Introduction: The use of anticoagulants during continuous renal replacement therapy (CRRT) is essential. Regional citrate anticoagulation (RCA) is recommended rather than systemic heparinization to prolong the filter’s lifespan in patients at high risk of bleeding. However, commercial citrate is expensive and may not be available in resource-limited areas. The objective of this study is comparing filter life between our locally made customized RCA and no anticoagulation. The primary outcomes were the first circuit life in hours and the number of filters used within the first 72 h of therapy. Methods: We conducted a single-center prospective randomized controlled trial in critically ill patients requiring CRRT. The participants were randomized to receive continuous venovenous hemofiltration (CVVH) with either customized RCA or no anticoagulant. Results: Of 76 patients, 38 were randomized to receive customized RCA and 38 to receive CVVH without anticoagulant. There was no significant difference in baseline characteristics between the two groups. Compared to anticoagulant-free group, the median circuit life of customized RCA group was significantly longer [44.9 (20.0, 72.0) vs. 14.3 (7.0, 22.0) hours; p < 0.001]. The number of filters used within 72 h was significant lower [2.0 (1.0, 2.0) vs. 2.5 (1.0, 3.0); p < 0.015]. RCA was prematurely discontinued in 5 patients due to citrate accumulation (2 cases) and severe metabolic acidosis requiring higher dose of CVVH (3 cases). No differences in bleeding complications were observed (p = 0.99). Conclusion: Customized citrate-based replacement solution improved filter survival in CVVH compared to anticoagulant-free strategy. This regimen is safe, feasible, and suitable for low- to middle-income countries.

© 2023 The Author(s). Published by S. Karger AG, Basel

Introduction

Continuous renal replacement therapy (CRRT) is increasingly used in the intensive care unit (ICU) [1]. The major disadvantage is the necessity of continuous anticoagulation for patency and function of the extracorporeal circuit [2, 3]. Current guidelines recommended using regional citrate anticoagulation (RCA) as the first-line anticoagulant for patients at high risk of bleeding or a contraindication to heparin [4]. Nonetheless, RCA is not common used in some centers including our institute and some critically ill patients have RRT without any anticoagulant, resulting in premature circuit clotting and the need for frequent filter changes [5-8]. Moreover, citrate can accumulate and cause metabolic alkalosis, citrate toxicity and hypocalcemia, especially in liver failure [9].

Recently, several studies have demonstrated the effectiveness of RCA in CRRT [10-13]. Several randomized controlled trials (RCTs) comparing citrate with heparin treatment in critically ill patients found that RCA was associated with longer or similar circuit life, less bleeding and fewer transfusions [14-16]. However, most studies used commercial citrate solutions which are costly and may not be available in some countries. This results in limited usage of RCA in low to middle-income countries, including Thailand. A customized RCA solution can be made by ICU nurses or pharmacists mixing hypertonic trisodium citrate solution with a hypotonic replacement solution, which is much cheaper than commercial citrate solution. Moreover, the application of customized RCA may be feasible and suitable for resource limited areas. However, the efficacy and safety of customized RCA are important considerations. Accordingly, we conducted a prospective RCT in critically ill patients with acute kidney injury (AKI) treated with CRRT to compare customized citrate-based replacement solution and anticoagulant-free treatment.

Materials and MethodsStudy Design

This is a prospective RCT conducted at the medical intensive care units of Siriraj Hospital, affiliated with Mahidol University in Bangkok, Thailand. The trial was retrospectively registered in the Thai Clinical Trials Registry (TCTR) on September 24th, 2021.

Patients

All patients with AKI aged >18 years, with or without contraindication for systemic coagulation admitted to our Medical ICU who fulfilled at least one of the following criteria for initiating CRRT were enrolled: (1). refractory volume overload, (2). refractory hyperkalemia, (3). uremic symptom, and (4). refractory metabolic acidosis. Patients with the following conditions were excluded: need for systemic anticoagulation, chronic renal replacement therapy, pregnancy, breastfeeding, severe acute liver failure or waiting list for liver transplantation, serum Na >160 mEq/L or serum HCO3 >40 mEq/L or pH > 7.5, uncontrolled bleeding, persistent symptomatic hypocalcemia or total calcium (tCa): ionized calcium (iCa) ratio >2.5, no informed and signed consent for this trial, and previous allergic reaction to citrate.

