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Effects of dermatan sulfate for anticoagulation in continuous renal replacement therapy

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Dermatan sulfate (DS) is a natural glycosaminoglycan with a unique mechanism of action on the coagulation system. Unlike unfractionated heparin (UFH), DS selectively inhibits thrombin, does not inhibit factor Xa, is effective on both free and
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   JN EPHROL2008; 21: 205-212 ORIGINAL ARTICLE 205  A  BSTRACT  Background  : Dermatan sulfate (DS) is a natural gly-cosaminoglycan with a unique mechanism of action onthe coagulation system. Unlike unfractionated heparin(UFH), DS selectively inhibits thrombin, does not inhibitfactor Xa, is effective on both free and fibrin-bound throm-bin and does not interfere with platelets. This study repre-sents the first experience using DS as anticoagulant in pa-tients on continuous renal replacement therapy (CRRT).  Methods : A total of 147 patients in our intensive care unitwho developed acute renal failure after cardiovascularsurgery were on CRRT according to the same protocol:machine, Gambro Prisma; filter, AN69, 0.9 m 2 ; Q B , 150ml/min; Q D , 2,000 ml/hour; and Q Infusate , 500 ml/hour. In aretrospective cohort of 100 patients, anticoagulation wasperformed with UFH (UFH-CRRT): initial bolus of 530 ± 363IU, then i.v. infusion of 598 ± 261 IU/hour. A prospectivecohort of 47 patients received DS (DS-CRRT) as a 150-mgbolus followed by a 13.5 ± 3 mg/hour infusion. Hematology tests were performed at baseline and during CRRT; filterlifetime was measured from the start to filter clotting.  Results : Median filter lifetime was 58 hours in DS-CRRT vs.47 hours in UFH-CRRT (p<0.001). No differences emergedin basal hematology and hemostasis tests betweengroups. During CRRT, DS produced a smaller activatedpartial thromboplastin time increase than UFH (p<0.01).Platelet count exhibited a comparable small decline inboth DS-CRRT and UFH-CRRT (p<0.01). No significantbleeding episodes occurred during DS-CRRT. In-hospitalmortality was similar in the 2 cohorts. Conclusions : DS can be suggested as an anticoagulant forCRRT in patients who develop acute renal failure followingmajor cardiovascular surgery.Key words:  Acute renal failure, Continuous renal replace- ment therapy, Dermatan sulfate, Intensive care, Hemodi- afiltration, Hemodialysis I NTRODUCTION Continuous renal replacement therapy (CRRT) is widely usedfor the management of acute renal failure (ARF) in critically illpatients. One of the major drawbacks potentially affectingCRRT is the frequent coagulation of the blood circuit so asto increase the cost of treatment and the workload of thenursing staff, on the one hand, and impair the entire efficien-cy of the blood purification process, on the other hand.However, a cautious approach to anticoagulants is mandato-ry with critically ill patients, as they frequently present withan increased risk for hemorrhage due to recent trauma orsurgery (1).To date, unfractionated heparin (UFH) is the routine optionfor anticoagulation in CRRT, unless heparin-induced throm-bocytopenia (HIT) or hemorrhagic risk are feared. In thosecases, it is recommended either to use alternative anticoagu-lants, such as sodium citrate, r-hirudin and heparinoids, or toprovide an anticoagulant-free CRRT (2, 3). As far as sodium citrate is concerned, it has recently beenreported that regional anticoagulation with this drug can beeven superior to systemic anticoagulation with UFH, yieldingan increase in filter survival time with no increase in bleedingrisk (4). However, this procedure is more labor-intensive andexpensive than anticoagulation with UFH. Moreover, citratemetabolism can be impaired in liver insufficiency, so that itsuse is not recommended in that condition (5). In cases of HIT, the substitution of UFH for either r-hirudin ordanaparoid has been suggested (6). However, relevant andpotentially unsafe increases in their half-life (to 52 hours and31 hours for hirudin and danaparoid, respectively) werereported in patients with renal failure (7). Furthermore, bothare very expensive. Briefly, what the more adequate anticoagulant is for CRRTwith patients at increased risk of bleeding is still debated, sothat further information on this issue would be useful. Corrado Vitale 1 , Claudio Verdecchia 2 , Cristiana Bagnis 1 ,Marco Ganzaroli 2 , Giovanni Giorcelli 1 , Martino Marangella 1 1 Nephrology and Dialysis Unit, A.S.O. Ordine Mauriziano,Torino - Italy 2 Cardiovascular Intensive Care