertension, which occurs as a consequence of liver cirrhosis, leads to splenic vasodilatation and alterations in the systemic circulation. Arterial vasodilatation in the splanchnic circulation appears to play a central role in hemodynamic changes and in the decline in renal function in cirrhosis. Peripheral vasodilatation, which occurs as a part of alterations in the systemic circulation, may decrease the renal blood flow and subsequently raise plasma renin activity. Midodrine is a α agonist and acts as a peripheral vasoconstrictor; therefore, it may reduce plasma renin activity and improve renal function.
Aim of the work
The aim of the study was to evaluate the relationship between renal resistive indices (RIs) in cirrhotic patients before and after oral administration of 7.5 mg midodrine three times daily for 3 days.
Patients and methods
The study was conducted on 40 patients with liver cirrhosis and ascites and on 40 healthy controls from October 2014 to March 2015 at Al-Azhar University Hospital, Assiut, where all patients were subjected to history and clinical examination as well as to routine investigations such as total bilirubin, albumin, international normalized ratio, and serum creatinine. Patients underwent an abdominal ultrasound with duplex Doppler examination of the kidneys, and RI was calculated before and 3 days after oral intake of midodrine.
Patients with liver cirrhosis and ascites had significantly higher RI in the right kidney (0.69 ± 0.101 vs. 0.57 ± 0.055,P < 0.001) and in the left kidney (0.69 ± 0.097 vs. 0.59 ± 0.047,P < 0.001) compared with healthy controls. After oral administration of midodrine for 3 days, RI showed significant improvement (RI = 0.928,P < 0.001) in the right kidney and in the left kidney (R = 0.993,P < 0.001). RI had significant positive correlation with Child–Pugh score (R = 0.75,P < 0.001, in the right kidney and R = 0.75,P < 0.001, in the left kidney) and significant positive correlation with Model for End-Stage Liver Disease score (R = 0.536,P < 0.008, in the right kidney and R = 0.487,P < 0.005, in the left kidney).
Oral midodrine improved renal hemodynamics as assessed by RI in cirrhotic patients. RI is correlated with severity of liver disease as assessed by Child–Pugh and Model for End-Stage Liver Disease scores.
Keywords: ascites, hepato-renal, liver cirrhosis, midodrine, renal resistance
|How to cite this article:|
Moustafa HM, Eid KA, Hassan AM, Ahmed AA. Evaluating the effect of midodrine on renal resistance index in patients with liver cirrhosis and ascites. Al-Azhar Assiut Med J 2016;14:19-23
|How to cite this URL:|
Moustafa HM, Eid KA, Hassan AM, Ahmed AA. Evaluating the effect of midodrine on renal resistance index in patients with liver cirrhosis and ascites. Al-Azhar Assiut Med J [serial online] 2016 [cited 2018 Jul 15];14:19-23. Available from: http://www.azmj.eg.net/text.asp?2016/14/1/19/180465
| Introduction|| |
Hepatorenal syndrome (HRS) is characterized by renal failure and major disturbances in circulatory function in patients with end-stage liver cirrhosis and is associated with an extremely short survival time. It was estimated that 11% of patients with advanced cirrhosis and refractory ascites develop HRS .
The pathogenesis is complex, but the final common pathway seems to be that sinusoidal portal hypertension, in the presence of severe hepatic decompensation, leads to splanchnic and systemic vasodilatation, decreased effective arterial blood volume, and activation of various vasoconstrictor and antinatriuretic neurohumoral systems (the renin–angiotensin–aldosterone system and sympathetic nervous system), leading to renal sodium and water retention and an increase in intravascular volume, which in turn leads to a hyperdynamic circulatory state  and increase in renal vasoconstriction; thus, renal hemodynamics worsen and renal failure occurs .
Renal arterial vasoconstriction may persist for weeks, even months, before an increase in blood urea nitrogen or serum creatinine values can be seen. Therefore, better methods to diagnose this early stage of renal disease are needed . Resistive index (RI) is the most widely used index for estimation of intrarenal vascular resistance . The intrarenal RI is the most frequently used parameter to assess intrarenal resistance and is calculated on the basis of intrarenal duplex Doppler ultrasound measurements .
Renal duplex Doppler of interlobar arteries is a simple, effective, and noninvasive method and enables the early detection of renal hemodynamic disturbances in patients with liver cirrhosis even before renal dysfunction becomes clinically evident . Midodrine hydrochloride is an orally available α-mimetic drug acting directly on the peripheral α-receptor, which is widely used in the treatment of hypotensive disorders. Midodrine causes systemic vasoconstriction, improving effective circulatory volume and hence renal perfusion .