Study Protocol

After enrollment, patients were randomly assigned in a 1:1 ratio to receive no anticoagulation or customized RCA for continuous venovenous hemofiltration (CVVH) by block of four randomizations. The random allocation sequence is generated by using sequentially numbered opaque envelops that contain a study allocation and was done by the statistician by means of a computer randomization on those who did not take part in the study and then sealed opaque envelops will be used to allocate eligible patients. Vascular access was applied by inserting an 11.5-Fr double lumen catheter into the jugular (Medcomp®, Harleysville, PA, USA) or femoral vein. CVVH was carried out using a CRRT machine (Prismaflex®, Baxter, Lund, Sweden, or Aquarius® System, Nikkiso, Tokyo, Japan). We used either an M100 for Prismaflex® or an HF12, Nikkiso, Tokyo, Japan, for AquariusTM hemofilter. Filters were routinely changed after 72 h. Laboratory measurements included pH, acid-base balance, blood urea nitrogen, creatinine, electrolytes, magnesium, phosphorous, tCa, iCa, liver test, complete blood counts, and coagulogram before CVVH initiation and then measured daily for 3 days.

In the group receiving no anticoagulation, a custom-made 2-bag formula of bicarbonate-based replacement fluid or commercial replacement fluid (Accusol-35®, Nikkiso) was used. The blood flow rate was set at 150–200 mL/min. Replacement solutions were delivered prefilter, postfilter, or both with a pre- and postfilter replacement fluid ratio of 50%. The replacement solution was run at a rate of 1,000–3,000 mL/h according to the patient’s needs to meet the target RRT delivery dose of 20–25 mL/kg/h [6].

In the customized RCA group, the custom-made calcium-free trisodium citrate replacement fluid was supplied by the hospital pharmacy and mixed by ICU nurses. The final composition of the citrate replacement fluids is shown in eTable 1 in the online supplementary material (for all online suppl. material, see www.karger.com/doi/10.1159/000529076). This citrate-based replacement solution acts as an anticoagulant and buffer in the predilution technique (eFig. 1). Potassium chloride and 50% magnesium sulfate (MgSO4) were added as needed in replacement fluid.

The infusion rate of the citrate-based replacement solution was continuously coupled to the blood flow rate according to the patients’ weight range to keep constant citrate concentrations in the extracorporeal circuit. In the patients who received regional citrate, if the systemic iCa level before CVVH initiation was less than 4.01 mg/dL (1 mmol/L), 20 mL of 10% calcium gluconate was administered intravenously, and a calcium infusion protocol was started as shown in eFigure 1 and eTable 2. Calcium administration was adapted to concentrations of systemic iCa by a designed algorithm, targeting systemic iCa levels of 4.01–4.81 mg/dL (1.0–1.2 mmol/L) (eTable 3). The circuit iCa was not measured in order to simplify the protocol.

The pH, anion gap, tCa, iCa, and their ratios were monitored in the citrate group. The first measurement of iCa was done after initiation of CVVH for 1 h and followed-up every 2–6 h, as shown in eTable 3. Citrate accumulation was diagnosed if the patients fulfilled one or more of the following criteria: ratio of tCa to iCa greater than 2.5, clinical signs of hypocalcemia (tetanic symptoms or prolonged QT interval not explained by other medications), progressive acidosis (pH < 7.20) with an increased anion gap (>13 mmol/L) in the presumed absence of anions other than citrate, or persistent metabolic alkalosis with a base excess of more than 10 mmol/L. If there were signs of citrate accumulation, CVVH was continued with no anticoagulation. Crossover between the study arms could be done according to clinical needs at the discretion of the treating physicians.

Data Collection

Demographic data and clinical information were obtained at baseline. Severity of illness and organ failure were scored using the Acute Physiology and Chronic Health Evaluation II (APACHE II) and the Sequential Organ Failure Assessment (SOFA) on the day of CVVH initiation (day 0). The etiology of AKI was assessed by the treating physician.