Unit, A.S.O. Ordine Mauriziano,Torino - Italy Effects of dermatan sulfate for anticoagulation in continuous renal replacement therapy  www.sin-italy.org/jnonline –www.jnephrol.com  Dermatan sulfate (DS) is a natural glycosaminoglycanthat inhibits the coagulation system by potentiating theactivity of heparin cofactor II. It is currently prescribed forthe prevention of venous thromboembolism to patientsundergoing surgery (8, 9). Unlike UFH, DS is a selectiveindirect inhibitor of thrombin which does not affect othercoagulation factors, is also effective on fibrin-boundthrombin and does not interfere with platelet function(10-12). In animal models, DS inhibited both thrombusformation and extension, with a reduced hemorrhagiceffect compared with UFH (13, 14). In renal failure, thehalf-life of DS remained within a safe range of 2-3 hours(15). About 15 years ago, DS was tested in patients on inter-mittent hemodialysis (IHD) for end-stage renal failure(ESRF) (15-19). Afterwards, despite the first encouragingresults, its usefulness with renal replacement therapieswas not further investigated. In particular, DS has neverbeen tested in critically ill patients on CRRT for ARF. We herein report the results of an open study which isthe first experience using DS as anticoagulant in patientssubmitted to CRRT for ARF in a cardiovascular intensivecare unit (ICU). These were compared with patients hav-ing received systemic anticoagulation with UFH duringCRRT in our ICU. S UBJECTSANDMETHODS In our hospital, all patients in the ICU who need bloodpurification because of severe renal failure are treated withCRRT, according to a strategy of interdisciplinary manage-ment described elsewhere (20). A basic treatment sched-ule was defined and chosen as the default option forpatients starting CRRT (Tab. I). This study refers to critically ill patients in the cardiovascu-lar ICU who needed CRRT after the onset of ARF compli-cating major cardiovascular surgery: coronary bypass,substitution of heart valves, ventricular remodeling, chestvessel disease, repair of aortic aneurysm or dissection, orlower limb revascularization. The majority of patients had ARF occurring from 1 to 3 days after surgery. Others werealready on regular dialysis treatment (RDT, hemodialysis orperitoneal dialysis) because of ESRF, before their admis-sion to the ICU. In our ICU, critically ill patients are given low-molecular-weight heparin (LMWH) for prophylaxis against deepvenous thromboembolism. If CRRT is supplied, theamount of UFH administered to maintain the patency ofthe extracorporeal circuit is higher than that required forprophylaxis against deep venous thrombosis; conse-quently, LMWH is withdrawn. 206 Vitale et al: Dermatan sulfate for anticoagulation in CRRT  TABLE I DEFAULT SETTINGS FOR CONTINUOUS RENAL REPLACEMENT THERAPYMachine:Hospal PrismaCircuit:Prisma M100pre setMembrane:AN69, 0.9 m 2 Q B :150 ml/minQ D :2,000 ml/hourQ Infusion :500 ml/hour, predilutionNet UF:50-200 ml/hourPreliminary washout of the circuit:2 L saline + UFH 10,000 IU Anticoagulation:Starting bolus: UFH, 0-1,000 IUContinuous infusion:UFH, 500 IU/hour, to be adapted to aPTT profile during CRRTTarget aPTT during CRRT:50-70 secondsUFH withdrawn if:aPTT>70 secondsINR>2PLTS<60,000active bleeding presentaPPT = activated partial thromboplastin time; CRRT = continuous renal replacement therapy; INR = international normalizedratio (prothrombin time); PLTS = platelets; UFH = unfractionated heparin.  Since DS was reportedly suggested to have a reducedhemorrhagic effect compared with UFH (8, 13, 14), we ini-tially tested DS instead of UFH in some critically illpatients on CRRT, who had shown either active bleedingor high recurrence of filter clotting. Since the daily dosagerecommended for the prevention of deep venous throm-bosis in major surgery is 300 mg/day (9), a slightly higherdosage was prescribed in CRRT. Subsequently, the encouraging results in terms of clinicaltolerance and patency of the filters prompted us to modifyour CRRT protocol by substituting DS for UFH in all CRRTsessions requiring systemic anticoagulation. This changeof anticoagulation policy for CRRT was approved by theethics committee of our hospital. Therefore, from April 2005 to May 2006, 47 consecutivepatients in the cardiovascular ICU underwent CRRT usingDS as anticoagulant (DS-CRRT) (Tab. II). DS (Mistral, 300mg/3 mL ampoules; Mediolanum Farmaceutici, Milan,Italy) was administered as a single bolus of 150 mg at thestart of CRRT, then as a continuous i.v. infusion of 15mg/hour. The infusion was reduced in rate if activated par-tial thromboplastin