Aim of the study
The aim of this work was to evaluate the renal RI in patients with liver cirrhosis and ascites by Doppler ultrasound before and after oral administration of 7.5 mg midodrine three times daily for 3 days.
| Patients and Methods|| |
The study was conducted on 40 patients, 27 men and 13 women, aged 37–68 years, with liver cirrhosis and ascites. All patients were hospitalized at Al-Azhar University Hospitals, Assiut, and were subjected to history taking, thorough clinical examination, routine laboratory investigations [total bilirubin, albumin, serum creatinine, and international normalized ratio (INR)], and duplex Doppler ultrasound examination.
Exclusion criteria: Patients younger than 18 years old, having hepatic encephalopathy, suffering from HRS, with hemodynamic instability, having infection or gastrointestinal bleeding during the course of admission, or having diabetes and hypertension were excluded from the study. Informed consent was obtained from the selected patients after explaining the aim of the study and the nature of the investigations. The study was approved by the ethical and scientific committee of Al-Azhar Faculty of Medicine, Assiut.
All patients were examined after an 8 h fast by abdominal ultrasound with duplex Doppler ultrasonography examination of the kidneys using duplex US equipment (Esaote ID, CE0051; Technos, Genoa, Italy) with a 4.5–7.0-MHz convex probe provided with the color and pulsed wave Doppler device (Technos). The liver, spleen, kidneys, and ascites were evaluated, and renal duplex Doppler ultrasonography was carried out to determine the RI. Doppler US measurements of the right interlobar renal artery and the left interlobar renal artery were obtained by one experienced operator. During the patient's suspended normal respiration, measurements were taken in three renal areas (upper, middle, and lower poles), and the results were expressed as the average of the measurements in the three areas. Doppler ultrasound was performed to assess the renal RI before beginning the study and after oral administration of 7.5 mg midodrine three times daily for 3 days.
Laboratory investigations included simple urine analysis, complete blood picture, total and direct bilirubin, alanine transaminase, aspartate transaminase, alkaline phosphatase, total proteins, serum albumin and prothrombin time, blood urea, and serum creatinine. The Model for End-Stage Liver Disease (MELD) score and the Child–Turcotte–Pugh score were calculated to assess the severity of liver disease. The MELD was calculated for all patients according to the following formula: MELD score = 9.57 × loge [serum creatinine (mg/dl)]+3.78 × loge [serum bilirubin (mg/dl)+11.20 × loge (INR)+6.43]. The degree of liver insufficiency was assessed according to the Child–Pugh classification and divided into three stages: A, B, and C (score A ≤ 6, B 7–9, and C ≥ 10) , [Table 1].
|Table 1: Modified Child-Pugh classification of the severity of liver disease|
Click here to view
Data entry and data analysis were done using the statistical package for social science, version 16 (SPSS Inc., Chicago, Illinois, USA). Data were presented as number, percentage, mean, and SD. The c2-test was used to compare qualitative data between groups. The analysis of variance test was used to compare quantitative data between groups. The paired sample t-test was used to compare qualitative data between baseline and at each time point in each group separately. P values less than 0.05 were considered significant.
| Results|| |
The study was conducted on 40 patients, 27 (67.5%) men and 13 (32.5%) women, with liver cirrhosis and ascites. Their ages ranged from 37 to 68 years and their mean age was 56.45 ± 8.171 years. The mean age of the control group was 50.00 ± 13.410 years. According to the Child–Pugh classification 10 patients were of Child–Pugh score C (25%) and 30 patients were of Child–Pugh score B (75%) with mean Child–Pugh 8.75 ± 1.70 and mean MELD score 14.65 ± 6.376.
Patients 'characteristics are presented in [Table 1]. Ascites was present in all patients in different degrees: mild degree in three patients (7.5%), moderate degree in 25 patients (62.5%), and marked ascites in 12 patients (30%). Lower limb edema was present in 37 patients (92.5%).
Patients with liver cirrhosis and ascites had significantly higher RI in the right kidney compared with healthy controls (0.69 ± 0.101 vs. 0.57 ± 0.055, P < 0.001) and significantly higher RI in the left kidney (0.69 ± 0.098 vs. 0.59 ± 0.047, P < 0.001) [Table 2] and [Table 3].