Outcomes

The primary outcome of the study was the survival time in hours of the first filter (1st circuit lifespan) and the number of filters used within the first 72 h of therapy. Clotting as a reason for filter termination was defined as spontaneous clotting or a persistently high trans-membrane pressure (>200–250 mm Hg) prohibiting the continuation of CVVH [17]. Secondary outcomes included mortality at 14 and 28 days after initiation of CVVH, renal recovery, and safety of treatment which was defined as the absence of any adverse event necessitating discontinuation of RCA, such as citrate accumulation and any bleeding complications. Renal recovery was defined as urine output >30 mL/h and successful discontinuation of renal replacement therapy (RRT) in surviving patients [18].

Statistical Analysis

We hypothesized that the circuit lifespan for patients with citrate anticoagulant would increase by 20%, as compared to that of patients on no anticoagulant, based on an estimated circuit lifespan of 20.4 ± 3.1 h [7]. With the power of the study set at 80% (type II error 0.20) and 5% significance (type I error 0.05), the sample size calculation required 37 patients per group. Fifty cases per group were targeted to compensate for an anticipated 30% dropout rate. Prespecified interim analysis was done after 50% and 75% of patients had been recruited.

Categorical variables were presented as number and percentage, and continuous variables were presented with mean ± SD or median and interquartile range (IQR) as appropriate. The Student’s t test and Mann-Whitney U-test were used for comparison among continuous variables, and the χ2 test or Fisher’s exact test was used for comparisons among categorical variables. For the primary outcome (filter lifespan), survival analysis was assessed with Kaplan-Meier curves and groups were compared by log-rank test. Analyses were conducted on an intention-to-treat basis. A two-sided p value <0.05 was considered significant. All data analyses were performed using SPSS statistics version 20 (SPSS Inc., Chicago, IL).

Results

The study was conducted between March 2018 to November 2020, 76 patients were enrolled and randomized to the customized citrate (n = 38) or anticoagulant-free (n = 38), as shown in Figure 1. Recruitment was stopped on November 30, 2020, according to an interim analysis that showed the customized RCA group had a significantly longer filter lifespan than the anticoagulant-free group. Baseline characteristics were not statistically different between the two groups included age, comorbidities, reason for ICU admission, used of mechanical ventilator, used of vasopressors, cause of AKI, and indication for RRT. Overall, the patients had the mean age of 61.3 years and an APACHE II mean score of 26.6. Almost all patients (94.7%) were admitted to the ICU because of sepsis/septic shock, and most patients required vasopressor (84%) and mechanical ventilator (93%), as shown in Table 1. Metabolic acidosis was the most common indication for CRRT with mean pH of 7.3, and there was no difference in platelet count and degree of coagulopathy between the groups (Table 2).

Table 1.

Baseline characteristics of the patients at baseline

Table 2.

Baseline laboratory variables in the two treatment groups

Fig. 1.

Flow diagram of the study.

Primary Outcomes

Filter lifespan in the customized RCA group was significantly longer than that in the anticoagulant-free group (median, 44.9 h [IQR, 20.0, 72.0 h] versus 14.3 h [IQR, 7.0, 22.0 h]; p < 0.001) (Table 3). The Kaplan-Meier curve also demonstrated a longer survival time for the first filter in the customized RCA group (p < 0.001) (Fig. 2). Fewer filters were used within 72 h in the customized RCA group compared to the anticoagulant-free group (median, 2.0 [IQR, 1.0, 2.0] versus median, 2.5 [IQR, 2.0, 3.0; p = 0.015). The rate of circuit changes due to filter clotting was significantly higher in the anticoagulant-free group (71.1% vs. 28.9%, p = 0.016) (Table 3).

Table 3.

Primary and secondary outcomes of the study

Fig. 2.

Kaplan-Meier curve for filter life of filter lifespan in CVVH with and without customized regional citrate anticoagulation (RCA). The figure shows the survival curve for the first filter file expressed in hours between customized RCA and anticoagulation-free group.

