Multi-centre evaluation of anticoagulation in patients receiving continuous renal replacement therapy (CRRT)

Patrick D. Brophy1, Michael J. G. Somers2, Michelle A. Baum2, Jordan M. Symons3, Nancy McAfee3, James D. Fortenberry4, Kristine Rogers4, Joni Barnett5, Douglas Blowey6, Cheryl Baker7, Timothy E. Bunchman8 and Stuart L. Goldstein7

1 C. S. Mott Children's Hospital, Ann Arbor, MI, 2 Children's Hospital, Boston, MA, 3 Children's Hospital Regional Medical Center, Seattle, WA, 4 Children's Healthcare of Atlanta at Egleston, Atlanta, GA, 5 University of Alabama, Birmingham, AL, 6 Children's Mercy Hospital and Clinics, Kansas City, MO, 7 Baylor College of Medicine, Houston, TX and 8 DeVos Children's Hospital, Grand Rapids, MI, USA

Correspondence and offprint requests to: Patrick D. Brophy, C. S. Mott Children's Hospital, University of Michigan, F6865-0297, 1505 Simpson Rd E, Ann Arbor, MI 48109, USA. Email: pbrophy{at}umich.edu



   Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background. Heparin (hepACG) and regional citrate anticoagulation (citACG) remain the most commonly reported continuous renal replacement therapy (CRRT) ACG methods employed. No prospective multi-centre published data exist that compare different ACG methods with respect to CRRT filter life span or patient complications.

Methods. A total of 138 patients from seven US centres receiving 18 208 h of CRRT comprising a total of 442 CRRT circuits were utilized to assess filter life span and ACG-related complications in patients receiving CRRT with hepACG, citACG or no ACG (noACG).

Results. Mean circuit life was 41.2±30.8 h. Mean circuit survival was no different for circuits receiving hepACG (42.1±27.1 h) and citACG (44.7±35.9 h), but was significantly lower for circuits with noACG (27.2±21.5 h, P<0.005). Kaplan–Meier analyses revealed no survival difference between hepACG and citACG circuits, but significantly lower survival for noACG circuits (P<0.001). Log-rank analysis showed that 69% of hepACG and citACG circuits whereas only 28% of noACG were functional at 60 h. Clotting rates were similar for hepACG circuits (58 out of 230, 25%) and citACG circuits (43 out of 158, 27%), but were significantly higher for noACG circuits (27 out of 54, 50%, P < 0.001). Life-threatening bleeding complications attributable to ACG were noted in the hepACG group but were absent in the citACG group.

Conclusions. The current analysis represents the largest evaluation of CRRT ACG methods to date. While the standard hepACG and citACG methods studied in the prospective paediatric CRRT registry led to similar filter life spans and were superior to noACG, our data suggest that citACG may result in less life-threatening complications.

Keywords: anticoagulation; citrate; continuous renal replacement therapy; heparin; paediatric



   Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Multiple advancements affecting continuous renal replacement therapy (CRRT) delivery to critically ill adult and paediatric patients have been developed over the past decade [1]. Dedicated CRRT equipment with better thermal control, more precise volumetric control and tubing now allows safe CRRT provision for children and infants [1,2]. The past several years demonstrate a shift toward the preferential use of CRRT by paediatric nephrologists to support paediatric patients with acute renal failure [3].

While issues such as indications for implementation of CRRT, treatment dose, dialysis vs filter replacement fluid (FRF), type of solution and equipment used have created much debate in both the adult and paediatric literature, CRRT anticoagulation (ACG) methodology remains one of the most critical issues currently being considered in the field [4,5].

A variety of ACG approaches have been described and assessed for CRRT [5,6]. An optimal ACG method would be: regional in nature to prevent unwanted systemic patient ACG, easy to implement and to monitor, cost effective and have minimal patient side effects. Currently, heparin ACG (hepACG), and regional citrate ACG (citACG) remain the most commonly reported CRRT ACG methods in the USA. CitACG use has become more widespread as a result of recently published simple citACG practice algorithms [7–9]. Many clinicians advocate the use of no ACG (noACG) for patients with coagulopathy associated with hepatic failure, fulminant sepsis, ongoing bleeding or heparin-induced thrombocytopenia (HIT), suggesting that many of the issues associated with ACG delivery can be bypassed in these patients [10].