In our study, RI in the right kidney before midodrine administration was 0.69 ± 0.101 and that after midodrine administration was 0.68 ± 0.106 (R = 0.928 and P < 0.001). RI in the left kidney before midodrine administration was 0.69 ± 0.098 and that after midodrine administration was 0.67 ± 0.105 (R = 0.993 and P < 0.001). Both sets of values were significant ([Table 4] and [Figure 1]).
|Figure 1: Renal duplex examination for cirrhotic patients before (a) and after (b) midodrine administration. Resistance index improved.|
Click here to view
There was significant correlation between RI and Child–Pugh score (R = 0.75 and P < 0.001), ([Table 5] and [Figure 2]), as well as between RI and MELD (R = 0.75 and P < 0.001) [Table 6].
|Figure 2: Renal duplex examination for cirrhotic patients before (a) and after (b) midodrine administration. Resistance index did not improve.|
Click here to view
Our results showed significant relation between RI and total bilirubin (R = 0.398 and P < 0.001) and also between RI and INR (R = 0.619 and P < 0.002). Our study showed no significant relation between RI and normal serum creatinine (R = 0.242 and P < 0.202), nor between RI and serum albumin (R = 0.292 and P < 0.112).
| Discussion|| |
HRS is a form of functional renal failure in patients with liver disease with portal hypertension and it constitutes the climax of systemic circulatory changes associated with portal hypertension. The main pathophysiological mechanisms of HRS include increased renal arterial resistance, especially affecting the cortex of the kidneys, which results in renal hypoperfusion and arterial hypotension .
The short-term mortality of cirrhotic patients who develop renal dysfunction remains unacceptably high. Although predisposing factors are well known, there is no specific investigation that can predict the patients who will develop HRS.
Renal arterial vasoconstriction may persist for weeks, even months, before an increase in blood urea nitrogen or serum creatinine values can be observed. Therefore, better methods to diagnose this early stage of renal disease are needed . The evaluation of the renal hemodynamics in patients with liver cirrhosis is based mainly on the index of resistance of the intrarenal arteries . Renal duplex Doppler ultrasonography is used for identification of early kidney vasoconstriction in nonazotemic patients with established liver disease .
Midodrine hydrochloride is an α-amimetic drug with direct effect on the peripheral α-receptors of the sympathetic nervous system. It is usually used in orthostatic hypotension and secondary hypotensive disorders .
In our study, we had investigated the effect of a short course of oral midodrine on systemic hemodynamics in patients with cirrhosis without HRS.
In our study, we found that patients with liver cirrhosis and ascites had a significantly higher renal RI compared with healthy controls (P < 0.001). This agrees with the study by Cazzaniga et al.  and also with the studies by Ustundag et al.  and Abdel-Bary et al. , who reported higher RI in cirrhotic patients than in healthy controls (P < 0.05, P < 0.01, and P < 0.001, respectively).
A positive correlation between RI and MELD score was noted in our study. Patients with high MELD score had higher RI. These results are in agreement with those of Umbro et al. , Colli et al. , and Abdel-Bary et al. .
In our study, there was a positive correlation between RI and Child–Pugh classification (P < 0.0001), which agrees with the results of other studies ,. Our study also showed no significant positive correlation between RI and serum creatinine (R = 0.242, P < 0.20) , nor between RI and serum albumin. Our study also showed significant positive correlation between RI and total bilirubin (R = 0.391 and P < 0.001) and between RI and INR (R = 0.683 and P < 0.001) .
We reported significant improvement in renal hemodynamics (RI) after administration of midodrine when the MELD score was low (≤10), but as the MELD score increased to greater than 10 there was no improvement.
| Conclusion|| |
Our observations suggest significant improvement in renal hemodynamics (RI) after administration of midodrine when the MELD score was low (≤10), but as the MELD score increased to more than 10 there was no improvement. RI also had a prognostic value comparable to MELD score, as evident by increases in RI as MELD score increased. Abnormal renal RI predicts the possibility of development of HRS.
Given the small sample size, we recommend a second study involving more patients. Long-term administration of midodrine and variable doses of the drug should be evaluated to determine its effect in the prevention of HRS. There was no improvement in RI when MELD score was greater than 10 when midodrine was administered at a dose of 7.5 mg three times daily for 3 days.
The authors thank Professor Hamdy Mahfouz, Chairman of Gastroenterology and Hepatology at Al Azhar Assiut Faculty of Medicine, and Dr Khaled Abdel-Azeem Eid, Assistant Professor of Gastroenterology and Hepatology at Al Azhar Assiut Faculty of Medicine, for their encouraging support. They also thank Dr Abd El-Moaty Arafat Abd El-Moaty for preparing the patients and for recording their data.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Planas R, Montoliu S, Ballesté B, Rivera M, Miquel M, Masnou H, et al.