Secondary Outcomes

There was no significant difference in secondary outcomes between the customized RCA and the anticoagulant-free group, including renal recovery (36.8% vs. 34.2%, p = 0.811) length of ICU stay (14.0 days [IQR, 6.0, 28.0 days] vs. 11.0 days [IQR, 7.0, 15.0 days], p = 0.242), 14-day mortality (23.7% vs. 34.2%, p = 0.312), and 28-day mortality (34.2% vs. 31.6%, p = 0.807). The rate of bleeding complications was not different (2.6% vs. 2.6%), and citrate accumulation occurred in 13.2% of the customized RCA group (Table 3).

DiscussionKey Findings

This analysis of critically ill patients with severe AKI requiring CRRT found that predilution CVVH with custom-made RCA provided a better filter life and fewer filters used within the first 72 h of CRRT initiation without an increased risk of bleeding. There was no difference in mortality at day 14 and 28, or the renal recovery rate. However, some patients developed citrate accumulation.

Relationship with Previous Studies

Our findings are in line with the Kidney Disease Improving Global Outcomes (KIDIGO) guidelines for use of RCA in the management of AKI in the critically ill [6]. Moreover, the median filter lifespan of the RCA group in our study is comparable with other studies [4, 14-16], and our patients had higher illness severity, indicated by a high mean APACHE II score of 26.5, higher percentage of vasopressor requirement (84%), and mechanical ventilator requirement (93%), as shown in eTable 4. The largest, recent RCT of regional citrate versus systemic heparin anticoagulation for CRRT in critically ill patients with AKI (RICH) confirmed the benefit of CRRT with RCA for longer filter survival [16]. The median filter lifespan in the RCA group of the RICH trail was 46.5 h (IQR, 18.8, 70.3), which is similar to our study. However, almost all of our participants were sepsis patients (72/76; 95%) that are at increased risk of bleeding compared to the cardiac surgery patients (75–85%) in the RICH study [16]. Moreover, the RCA group of the RICH trial performed CRRT with different commercial solutions, while our RCA group received a customized citrate solution formulated by hospital pharmacists and ICU nurses that is simple, fast, and safe. Moreover, it is much cheaper, and this practice may be transferrable to other low- and middle-income countries, although citrate is more expensive than no anticoagulation. However, by increasing circuit life, there is a relative cost saving compared to the cost of filter. Our customized RCA solution costs 72 THB per liter (approximately 2 US dollars per liter), compared with 300 THB per liter (approximately 9 US dollars per liter) for commercial citrate solutions. The RICH study reported a higher rate of infection in patients receiving RCA. However, in our study, only one patient in the RCA group experienced a new infection.

The circuit survival of 14 h in the anticoagulation-free group (control) in our study was lower than that of the control groups of other studies (26–33 h) using systemic heparinization [14-16]. We chose CVVH without anticoagulant as control because almost all of our critically ill patients had a relative contraindication for heparinization such as low platelet count or coagulopathy. However, the median circuit lifespan of our control group was not different to the findings reported by Nurmohamed et al. [4] who demonstrated a median filter life of anticoagulant-free CRRT of 12 h.

There was no statistical difference in bleeding complications, and patients rarely had a new infection. Thus, customized RCA in CVVH was safe to use in critically ill patients. However, we reported that citrate accumulation occurred in five patients (13.2%), and two of those had progressive liver impairment resulting in crossing over to bicarbonate-based treatment with no anticoagulant treatment. After conversion to bicarbonate-based treatment with no anticoagulant, the total to iCa ratio normalized, and metabolic acidosis improved in all of those patients.

The liver plays a major role in citrate metabolism to produce bicarbonate [19]. Citrate accumulation in our study was slightly higher than in other studies that have reported an incidence of 1–12% [14-16]. This may be because most patients in our study had severe sepsis and septic shock who usually had liver dysfunction and impaired aerobic metabolism contributing to the event. Therefore, patients with severe liver failure or severe metabolic acidosis requiring high dose of vasopressor also affected citrate metabolism [20, 21]. In addition, citrate accumulation is associated with severe hyperlactatemia (>4 mmol/L) due to reduced skeletal muscle mitochondrial function and impaired citrate metabolism [22, 23]. However, Kramer et al. [24] showed that the use of citrate-based anticoagulant in patients with advanced liver cirrhosis was feasible with careful monitoring of citrate accumulation.

