Rapid Determination of Diuretic Resistant Ascites Using Furosemide Induced Natriuresis Test in Egyptian Cirrhotic Patients

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1 Rapid Deerminaion of Diureic Resisan Ascies Using Furosemide Induced Nariuresis Tes in Egypian Cirrhoic aiens *Mohamed Abd El-Hamid El-Bokl ; **Hanan Mahmoud Badawi; ***Marcel William Keddeas & ***George Safwa Riad * rofessor of Inernal medicine, ** Assisan professor of Inernal medicine, *** Lecurer of Inernal medicine, Ain Shams Universiy school of Medicine, Abbassia Square 11566, Cairo, Egyp. mwilliam2002@homail.com Absrac: Background: Diagnosis of refracory ascies is a challenging ask for physicians. This sudy aimed o evaluae he value of urinary sodium measuremen afer a single dose of inravenous furosemide (furosemide nariuresis es) in deerminaion of diureic resisan ascies. Mehods: fory five Egypian cirrhoic paiens wih massive ascies were included in he presen sudy. All of hem were mainained on low sodium die and were subjeced o furosemide nariuresis es hen hey were given maximum oral diureic herapy (160 mg furosemide and 400 mg spironolacone) for one week; he response o oral herapy was assessed by he difference in body weigh before and afer herapy. According o he resuls of oral herapy he paiens were divided ino wo main groups: Responsive group wih decrease in body weigh over 4 days >800gms, Resisan group wih decrease in body weigh over 4 days <800gms. Resuls: No significan difference in liver or renal funcions was found beween responsive and resisan group. Comparing he resuls of he furosemide nariuresis es o he resuls obained from response o oral diureic herapy; I was found ha all paiens resisan o oral herapy (welve paiens) had 8 hours urinary sodium <90mmol/L. In he responsive group (Thiry one paiens), weny eigh paiens had 8 hours urinary sodium >90mmol/L, hree paiens had 8 hours urinary sodium <90mmol/L and were found o be responsive o oral herapy. According o hese resuls he sensiiviy of he es is 100%, he specificiy is 90.3%, he posiive predicive value is 80% and he negaive predicive value is 100% for deecion of diureic resisan ascies. Conclusion: measuremen of urinary sodium eigh hours afer adminisraing 80 mg of inravenous furosemide is helpful in deecion of diureic resisan ascies paiens [Naure and Science. 2009;7(10):62-67]. (ISSN: ). Key Words: Furosemide nariuresis es; diureic resisan ascies; single dose of inravenous furosemide. Inroducion: The diagnosis of refracory ascies carries a poor prognosis wih survival raes of 30% o 40% a 1 year. Therefore i is imporan o idenify hose paiens reliably and rapidly as liver ransplanaion is urgenly needed in his siuaion Spahr e al., For he ascies o be considered as non responsive o diureic herapy he paien should be on spironolacone 400mg/day and furosemide 160mg/day for a leas one week and o be on sal resriced die of <90mmol/day. Lack of response is defined as a mean weigh loss of less han 0.8kg over 4 days and urinary sodium oupu less han sodium inake. Early recurrence is defined as he reappearance of grade 2 or 3 ascies wihin 4 weeks of iniial mobilizaion. Diureic induced complicaions include diureic induced hepaic encephalopahy, renal impairmen (increase is serum creainine >100% o a value of >2mg/dL) hyponaremia (decrease in serum sodium >10mmol/L o serum sodium <125mmol/L) and hypo or hyperkalemia (a change in serum poassium <3mmol/L or >6mmol/L respecively despie appropriae measures). These complicaions increase, as he dosage of diureics is increased Arroyo e al., 1996 & Moore e al., In addiion i is imporan o ascerain ha he lack of response is no relaed o dieary noncompliance or inadequae dosage of diureics. Due o hese facs, i is very difficul o apply his definiion of refracory ascies o paiens in oupaien deparmen; idenificaion of refracory ascies according o he proposed definiion ofen requires prolonged observaion, preferably in hospial o opimize he die and he diureic reamen. In his sudy, we ried o deermine if ascies is ruly diureic resisan rapidly by measuring urine sodium afer he adminisraion of inravenous furosemide. The furosemide nariuresis es can be he sandard in early differeniaion of he response o diureics reamen. 62