Natural history of patients hospitalized for management of cirrhotic ascites. Clin Gastroenterol Hepatol 2006; 4 (11):1385–1394.
Iwakiri Y, Groszmann RJ. The hyperdynamic circulation of chronic liver diseases: from the patient to the molecule. Hepatology 2006; 43 (Suppl 1): S121–S131.
Wong F, Blendis L. New challenge of hepatorenal syndrome: prevention and treatment. Hepatology 2001; 34 (6):1242–1251.
Platt J, Ellis JH, Rubin JM, Merion RM, Lucey MR. Renal duplex Doppler ulrasonography: a noninvasive predictor of kidney dysfunction and hepatorenal failure in liver disease. Hepatology 1994; 20:362–369.
Platt JF, Rubin JM, Eills JH. Intrarenal arterial Doppler sonography in patients with non-obstructive renal disease: correlation of resistive index with biopsy findings. Am J Roentgenol 1990; 154:1223–1227.
Zeller T, Bonvini RF, Sixt S. Color-coded duplex ultrasound for diagnosis of renal artery stenosis and as follow-up examination after revascularization. Catheter Cardiovasc Interv 2008; 71 (7):995–999.
Kastelan S, Ljubicic N, Kastelan Z, Ostojic R, Uravic M. The role of duplex-Doppler ultrasonography in the diagnosis of renal dysfunction and hepatorenal syndrome in patients with liver cirrhosis. Hepatogastroenterology 2004; 51 (59):1408–1412.
Kalambokis G, Economou M, Fotopoulos A, Al Bokharhii J, Pappas C, Katsaraki A, Tsianos EV The effects of chronic treatment with octreotide versus octreotide plus midodrine on systemic hemodynamics and renal hemodynamics and function in nonazotemic cirrhotic patients with ascites. Am J Gastroenterol 2005; 100 (4):879–885.
Londoño MC, Cárdenas A, Guevara M, Quintó L, de las Heras D, Navasa M, et al.
MELD score and serum sodium in the prediction of survival of patients with cirrhosis awaiting liver transplantation. Gut 2007; 56:1283–1290.
Ćulafić D, Štulić M, Obrenović R, Miletić D, Mijač D, Stojković M, et al
. Role of cystatin C and renal resistive index in assessment of renal function in patients with liver cirrhosis. World J Gastroenterol 2014; 20 (21):6573–6579.
Lata J. Hepatorenal syndrome. World J Gastroenterol 2012; 18 (36):4978–4984.
Berzigotti A, Casadei A, Magalotti D, Castaldini N, Losinno F, Rossi C, Zoli M. Renovascular impedance correlates with portal pressure in patients with liver cirrhosis. Radiology 2006; 240 (2):581–586.
Low PA, Gilden JL, Freeman R, Sheng KN, McElligott MA. Efficacy of midodrine vs placebo in neurogenic orthostatic hypotension. A randomized, double-blind multicenter study. Midodrine Study Group. JAMA. 1997; 277 (13):1046–1051.
Cazzaniga M, Salerno F, Visentin S, Cirello I, Donarini C, Cugno M. Increased flow-mediated vasodilation in cirrhotic patients with ascites: relationship with renal resistive index. Liver Int 2008; 28 (10):1396–1401.
Ustundag Y, Hekimoğlu K, Ilikhan S, Zaimoğlu G, Acikgöz S, Aydemir S. Serum glucagon and cystatin C levels with renal Doppler sonography findings in nonazotemic liver cirrhosis cases. Hepatogastroenterology 2011; 58:926–931.
Abdel-Bary SA, Safwat E, Hussein HA, Hussein AM, Botros SM. Value of renal resistive index in hepatitis C virus related liver cirrhosis and its response to midodrine. The Egypt J Radiol Nucl Med 2014; 45:1079–1087.
Umbro I, Tinti F, Fiacco F, Zavatto A, Piselli P, Di Natale V, et al.
Resistive index and MELDNa: nephrologic monitoring in cirrhotic patients awaiting liver transplantation. Transplant Proc 2013; 45:2676–2679.
Colli A, Cocciolo M, Riva C, Martinez E Abnormal renovascular impedance in patients with hepatic cirrhosis: detection with duplex US. Radiology 1993; 187 (2):561–563.
Koda M, Murawaki Y, Kawasaki H. Renovascular resistance assessed by color Doppler ultrasonography in patients with chronic liver diseases. J Gastroenterol Hepatol 2000; 15 (12):1424–1429.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]