While a recent single centre small prospective randomized control adult trial exists [11], this study excluded patients with systemic bleeding from analysis. Despite the refinements in CRRT ACG practice, no prospective multi-centre adult or paediatric published data exist that compare different ACG methods with respect to CRRT filter life span or patient complications. We now report data from the first multi-centre study to assess both CRRT patient and filter outcome using hepACG, citACG or noACG. The current study aims to assess for potential benefits associated with the various forms of ACG in terms of efficacy, filter life span and patient side effects.



   Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The Prospective Pediatric Continuous Renal Replacement Therapy (ppCRRT) Registry Group is a multi-centre collaborative effort designed to evaluate various clinical and therapeutic aspects of paediatric CRRT. The ppCRRT Registry Group is currently designed in a prospective observational format; all centres practise according to local standards of care and have agreed to collect the same data. The current analysis comprises data collected between January 1, 2000 and August 31, 2003 from seven US paediatric centres: Texas Children's Hospital (Houston), The Children's Hospital (Boston), Children's Regional Medical Center (Seattle), C. S. Mott Children's Hospital (Ann Arbor), University of Alabama Children's Hospital (Birmingham), Mercy Children's Hospital and Clinics (Kansas City) and Children's Healthcare of Atlanta at Egleston (Atlanta). The Institutional Review Board for each centre approved the study prior to patient enrolment. All centres care for critically ill patients with complex congenital heart disease as well as solid and stem cell organ transplants.

Anticoagulation methods
Each centre followed local practice with respect to ACG method. The two methods employed by the ppCRRT were hepACG and citACG. In addition, some circuits received no pharmacological ACG (noACG) when patients already had systemic bleeding and the investigator did not want to expose the patient to systemic heparinization. In these, normal saline flushes were used to keep the filters from clotting as much as possible.

HepACG was achieved by a pre-filter heparin bolus and/or continuous infusion to maintain post-filter activated clotting times (ACTs) between 180 and 240 s. Regional ACG using heparin and protamine was not employed by any centre in the ppCRRT.

Regional citACG was accomplished using the protocol previously described [7] in which ACD-A (Anticoagulant Dextrose-A, Baxter) is infused via a stopcock or port in the arterial limb of the CRRT circuit to maintain a circuit ionized calcium level between 0.25 and 0.5 mmol/l. The patient systemic ionized calcium is maintained between 1.10 and 1.30 mmol/l by administration of calcium chloride (8 g in 1 l of normal saline) into a separate central line or the third lumen of a triple lumen haemodialysis catheter. Using this protocol, paired circuit and systemic ionized calcium levels are assessed at the time of and 2 h after each new circuit initiation, and then every 6 h thereafter.

The decision not to use pharmacological ACG was generally based on the presence of pulmonary or cerebral bleeding or the presence of HIT.

Data analysed
Each circuit had the following data collected: machine type and membrane composition, circuit life (h), extracorporeal volume (ml), priming solution, blood pump flow rate (Qb, ml/min), ACG type (hepACG, citACG or noACG), CRRT mode [continuous venovenous haemofiltration (CVVH), continuous venovenous haemodialysis (CVVHD) or continuous venovenous haemodiafiltration (CVVHDF)], replacement and/or dialysis fluid volumes used (ml), dialysis fluid composition (Baxter Hemofiltration® fluid, Normocarb®, Baxter Peritoneal Dialysis® fluid or custom-made pharmacy-prepared fluid) and the percentage of patient blood volume ultrafiltered per h.

For circuits receiving hepACG, additional data collected were: heparin rate (U/kg/h), mean ACT (s), number of ACTs <180 s, and mean ACTs measured per h.

The reasons for CRRT circuit change were divided into six categories: (i) clotted; (ii) scheduled change; (iii) access malfunction; (iv) machine malfunction; (v) an unrelated patient issue [e.g. the circuit was discontinued because the patient went to the radiology department for a magnetic resonance imaging (MRI) scan or because the patient regained renal function]; and (vi) other.

Statistical analysis
Mean circuit survival (h) for each ACG method and for each CRRT modality was assessed by analysis of variance (ANOVA). Comparative circuit survival for each ACG method was assessed using log-rank tests with Kaplan–Meier analysis. Circuits were censored for Kaplan–Meier analysis if changed because of a scheduled change as per the manufacturer's recommendations, access malfunction, machine malfunction or unrelated patient issues. Potential correlation between patient size, heparin dosage rates (U/kg/h), ACT sampling rates (number of ACTs measured per h), low ACT values (number of ACTs <180 s) and circuit survival was assessed by linear regression analysis. Clotting rates observed with each ACG method were assessed using {chi}2 analysis. A P-value <0.05 was considered significant.



   Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
During the course of the current study, 138 patients (mean age 8.6±7.2 years; range 1 day to 25 years; Houston n = 27, Boston n = 27, Seattle n = 24, Michigan n = 31, UAB n = 21, Atlanta n = 5 and Missouri n = 3) received 18 208 h of CRRT comprising a total of 442 CRRT circuits. The most common primary diagnoses for patients receiving CRRT were: sepsis (n = 40), cardiovascular shock without sepsis (n = 24), stem cell transplant (n = 18), liver transplant (n = 5) and metabolic inborn error (n = 5). Ninety-three patients initially received hepACG, 37 patients initially received citACG and eight patients initially received noACG. Mean circuit life was 41.2± 30.8 h (range 1–188 h). No correlation was noted between patient size and circuit survival (r = 0.19), and circuit survival was not different between circuits receiving CVVH vs CVVHD vs CVVHDF. The breakdown of the reasons for CRRT circuit change is depicted in Figure 1. Clotting (29%), scheduled changes (25%) and unrelated patient issues (28%) were the most common reasons to change the CRRT circuit.



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Fig. 1. The breakdown of the number of CRRT circuit change requirements. Notably, clotting (29%), scheduled changes (25%) and unrelated patient issues (28%) represented the most common reasons necessitating CRRT circuit change. n = 138 patients receiving 18 208 h of CRRT comprising a total of 442 CRRT circuits. Mean circuit life was 41.2±30.8 h (range 1–188).

 
A total of 230 circuits received hepACG (52%), 158 circuits received citACG (36%) and 54 circuits received noACG (12%). Three centres used only hepACG (Boston, Seattle and Atlanta), two centres used only citACG (Kansas City and Alabama) and two centres converted from hepACG to citACG (Houston and Ann Arbor) during the course of study.

Anticoagulation method, circuit survival and clotting rates
Mean circuit survival was no different for circuits receiving hepACG (42.1±27.1 h) and citACG (44.7±35.9 h), but was significantly lower for circuits with noACG (27.2±21.5 h, P<0.005). Kaplan–Meier analyses also revealed no circuit survival difference between hepACG and citACG circuits, but significantly lower survival for noACG circuits (P<0.001, Figure 2). Log-rank analysis showed that 69% of hepACG and citACG circuits, but only 28% of noACG, were functional at 60 h. Multivariate analysis revealed no correlation between circuit survival, blood pump flow rates, patient weights or filtration fraction.



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Fig. 2. Comparison of CRRT circuit life for all circuits with: no anticoagulation (filled squares), heparin anticoagulation (filled circles) or citrate anticoagulation (filled triangles). Mean circuit survival was no different for circuits receiving hepACG (42.1±27.1 h) and citACG (44.7±35.9 h), but was significantly lower for circuits with noACG (27.2±21.5 h, P<0.005). Kaplan–Meier analyses revealed no circuit survival difference between hepACG and citACG circuits, but significantly lower survival for noACG circuits (P<0.001). Circuits were censored for Kaplan–Meier analysis if changed because of scheduled change as per the manufacturer's recommendations, access malfunction, machine malfunction or unrelated patient issues. Log-rank analysis showed that 69% of hepACG and citACG circuits, but only 28% of noACG circuits, were functional at 60 h. Note, clotting rates were similar for hepACG circuits (58 out of 230, 25%) and citACG circuits (43 out of 158, 27%), but were significantly higher for noACG circuits (27 out of 54, 50%, P<0.001).

 
Clotting rates were similar for hepACG circuits (58 out of 230, 25%) and citACG circuits (43 out of 158, 27%), but were significantly higher for noACG circuits (27 out of 54, 50%, P<0.001). Forty-six patients experienced a clotted filter, 29 of which were the first filter used for the CRRT course. The mean time to first clotted filter was no different for hepACG circuits vs citACG circuits vs noACG circuits.

Access malfunction and elevated pressures may also signify circuit clotting. For this reason, we performed an additional Kaplan–Meier analysis where circuits changed for elevated filter pressure or access malfunction were no longer censored for log-rank analysis. Figure 3 demonstrates once again that circuits receiving hepACG or citACG demonstrated similar survival times.



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Fig. 3. Since access malfunction and elevated pressure may also signify circuit clotting, we performed an additional Kaplan–Meier analysis where circuits changed for elevated filter pressure or access malfunction were no longer censored for log-rank analysis. Circuits receiving hepACG or citACG demonstrated similar survival times.