time (aPTT) exceeded 60 seconds anddiscontinued if aPTT exceeded 70 seconds. This dosageregimen had been developed during our initial experienceof the drug. The results obtained in these patients on DS-CRRT wereprospectively recorded and compared with those from aretrospective cohort of 100 consecutive patients in thesame cardiovascular ICU who had been given CRRT withUFH (Eparina Vister, 50,000 IU/10 mL ampoules; MSPharma, Agrate Brianza, Italy) from January 2002 toMarch 2005. This group will be referred to as UFH-CRRT(Tab. II). Besides the anticoagulant, all the other CRRT set-tings, as detailed in Table I, remained unchanged in theDS-CRRT group compared with the UFH-CRRT group. For each patient, only the data referring to the first sessionwere used, both for the calculations of the circuit lifetimeand the hematology and hemostasis tests, even if moreCRRT sessions were performed during the ICU stay. In systemic venous blood, serum creatinine (Cr), aPTT(STA APTT; Roche Diagnostics, Mannheim, Germany),prothrombin time expressed as international normalizedratio (INR; STA Neoplastin Plus; Roche Diagnostics), (Fib;normal values: 200-400 mg/dL), hemoglobin (Hb) and 207  JN EPHROL2008; 21: 205-212 TABLE II PATIENTS AND DIALYSIS SESSIONS CONSIDERED FOR THE STUDY DS-CRRTUFH-CRRT Patients (number) 47100 Age (years)74 ± 10*70 ± 11M/F20/27*63/37Post-surgery ARF4480 Already on RDT320Median circuit lifetime (hours) † 58 ‡ 47 CRRT hours (number) § 4,4577,718Mortality at the 7th day (%) || 1825Mortality at discharge (%) || 5053Hospital stay of surviving patients (days) || 19 ± 1323 ± 19Hospital stay of deceased patients (days) || 17 ± 1915 ± 14 ARF = acute renal failure; CRRT = continuous renal replacement therapy; DS-CRRT = continuous renal replacement therapy,with dermatan sulphate; RDT = regular dialysis treatment; UFH-CRRT = continuous renal replacement therapy, with unfraction-ated heparin.*p<0.05, vs. UFH-CRRT. † Data refer to the first CRRT session for each patient. ‡ p<0.001, vs. UFH-CRRT. § Data refer to the whole time of CRRT during ICU stay. || Data refer to postsurgery ARF patients.  platelet (PLTS) count were determined in all patientsbefore the start of CRRT session. During CRRT, the sameparameters were checked 3 times a day (at 6  AM , 2 PM and10 PM  ) except for Cr (1 daily dose). For each parameterand patient, the mean value measured from the 24th hourthrough the end of the CRRT session was calculated anddefined as the through CRRT value. Lifetime of blood circuits was measured from the start ofeach session of CRRT to its end, due to either the end ofusable circuit time as specified by the manufacturer (72hours of CRRT), filter failure or treatment discontinuationfor any other cause (recovery of renal function, radiologytests, death). Filter failure was diagnosed if significantclotting appeared after filter flushing with isotonic saline(routinely performed 3 times a day) or in case of trans-membrane pressure higher than 450 mm Hg.To take into account bleeding events, fluid flow ratesthrough the drainage tubes inserted in surgical woundsand Hb levels were monitored. According to establishedprotocols a flow rate greater than 50 ml/2 hours in the first12 hours after the operation, or any significant relapse ofbleeding after it had ceased, as well as a fall in Hb levelgreater than 2 g/day, was considered as a major bleedingepisode. A dual-lumen catheter was inserted into the femoral veinand used as vascular access in patients with ARF. Thiswas applied also to patients on RDT, despite having anarteriovenous fistula. Both hospital stay and mortality of patients on both DS-and UFH-CRRT were evaluated. Hospital stay we definedas the time from the start of CRRT to the patient’s dis-charge or death. The mortality rate was investigated bothon the seventh day after the start of CRRT session and atthe end of the patient’s stay in hospital.  ARF increases the mortality rate among critically illpatients and is the worst outcome related to the severeforms of renal failure requiring dialysis (21). Consequently,for the comparison of both hospital stay and mortalityrates between UFH-CRRT and DS-CRRT, patients withESRF on RDT before admission to ICU were excluded. Circuit lifetime was estimated in each treatment groupwith the Kaplan-Meier method, and compared betweengroups using the log-rank test (XLstat 2006; Addinsoft,NY, USA); treatment discontinuation unrelated to filter fail-ure was computed as censored data in the analysis. For data other than circuit lifetime, differences in meanswere assessed with Student’s t  -test and