2 aiens and Mehods Fory five paiens wih massive ascies due o liver cirrhosis paricipaed in he sudy. A wrien informed consen was obained from each paien. Diagnosis of liver cirrhosis was based on clinical & laboraory evidences. aiens wih malignan ascies, uberculous, chylous and pancreaic ascies as well as ascies due o consricive pericardiis, hepaic venous congesion, ovarian umors sponaneous bacerial perioniis and ascies due o bowel perforaion were excluded from he sudy. All paiens were subjeced o he following: Liver enzymes (AST and ALT), serum albumin, serum bilirubin (direc and indirec), prohrombin ime and Child- pugh scoring was obained afer full clinical evaluaion. Urea, creainine, creainine clearance, abdominal ulrasound, viral markers, diagnosic abdominal paracenesis, follow up of serum sodium and poassium, urea and creainine all hrough he sudy ime. aiens were subjeced o he furosemide es as follows: All diureics were wihdrawn for 3 days. On he fourh day he paien was asked o void his bladder and a bolous of furosemide, 80mg I.V. was injeced. The urine was colleced for 8 hours for deecion of urinary sodium and urinary volume. The blood pressure was measured immediaely and afer 12 and 24 hours respecively and paiens were asked abou sympoms of hypoension (Spahr e al., 2001). Then afer wo days, All paiens were given inensive diureic herapy in hospial (160mg furosemide and 400mg spironolacone) for one week while being under sodium resricion. <90mmol/day (= less han 5.2gm/day) (Moore e al., 2003). The body weigh was measured over he las 4 days and he average weigh was aken. Two paiens did no complee he sudy because of diureic induced hepaic encephalopahy and were no included in furher daa analysis. According o he obained resuls from he oral herapy he fory hree paiens who compleed he sudy were classified ino 2 groups wihou knowing he resuls of he furosemide es: Diureic responsive group: in which he loss in body weigh was >800gms over he las 4 days (he loss is >200gms/day). b- Diureic resisan group: in which he loss in body weigh was <800gms over he las 4 days (he loss is <200gms/day). aiens of resisan group were subjeced o 24 hours urine collecion and 24 hours urinary sodium excreion was measured o confirm dieary sodium resricion (aiens who excree greaer han 90 mmol of sodium per day, and who fail o lose ascies are no complian wih heir die) Moore e al., 2003 Saisical mehodology Analysis of daa was done by IBM compuer using SSS (saisical program for social science package 16) as follows Descripion of quaniaive variables as mean, SD and range descripion of qualiaive variables as no and %, Chi-square es was used o compare qualiaive variables, Unpaired -es was used o compared wo independen groups as regard a quaniaive variable, paired -es was used o compare variables in he same group before and afer, correlaion co-efficien rank es was used o rank differen variables agains each oher in linear correlaion. sensiiviy = rue +ve /rue +ve + false - ve = abiliy of he es o deec +ve cases, specificiy = rue -ve/ rue -ve + false +ve = abiliy of he es o exclude negaive cases, posiive predicive value (V) = rue +ve/ rue +ve + false +ve = % of rue +ve cases o all posiive cases, NV = rue-/rue-ve + false -ve = % of he rue -ve o all negaive cases. Level of significance; value >0.05 insignifican, <0.05 significan, <0.01 highly significan. Alman, Resuls: 43 Egypian paiens wih liver cirrhosis secondary o hepaiis C infecion and massive ascies were included in his sudy. They were 33 males and 10 females, heir age range from 42 o paiens were Child-pugh class B and he remaining 28 paiens were of Child- pugh class C. According o he resuls of oral diureic herapy while being on sodium resriced die; he paiens were divided ino wo groups: Responsive group: Those wih decrease in body weigh over 4 days >800gms. Included 31 paiens, 24 males and 7 females, mean age was 47.3± paiens were of Child B class and 19 of Child C. Resisan group: Those wih decrease in body weigh over 4 days <800gms. Included 12 paiens, 9 males and 3 females, mean age was 50.3±7. 3 paiens were of Child B class and 9 of Child C. No significan difference was found beween responsive and resisan groups as regard age, sex or Child-pugh class. No saisically significan difference was found beween he wo groups regarding biochemical variables before he es as shown in Table 1. 63