 
We also analysed circuit survival as a function of access size, since, conceivably, smaller access size may predispose to circuit clotting as a result of smaller intraluminal calibre. Log-rank analysis demonstrates no difference in filter survival for circuits with different access sizes (Figure 4), an observation that held true for circuits receiving either hepACG or citACG.



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Fig. 4. Analysis of circuit survival as a function of access size; smaller access size may predispose to circuit clotting as a result of smaller intraluminal calibre. A variety of catheter sizes are present ranging from 7 french up to 12 french. Log-rank analysis demonstrates no difference in filter survival for circuits with different access sizes, an observation that held true for circuits receiving either hepACG or citACG.

 
Heparin rates, ACT sampling and circuit survival
Mean heparin rates administered were 13.7±7.1 U/kg/h (median 11.1, range 3.8–28.2) and mean ACT sampling rates were 1.4±0.7 samples/h (median 1.2, range 0.4–1.4). Circuit survival was not associated with heparin administration rates, ACT sampling rates or number of ACT values <180 s.

CRRT machine/membrane type, centre and circuit survival
Five centres used the PRISMA® (Gambro Renal Products), one centre used a BM-25® (Baxter Corporation) and one centre used a Diapact® (Braun) CRRT machine during the course of the study. The filling volume for paediatric lines depending on CRRT machine utilized on average was ~100 ml depending on the choice of filter. Blood priming was utilized if the line/filter extracorporeal volume was >10% of the patient's body weight. For larger ‘adult size’ children, appropriate adult lines were employed. The PRISMA® offers the choice of three different filter/line combinations (the AN69-M60, M100 and the polysulfone HF1000), with the M60 utilized in the smallest patients. The BM-25® and Diapact® allow for more independent filter choices which were determined by the centres employing these machines (polysulfone membranes for the BM-25 centre and PAN membranes for the Diapact centre). The filter choice was determined on the basis of patient size. To control for CRRT machine brand in ACG method comparison, we analysed circuit survival with each ACG method in PRISMA® circuits only. In PRISMA® circuits, hepACG and citACG demonstrated similar survival (76% of hepACG vs 70% of citACG circuits surviving 60 h, P = 0.08), but still had significantly longer survival than noACG circuits (Figure 5). No inter-centre circuit survival difference was noted, even for those centres that switched from hepACG to citACG during the study.



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Fig. 5. Comparison of CRRT circuit life with: no anticoagulation (filled squares), heparin anticoagulation (filled circles) or citrate anticoagulation (filled triangles) for only the PRISMA® circuits. HepACG and citACG demonstrated similar survival (76% of hepACG vs 70% citACG circuits surviving 60 h, P = 0.08), but still had significantly longer survival than noACG circuits. Circuits were censored for Kaplan–Meier analysis if changed because of a scheduled change as per the manufacturer's recommendations, access malfunction, machine malfunction or unrelated patient issues.

 
Complications
Nine patients with hepACG had evidence of systemic bleeding including epistaxis, intracranial, pulmonary, gastrointestinal, bladder and vaginal haemorrhage, which resulted in hepACG discontinuation in four patients. One patient developed HIT, which led to hepACG discontinuation. This patient was subsequently managed with noACG. Four patients with citACG developed alkalosis, which was managed by decreasing the Normocarb® rate by 25% and adding normal saline as replacement fluid to replace the decreased Normocarb® clearance. Two patients with hepatic failure demonstrated signs of citrate lock, defined as elevated serum total calcium level but low serum ionized calcium level resulting from decreased citrate metabolism leading to a citrate buffering of free calcium. Citrate lock was managed by a 4 h discontinuation of ACD-A infusion followed by restarting ACD-A at 50% of the previous rate. The citACG complications were evenly spread between each of the three centres that employed citACG at some point during the study.



   Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Optimal CRRT circuit functioning depends upon safe and reliable circuit ACG. Not surprisingly, our data demonstrate significantly longer CRRT circuit survival with hepACG or citACG vs noACG. Thus, comparison of different ACG methods with respect to both patient outcome and circuit functional life span is an important area of study. However, while a previous small adult study found that citACG led to longer filter life span compared with hepACG, patients with coagulopathy or at high risk of bleeding were excluded from analysis. To our knowledge, our study is the largest conducted to date and examines the potential side effects of all ACG methods for the entire spectrum of patients who require CRRT.