differences inproportions with Fisher’s exact test. Data are presented asmeans ± standard deviation, unless specified otherwise. R ESULTS The main features of patients and dialysis sessions areshown in Table II. Forty-four patients on DS-CRRT and80 patients on UFH-CRRT had ARF after cardiovascularsurgery; 3 patients in the DS-CRRT group and 20patients in the UFH-CRRT group were already on RDTbefore their admission in the ICU. Considering onlypatients with ARF, the mortality rate at the seventh dayafter the start of CRRT was 25% for UFH-CRRT and18% for DS-CRRT (p=n.s.), whereas these values atpatients’ discharge were 53% and 50%, respectively(p=n.s.). As far as both the hospital stay of survivors andthe hospital stay of deceased patients are concerned,the differences between DS-CRRT and UFH-CRRT werenot significant.Survival time of blood circuits was significantly longer onDS-CRRT compared with UFH-CRRT (median survival 58vs. 47 hours; hazard ratio 0.4913; 95% confidence ratio,0.3178-0.7596; p=0.0008). Kaplan-Meier analysis isshown in Figure 1. Similar results emerged if RDT patientswere excluded (median survival 58 vs. 48 hours; hazardratio 0.4675; 95% confidence interval, 0.2925-0.7473;p=0.0015). In the DS-CRRT group, 38 circuits (81%) were removedfor end of usable circuit time or filter clotting, and 9 (19%)were disconnected for other causes. With UFH-CRRT, 67circuits (67%) were removed for end of usable circuit time 208 Vitale et al: Dermatan sulfate for anticoagulation in CRRT  Fig. 1 - Comparison of survival time of blood circuits duringcontinuous renal replacement therapy, with dermatan sul-phate (DS) vs. unfractionated heparin (UFH) (Kaplan-Meieranalysis).  or filter clotting, and 33 (33%) were disconnected for othercauses (p=n.s., between groups). Actually administered DS doses were 150 mg as a bolus,followed by 13.5 ± 3 mg/hour as a continuous infusion.With UFH, initial bolus and continuous infusion were 530 ±363 IU and 598 ± 261 IU/hour, respectively.  As explained above, continuous anticoagulation wasreduced in rate if aPTT exceeded 60 seconds and discon-tinued if aPTT exceeded 70 seconds. Fewer determina-tions of aPTT above the target values occurred with DS-CRRT than with UFH-CRRT, with the differences beingsignificant after 48 hours and at the end of dialysis ses-sions (Tab. III).During DS-CRRT, no major bleeding episodes, as previ-ously defined, occurred, whereas 3 occurred during UFH-CRRT (p=n.s.). Time courses of Cr, from start to end of CRRT, are shownin Figure 2. The same profiles were recorded in UFH-CRRT and in DS-CRRT. Results of hematology and hemo-stasis tests at start of CRRT (baseline) and during treat-ment (through) are listed in Table IV. No differencesemerged as regards baseline aPTT, INR, Fib, Hb and PLTScount between DS-CRRT and UFH-CRRT. aPTT increasedsignificantly through both DS-CRRT and UFH-CRRT.However, DS-CRRT produced lower increases in aPTTthan UFH-CRRT during treatment (p<0.01). Modestchanges in INR were seen only with UFH-CRRT (p=0.05,through vs. baseline values). However, the through valueswere similar with either treatment. Fib levels showed simi-lar increases with both DS-CRRT and UFH-CRRT, with nodifference in the through values between treatments.While Hb remained stable with both treatments, PLTScount exhibited comparable small declines with both DS-CRRT and UFH-CRRT (p<0.01). D ISCUSSION Control of the coagulation system is essential in patientsundergoing cardiovascular surgery, and, usually, largeamounts of UFH are used to avoid lethal episodes of 209  JN EPHROL2008; 21: 205-212 TABLE III DETECTION OF aPTT VALUES ABOVE 60 SECONDS (THRESHOLD FOR REDUCTION OF CONTINUOUS ANTICOAGULATION) AND 70 SECONDS (THRESHOLD FOR ANTICOAGULANT DISCONTINUATION) DURING DS-CRRT AND UFH-CRRT SESSIONS 24 hours48 hoursEnd of CRRT>60 seconds>70 seconds>60 seconds>70 seconds>60 seconds>70 seconds UFH-CRRT42.1%23.7%34.7%16.3%47.8%26.1%(32/44)(18/58)(17/32)(8/41)(11/12)(6/17)DS-CRRT31.8%13.6%28.6%0%*6.3% † 6.3%(14/30)(6/38)(10/25)(0/35)(1/15)(1/15)In parentheses: cases above / cases below, the target value.aPPT = activated partial thromboplastin time; DS-CRRT = continuous renal replacement therapy, with dermatan sulphate;UFH-CRRT = continuous renal replacement therapy, with unfractionated heparin.*p=0.02, vs. UFH-CRRT † p=0.01, vs. UFH-CRRT. Fig. 2 - Serum creatinine profiles during continuous renalreplacement therapy, with unfractionated heparin (whitebars) and dermatan sulphate (dark bars). The whiskers insidethe bars represent standard deviation.
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