Three patients in the customized RCA group were converted to CVVH with no anticoagulant due to severe metabolic acidosis requiring higher dose of CVVH. Because in our protocol the citrate rate was fixed according to body weight to prevent citrate accumulation, these patients may have received an insufficient dose of CVVH. Therefore, in patients with severe metabolic acidosis that require higher doses of CVVH to meet a higher metabolic demand, this replacement fluid protocol might be not applicable.

Clinical Implications

Our finding implied that in critically ill patients with severe AKI treated with CRRT, customized RCA can safely improve circuit and filter life and decrease costs. Moreover, this regional technique can be safely used in patients at high risk of bleeding and is more effective than no anticoagulation. Finally, this technique can be applied in severe sepsis, metabolic acidosis, and severe liver impairment patients. However, there is a potential for citrate accumulation that should be closely monitored.

Strengths and Limitations

This randomized controlled study used a customized RCA as a prefilter replacement fluid in CVVH; a practical and simplified technique compared to other modalities. iCa in extracorporeal circuit (postfilter iCa) was not routinely measured in order to keep the treatment protocol simple. Furthermore, citrate fluid was used as both buffer solution and an anticoagulant. Thus, this protocol is less complex, less costly, and easier to implement.

We acknowledge several limitations. First, this was a single-center study in medical ICUs in a tertiary and referral hospital, which could limit the generalizability of our findings. However, while our patients had high illness severity scores, this technique can be used without any serious adverse complications and is feasible in resource-limited settings. Second, we could not blind the intervention to nursing staff and treating physicians because the packaging of the replacement fluids was different. Moreover, either commercial or customized replacement fluid was used in the no anticoagulant group. Consequently, the unblinded study design may have introduced some bias. Third, the prescription of citrate-based replacement flow rate (dose of RRT) in this study was lower than in other published studies from western countries, resulting in limitations when applied in patients with higher metabolic demands. Nonetheless, RRT dose in our protocol achieved the 20–25 mL/kg/h target recommended in current guidelines. Indeed, either post-dilution replacement or dialyzate fluid could be flexibly added to our protocol as appropriate to meet the metabolic demands of patients. Fourth, the RCA system requires a high degree of measurement accuracy and a reliable supply of iCa, so it should not be used in hospitals where iCa measurement is not available. Fifth, patients at risk for citrate accumulation required close monitoring of the tCa/iCa ratio which increased workload and cost. Finally, there is a possibility of error with custom-made citrate solutions which must be monitored carefully to prevent severe adverse events.

Conclusions

Regional anticoagulation with a customized citrate-based replacement solution improved circuit and filter survival and decreased costs in CVVH compared to an anticoagulant-free strategy. This regimen is safe, feasible, and suitable for low- to middle-income countries.

Acknowledgments

We acknowledge the dedication of the pharmacists, ICU nurses, and physicians who participated in this study. We would like to express our deep gratitude to Suthipol Udompunthurak for statistical analysis, consultation, and correction.

Statement of Ethics

This study was compliant with the Declaration of Helsinki. Written informed consent was obtained for participation in this study, and the study protocol was approved by the Siriraj Institutional Review Board (No. Si 157/2018).

Conflict of Interest Statement

The authors declare that they have no conflict of interest.

Funding Sources

The authors did not receive any research funding.

Author Contributions

Research idea and study design: R.R. and P.P.; data acquisition: P.P., S.K., and R.R.; data analysis/interpretation: all authors; statistical analysis: P.P., S.K., and T.N.; supervision or mentorship: R.R. and T.N. Each author contributed important intellectual content during manuscript drafting or revision, and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work were appropriately investigated and resolved.

Data Availability Statement

All data generated or analyzed during this study are included in this article and its supplementary material files. Further inquiries can be directed to the corresponding author.

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