3 Table (1): Comparison beween boh groups as regard differen laboraory daa before he es Resisan Responsive Serum Na (meq/l) >0.05 Serum K (meq/l) >0.05 AST (mg/dl) >0.05 ALT (mg/dl) >0.05 Toal bilirubin (mg/dl) >0.05 Direc bilirubin (mg/dl) >0.05 Toal proein (g/dl) >0.05 Albumin (g/dl) >0.05 T (minues) >0.05 INR >0.05 Urea (mg/dl) >0.05 Creainine clearance (ml/min) >0.05 Serum creainine (mg/dl) >0.05. Following furosemide nariuresis es, i was found ha 8 hours urine volume and 8 hours urinary sodium showed highly significan decrease in resisan han responsive group ( able 2) Table (2): Comparison of Resuls of furosemide nariuresis es beween boh groups Resisan Responsive Urine volume (ml) <0.0001** Urine Na (meq) <0.0001** Serum Na (meq) >0.05 Serum K (meq) >0.05 In he responsive group, following furosemide nariuresis es here was highly significan decrease in body weigh, significan decrease in serum sodium and non significan decrease in serum poassium (Table 3). While here was no significan change in any of hese parameers in he resisan group (Table 4) 64

4 Table 3 : Changes in body weigh and serum elecrolyes before and afer he es among responsive group Before Afer Weigh (kg) <0.01 Serum Na (meq/l) <0.05 Serum K (meq/l) <0.05 Table (4): Changes in body weigh and serum elecrolyes before and afer he es among resisan group Before Afer Weigh (kg) >0.05 Serum Na (meq/l) >0.05 Serum K (meq/l) >0.05 No significan change in blood pressure was deeced in boh groups in serial blood pressure follow up afer furosemide nariuresis es excep for significan decrease in sysolic blood pressure 12 hours afer he es in he responsive group (110.97±6.38 welve hours afer he es versus ± before he es, = 2.998, p<0.05). In he responsive group 8 hours urinary sodium afer he es were saisically correlaed versus all sudied variables before he es and no significan correlaion could be deeced wih any one of hem. The resuls were presened in able (5). The same correlaion was sudied in diureic resisan group and no significan correlaion was found. Table (5): Correlaion beween urinary Na 8 hours afer he es versus oher variables among responsive group r Age >0.05 Weigh >0.05 Serum Na >0.05 Serum K >0.05 AST >0.05 ALT >0.05 Toal bilirubin >0.05 Direc bilirubin >0.05 Toal proein >

5 Albumin >0.05 T >0.05 INR >0.05 Urea >0.05 Creainine clearance >0.05 Serum creainine >0.05 The resuls of he furosemide nariuresis es were compared wih he resuls obained from response o oral diureic herapy. According o hese resuls, he sensiiviy and specificiy of he es as well as is posiive and negaive predicive value were calculaed. The sensiiviy was 100% which means ha all cases wih urinary sodium <90mmol/L were found o be resisan o oral herapy (12 cases) (rue +ve cases). The specificiy was 90.3% which means ha among 31 paiens responsive o diureic herapy, 28 paiens only had urinary sodium >90mmol/L (rue -ve) and 3 paiens had urinary sodium <90mmol/L (false +ve). The V of he es was 80% which means ha among he fifeen paiens wih urinary sodium <90mmol/L 12 paiens only were ruly resisan o oral herapy (rue +ve). The NV was 100%, which means ha all paiens wih urinary sodium >90mmol/L (28 paiens) were responsive o oral herapy (rue ve). Discussion: The developmen of ascies in paiens wih cirrhosis indicaes a poor prognosis. The probabiliy of deah in cirrhoic paiens hospialized wih ascies is nearly 40% a 2 years. The prognosis is worse for hose wih refracory ascies, Moore e al., This sudy was designed o evaluae he furosemide induced nariuresis es as simple, cheap and rapid mehod for early deerminaion of he resisan ype of refracory ascies. Resul of he presen sudy revealed ha he number of resisan cases was 28% of oal cases while responsive cases represened he remaining 72%. This is in accordance wih Zervos and Rosemurgy, 2001 and Moreau e al., 2004; boh auhors repored ha percenage of refracory ascies was less han ha of responsive one, and less han 30% of oal cases. I was proved ha medical reamen based on sodiumresriced dies, ani-mineralocoricoids, and loop diureics achieves a response rae in up o 90% of paiens wihou renal failure in conrolled clinical rials Moore e al., However he selecion of paiens for he presen sudy could accoun for higher percenage of diureic resisance as we seleced paiens wih massive ascies which reflecs more disurbances in sal and waer homeosasis. We found non significan difference in almos all sudied biochemical parameers beween diureic resisan and responsive paiens; i was repored ha he course of underlying chronic liver disease and he prognosic facors in relaion o he oucome