Automated regional citrate anticoagulation system based on individualized dosing models in nonliver failure patients undergoing PIRRT therapy

Abstract

Introduction

Regional citrate anticoagulation is a preferred option for renal replacement therapy in critically ill patients. However, current implementations ignore individual differences that may exist in the fluctuation of patients’ ionized calcium levels. To address this problem, individualized citrate and calcium supplementation models were established based on the pharmacokinetic and clearance characteristics of citrate, and an automated regional citrate anticoagulation system was built with these models as its core to facilitate the treatment of clinical patients. This study was designed to preliminarily evaluate the safety and efficacy of this system, the SuperbMed^® RCA-SP100 automated regional citrate anticoagulation system, in prolonged intermittent renal replacement therapy.

Methods

Seven patients undergoing prolonged intermittent renal replacement therapy completed treatment with the SuperbMed^® RCA-SP100 system. In vivo and in vitro ionized calcium levels were measured every hour before and after the start of dialysis. The accuracy and alarm sensitivity of the pumps were also monitored.

Results

During seven treatments, the average extracorporeal ionized calcium level was 0.34 ± 0.02 mmol/L, and the mean ionized calcium level in vivo was 1.09 ± 0.07 mmol/L. No patient required intervention, and there was no filter coagulation. The pumps all had an absolute accuracy less than 5%, and alarms could be triggered precisely.

Conclusions

We reported on an automated system that allows for individualized citrate and calcium supplementation in prolonged intermittent renal replacement therapy and enables the precise and secure implementation of regional citrate anticoagulation.

Introduction

It is well established that regional citrate anticoagulation (RCA) is the preferred option for renal replacement therapy in critically ill patients, especially those with a very high risk of bleeding. Compared to systemic heparin anticoagulation, RCA not only reduces the risk of bleeding but also effectively prolongs filter life [1,2]. The implementation of RCA is now relatively mature, and many continuous renal replacement therapy (CRRT) machines have introduced RCA modules, such as Fresenius’ Ci-Ca and Campbell’s Prismaflex [3,4]. However, these methods have certain limitations in their use and also ignore individual patient differences. For example, patient’s dialysate and replacement fluid flow need to be proportional to blood flow, and many patients are prone to significant hypocalcemia at blood flows ≥180 mL/min in CRRT. Therefore, there is a need for personalized citrate and calcium dosing for use in RCA. Our group developed and validated a series of citrate and calcium supplementation models for different hemodialysis modalities based on citrate and calcium pharmacokinetics and metabolism patterns [5–9]. An automated citrate anticoagulation system was also developed with these models as the core, expanding the scope of RCA application and improving the safety and efficacy of RCA [10]. Since prolonged intermittent renal replacement therapy (PIRRT) is widely used in China, we first used this system in a PIRRT population and now report the results.

Methods

SuperbMed ^® RCA-SP100 system

This instrument consists of two modules: the citrate module on the left and the calcium module on the right. A touch screen is located in the middle. Each module contains a peristaltic pump, bubble sensor, level pot, and pinch valve (Figure 1). The infusers of the citrate and calcium pumps are connected to the arterial and venous ends of the patient’s extracorporeal circulation, respectively (Figures 2–3). The patient’s weight, hematocrit, bilirubin level, albumin level, blood flow, dialysate and replacement fluid flow, and ultrafiltration volume are displayed on the screen (Figure 4), and the system automatically calculates and replenishes the patient’s required dose of citrate and calcium gluconate after these indicators are entered. The dosages are all individualized, based on the biochemical and dialysis parameters of the patients mentioned above, using algorithms that have been published elsewhere [5–10]. Briefly, the citrate dose is calculated from the patient’s plasma flow rather than blood flow. Calcium supplementation, on the other hand, is divided into two distinct phases, with supplementation of both dialysis-cleared calcium and citrate-chelated calcium in vivo in the first phase and supplementation of only in vitro-cleared calcium in the second phase, when the citrate concentration has stabilized. The core algorithms of the RCA-SP100 system were developed and patented by Shanghai Ninth People’s Hospital, and the machine was manufactured by Shanghai Superb Medical Technology Company. The images shown above have been licensed by the company.

Figure 1.

Components of the SuperbMed ® RCA-SP100 automated RCA system.

Figure 2.

SuperbMed ® RCA-SP100 system in use.

Figure 3.

The connection of SuperbMed ® RCA-SP100 system to extracorporeal circulation and sampling points.

Figure 4.

The screen of SuperbMed ® RCA-SP100 system.

Patients

Seven critically ill patients requiring PIRRT from December 2021 to February 2022 were enrolled in the study at the Department of Nephrology, Shanghai Ninth People’s Hospital. Patients with liver failure or significant metabolic acidosis or alkalosis were excluded. The study was conducted in accordance with the Helsinki guidelines and approved by the ethics committee of Shanghai Ninth People’s Hospital (approval No.: SH9H-2021-T370-2). Written informed consent was obtained from all enrolled patients.