From our data, it is clear that the noACG method of delivering CRRT results in frequent filter loss. In addition, over time, it may become cost-ineffective due to the greater number of filters required to deliver therapy. With the advent of an easily implemented, safe and reliable alternative in the form of citACG, the use of noACG due to potential bleeding complication associated with hepACG should be revisited by programmes employing such techniques.

No significant difference was noted between the hepACG and citACG in terms of clotting rates and filter life span. However, a variety of life-threatening bleeding complications was noted in the hepACG group, some of which led to discontinuation of hepACG and resultant increased risk of circuit clotting. Patients receiving CRRT with citACG developed some well-recognized metabolic complications (citrate lock, alkalosis and hyperglycaemia) [7,12,13] all of which were readily remedied by mild prescription modifications, and no life-threatening complications were apparent.

While our study suggests that there is no ACG method which can be considered optimal at this point in time, clinicians employ hepACG frequently because of their familiarity with systemic heparinization in patients receiving maintenance haemodialysis, relatively low cost, general effectiveness and ease of delivery with current solutions available for FRF or dialysate [1]. However, potential complications including HIT, systemic ACG with resultant patient bleeding in critically ill patients [6] and monitoring (ACT or PT/PTT) cost create significant disadvantages for hepACG. While some have advocated the use of protamine as a reversal agent for heparin [10] (delivered on the venous return to the patient), differential filter clearance properties and metabolism of heparin and protamine place the patient at risk for prolonged ACG and irreversible bleeding risk [14].

CitACG has been utilized in many adult programmes based on its fundamental properties of regional ACG, as it is fully reversible by calcium administration [15]. Monitoring is fast and cost effective as ionized measurement of calcium is available with most blood gases [8]. Potential issues that plague citACG include administration complexity due to the customized solutions required for its implementation in many protocols, metabolic alkalosis (or acidosis in patients with hepatic failure), and the requirement for triple lumen access or separate central access in the paediatric population [16]. More recently, the ‘citrate lock phenomenon’ has been described which can result in excessively high serum calcium levels [7]. While these issues remain of concern, a variety of techniques have been adapted in order to address them. Most notable has been the advent of easy protocols in order to implement citACG with standard commercially available FDA-approved solutions including ACD-A citrate and Normocarb® [7,8]. This has resulted in a decreased requirement for pharmacy-based solutions, a significant improvement in ease at delivering bedside care from a nursing perspective and a true establishment of regional circuit ACG. Finally, the use of citACG may provide a substantial cost saving to programmes offering CRRT therapies. A recently published large single centre analysis in 209 adults by Morgera et al. [17] found a significantly improved filter life span when using citACG vs hepACG. In their study, regional ACG with trisodium citrate in combination with a customized calcium-free dialysate was utilized in comparison with a standard heparin protocol. CitACG was the sole anticoagulant in 37 patients, 87 patients received low-dose heparin plus citrate, and 85 patients received only hepACG. Both groups receiving citACG had prolonged filter life when compared with the hepACG group. Their complications included metabolic alkalosis (50% of patients on citACG), alkalosis (resolved by increasing the dialysate flow rate) and hypercalcaemia. This study also demonstrated a significant cost saving due to prolonged filter life when using citACG.

The current analysis represents the largest multi-centre evaluation of CRRT ACG methods to date. While the standard hepACG and citACG methods studied in the ppCRRT led to similar filter life spans and were superior to noACG, our data suggest that citACG may result in fewer life-threatening complications. Our findings have relevance to both the adult and paediatric populations as very similar ACG techniques are utilized. Additionally, the reduction of life-threatening complications with citACG makes it an attractive option for both patient populations. The availability of simple citrate protocols is a relatively recent phenomenon, and several of our centres transitioned recently from hepACG to citACG. Thus, the potential for a centre effect exists. We suggest that as experience with citACG increases, we may observe a concomitant improvement of filter life span in the future when we revisit our data over the next several years. As the simplicity of citACG protocols improves, so should their wide applicability to both the adult and paediatric populations.



   Acknowledgments
 
The efforts of Gloria Morrison, RN University of Alabama, Birmingham, Alabama and Theresa Mottes, RN C. S. Mott Children's Hospital Ann Arbor, Michigan were paramount in our data collection. The ppCRRT Registry Group received unrestricted grant funding from Gambro Renal Products, Dialysis Solutions Incorporated and Baxter Healthcare.

Conflict of interest statement. None declared.



   References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

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Received for publication: 3. 8.04
Accepted in revised form: 10. 3.05





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