of ascies have no been deermined and refracory ascies may occur in he absence of poor liver funcion Moreau e al., The pahophysiological basis of ascies developmen in cirrhoic paiens could explain he highly significan increase in urine sodium 8 hours afer he es in he responsive group in comparison wih resisan group. The laer paiens have significan abnormaliies in heir fluid and elecrolye balance which is manifesed mainly by developmen of ascies and edema Cardenas and Arroyo, The response of ascies is usually beer in paiens wih moderae sodium reenion han in hose wih marked sodium reenion Bernardi e al., Wih he progression of he disease, paiens wih severe urinary sodium reenion develop refracory ascies Cardenas and Arroyo, Accordingly urinary sodium excreion in some cases of severe resisan ascies may approximae o zero Cárdenas and Arroyo, Impaired waer handling is common in cirrhoic paiens as indicaed by an impaired abiliy o eliminae waer load Cardenas and Arroyo, This explains he highly significan decrease in urine volume in he resisan group in comparison wih he responsive group. In addiion, Arroyo e al., 1996 repored ha when he renal abiliy o excree free waer is markedly reduced, paiens become unable o eliminae excess ingesed waer and diluional hyponaraemia develops. The significan decrease in serum Na afer he es among paiens of responsive group is mos probably he resul of he increase in urinary sodium excreion 66

6 in his group as a response o he es and he significan decrease in serum K afer he es in his group is mos probably he side effec o IV furosemide Arroyo e al., The furosemide nariuresis es was saisically evaluaed as regard is value in diagnosing resisan ascies and is safey for he paien. Firsly, eigh hours urinary sodium was saisically correlaed wih all sudied biochemical variables as well as he child classificaion in boh groups. The resuls revealed non significan correlaion of 8 hours urinary sodium wih any of he sudied variables. This resul indicaes sabiliy of he es which means ha is no changeable in response o any oher variable excep he degree of response of ascies. Daa of he presen sudy suppors he findings of oher auhors who proposed furosemide nariuresis es as a simple es o idenify paiens wih refracory ascies Spahr e al., Conclusion: From his sudy we can conclude ha when urinary sodium excreion following 80mg IV furosemide injecion is >90mmol/L (under dieary sodium resricion) he paien can be diagnosed as responsive o diureics. Meanwhile when i is <90mmol/L (under he same resricion) he paien is 80% resisan o diureics. Accordingly, he es is highly sensiive bu no highly specific. Correspondence o: Marcel W. Keddeas, MD Inernal medicine deparmen, Ain Shams Universiy school of Medicine, Abbassia Square 11566, Cairo, Egyp Cellphone: mwilliam2002@homail.com References: Alman DG: racical saisics for medical research. Chapman and Hall. London SE 18 HN UK. 4 h ed; 1994: & Arroyo V, Gines, Gerbes AL, Dudley FJ, Genilini, Laffi, Reynolds TB, Ring-Larsen H, Schölmerich J: Definiion and diagnosic crieria of refracory ascies and hepaorenal syndrome in cirrhosis. Hepaology 1996; 23(1): Bernardi M, Laffi G, Salvagnini M, Azzena G, Bonao S, Marra F, Trevlsani F, Gasbarrini G, Naccarao R, Genillni : Efficacy and safey of he sepped care medical reamen of ascies in liver cirrhosis: a randomized conrolled clinical rial comparing wo dies wih differen sodium conen. Liver Inernaional 1993; 13(3): Cárdenas A and Arroyo V : Mechanisms of waer and sodium reenion in cirrhosis and he pahogenesis of ascies Bes pracice and Research clinical Endocrinology and Meabolism 2003; 17 (4): Cardenas A and Arroyo V: Refracory ascies. Dig Dis 2005; 23 (1): Moore K, Wong F, Gines,Bernardi M, Ochs A, Salerno F, Angeli, orayko M, Moreau R, Garcia- Tsao G, Jimenez W, lanas R, Arroyo V: The Managemen of Ascies in Cirrhosis: Repor on he Consensus Conference of he Inernaional Ascies Club. Hepaology 2003;38: Moreau R, Delègue, essione F, Hillaire S, Durand F, Lebrec D, Valla DC: Clinical characerisics and oucome of paiens wih cirrhosis and refracory ascies. Liver Inernaional 2004; 24 (5): Spahr L, Villeneuve J, Tran HK, omier-layrargues G: Furosemide induced nariuresis as a es o idenify cirrhoic paiens wih refracory ascies. Hepaology2001; 33(1):28-31 Zervos EE and Rosemurgy AS: Managemen of medically refracory ascies. The American Journal of Surgery 2001; 181: /23/