PIRRT parameters

PIRRT was performed using the Aquarius machine (Edwards Lifesciences LLC, Irvine, CA, USA) and Renaflo II-HF 1200 dialyzer (surface area of 1.25m2, Medivators Inc., Minneapolis, MN, USA) in the postdilution continuous venovenous hemodiafiltration (CVVHDF) mode selection. Patients received a blood flow of 200 mL/min, and the dialysate and replacement fluid flow were both set at 2 L/h. A bicarbonate buffered solution that contained 135 mmol/L of Na⁺, 2.2 mmol/L of K⁺, 114 mmol/L of Cl^-, 0.77 mmol/L of Mg²⁺, 13 mmol/L of dextrose, and 25 mmol/L of bicarbonate was used for the dialysate and substitution fluid. The length of PIRRT was six hours.

Supplementation with 4% sodium citrate at the beginning of the extracorporeal circuit and 2% calcium gluconate at the end of the venous circuit was performed. Prior to initiating PIRRT, the patient’s weight, laboratory test results (including albumin and hematocrit levels), and dialysis parameters (e.g., blood flow, dialysate/replacement fluid flow, and ultrafiltration rate) were entered into the RCA system, which then automatically calculated the patient’s individualized citrate and calcium doses required for the procedure. To ensure effective anticoagulation and patient safety during PIRRT, the dose of citrate or calcium was adjusted promptly if the patient’s ionized calcium level fell below 0.95 mmol/L or rose above 1.35 mmol/L in vivo and the extracorporeal ionized calcium level was below 0.25 mmol/L or above 0.4 mmol/L. The effects of the modifications were assessed by conducting a retest half an hour after implementing the adjustments.

Data collection

In the study, hematocrit, alanine aminotransferase, aspartate aminotransferase (AST), bilirubin, albumin, blood urea nitrogen, serum creatinine (Scr), and serum total calcium levels were measured using routine laboratory procedures at Shanghai Ninth People’s Hospital. Ionized calcium levels both in vivo and in vitro were measured using an i-STAT 300 analyzer (Abbott Laboratories, Abbott Park, IL, USA) before and every hour after the start of PIRRT.

First, we calibrated a precision balance, which was used to assess the accuracy of the infusion pump. The density of the citrate and calcium gluconate solutions was measured using the balance and a measuring cylinder before the treatment began, and the difference in weight between the citrate and calcium gluconate solutions before and after the treatment was recorded so that the actual volume used could be calculated from the ratio of weight to density and then compared with the therapeutic dosage displayed on the device.

Statistics

The normally distributed data were presented using the mean and standard deviation. Statistical analysis was performed using SPSS 21.0 (SPSS Inc., Chicago, IL, USA).

Results

The baseline characteristics of all patients are shown in Table 1. The patients had a mean age of 53 ± 12 years, and four of seven were female. The mean hemoglobin level was 111 ± 14 g/L, and the mean hematocrit level was 34.5 ± 4.7%. Liver function parameters, including alanine aminotransferase, aspartate aminotransferase, and total bilirubin levels, were normal in all patients. The mean total calcium value was 2.3 ± 0.2 mmol/L.

Table 1.

Baseline characteristics.

Characteristics	All patients
Age, year	53 ± 12
Weight, kg	66.5 ± 11.2
Hemoglobin, g/L	111 ± 14
Hematocrit, %	34.5 ± 4.7
ALT, U/L	11 ± 8
AST, U/L	14 ± 5
Albumin, g/L	39 ± 4
Bilirubin, mmol/L	8.4 ± 1.3
BUN, mmol/l	31.5 ± 3.4
Scr, umol/L	1028 ± 256
Serum total calcium, mmol/L	2.3 ± 0.2
Mg, mmol/L	1.1 ± 0.2
APACHEII score	14.9 ± 3.8

ALT: alanine aminotransferase; AST: aspartate aminotransferase; BUN: blood urea nitrogen; Mg: serum magnesium; Scr: serum creatinine.

In seven cases of PIRRT, a total of 14 tests were performed to determine the absolute accuracy of both infusion pumps. The pumps had an average absolute accuracy of 1.33 ± 1.15%, and all had an absolute accuracy of less than 5%.

During 42 h of treatment in the seven cases of PIRRT, the average extracorporeal ionized calcium was 0.34 ± 0.02 mmol/L, remaining within the ideal range of 0.25–0.35 mmol/L for 32 h, which accounted for 76% of the total treatment time. The mean ionized calcium level in vivo was 1.09 ± 0.07 mmol/L. The level remained within the ideal range of 1.05–1.25 mmol/L for 31 h, which accounted for 74% of the total treatment duration (Figure 5). No patients required additional dose adjustments, and no filter coagulation and no side effects (e.g., muscle cramps) were reported during the seven PIRRT sessions. The patients’ pH, bicarbonate, and base excess were slightly elevated, and sodium levels were stable during PIRRT (Figure 6).

Figure 5.

The mean ionized calcium values in vivo (A) and in vitro (B) of 7 patients during RCA-PIRRT. The red dashed lines indicated intervention levels.

Figure 6.

The mean PH (a), bicarbonate (B), base excess (C) and Na⁺ (D) values during RCA-PIRRT.

During the experiment, the alarm was triggered twice. The first time was due to an air bubble in the pipeline detected by the citrate pump, and the second time was due to the out-of-range infusion system caused by the abnormal operation of the CRRT machine. The alarm sensitivity rate was 100%, and there were no false alarms. The infusion proceeded without any abnormal stoppages, pump speed anomalies, or operational problems.

Discussion

PIRRT is a hybrid renal replacement therapy between CRRT and intermittent hemodialysis (IHD) that has a longer treatment time than IHD and a higher blood and dialysate flow than CRRT [11]. In China, it is very common to perform flexible and cost-effective PIRRT in hemodynamically unstable critically ill patients with acute kidney injury (AKI) or end-stage renal disease (ESRD). Particularly during the COVID-19 pandemic, PIRRT significantly reduced the mismatch between patient needs and medical resources. RCA is also recommended for PIRRT when a CRRT machine is used, despite the lack of evidence-based medical evidence [11]. When using the CRRT’s own RCA module, the dose of citrate and calcium are proportional to the patient’s blood flow and effluent flow, which ignores individual differences, and a significant decrease in calcium level is observed in the first three hours in vivo, especially when blood flow is higher than 180 mL/min. The dialysis modality is also limited, and certain settings for blood and dialysate flow rates may not meet all clinical needs. These shortcomings are even more apparent with the use of CRRT machines for PIRRT, which results in fluctuations in calcium levels both in vitro and in vivo, requiring close monitoring for adjustments at any time [3,12,13].

We believed that calculating the required dose of citrate and calcium based on individual patient differences could improve the stability of blood calcium levels. We first explored the kinetics of citrate metabolism in critically ill patients in vivo, combined with clearance in vitro, and successively modeled citrate and calcium dose calculations in different CRRT modalities [5–9]. Their models incorporated the patient’s body weight, hematocrit, and albumin levels, as well as the patient’s dialysis parameters. For ease of use, an automated system was built with these core algorithms, including a visualization interface and high-precision infusion pumps. The SuperbMed^® RCA-SP100 system has no limitations in terms of dialysis machine type, dialysis mode, blood flow rate, and replacement fluid/dialysate flow rate. Besides PIRRT, it can be used with other commonly used clinical dialysis modes, such as CRRT and IHD, as well as with patients with hepatic insufficiency theoretically, covering the various needs of patients. In this small-sample study, we preliminarily demonstrated that RCA treatment with PIRRT using the SuperbMed^® RCA-SP100 system was effective in maintaining stable ionized calcium levels in patients. This is an improvement on the current technique of RCA.

This study has several limitations. It is unclear whether the in vivo pharmacokinetics of citrate established in AKI patients can be applied to ESRD patients. Additionally, the patients in this study had significantly higher blood flow than those undergoing CRRT. The anticoagulant effect of an in vitro ionized calcium level of 0.3–0.35 mmol/l at low flow rates and its impact on filter life require further observation. Although this system has no limitations related to the dialysis modality, further research is required to determine whether it can cover patients with different conditions or even liver failure. In addition, this study is limited by its small sample size and single-center design, and subsequent randomized controls are necessary to validate the results. The acid-base metabolism of the patient, as well as any changes in electrolytes and citrate accumulation, should be studied concurrently.

Conclusion

In this study, we reported on an automated system that allows for individualized citrate and calcium supplementation based on patients’ dialysis parameters and biochemical indices, confirming through a small-sample study that it worked well in a PIRRT population, enabling safe and effective RCA therapy.

Authorship contribution

QZ: conceptualization, investigation, data curation, formal analysis, writing the original draft. DD: investigation, writing the original draft. CW: investigation. JL: investigation. QZ: investigation. FD: conceptualization, investigation, project administration, supervision, writing – review and editing.

Statement of ethics

The study was conducted in accordance with the Helsinki guidelines and approved by the ethics committee of Shanghai Ninth People’s Hospital (approval No.: SH9H-2021-T370-2). Written informed consent was obtained from all enrolled patients.

Funding Statement

This study was supported by Biomaterials and Regenerative Medicine Institute Cooperative Research Project, Shanghai Jiaotong University School of Medicine (2022LHB01), fundamental research program funding of the Ninth People’s Hospital, affiliated with the Shanghai Jiao Tong University School of Medicine (JYZZ174), National Natural Science Foundation of China (81870462), Huangpu District Industrial Fund Randomized, Controlled, Multi Center Clinical Validation of Automated Regional Citrate Anticoagulantion (XK2020002).

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The authors confirm that data supporting the findings of this case study report are available within the article and or supplementary materials included.