Abstract
Background
Regional citrate anticoagulation (RCA) is the preferred strategy during continuous renal replacement therapy (CRRT). However, saline flushing is often used when anticoagulants are contraindicated, although its effectiveness remains uncertain. This study evaluated the efficacy of different saline flushing strategies in preventing circuit clotting during anticoagulant-free CRRT in critically ill patients.
Methods
This prospective, three-arm randomized controlled trial included critically ill patients initiating CRRT who had contraindications to anticoagulants. Patients were randomized into three groups: 30-minute flush (200 mL every 30 minutes), 2-hour flush (200 mL every 2 hours), or no flush. The primary outcome was circuit lifespan. The secondary outcomes included the delivered CRRT dose, filtration fraction, nurse satisfaction, length of hospital stay, 28-day mortality, and hypotension incidence within 2 hours of CRRT initiation.
Results
Among 144 randomized patients, 117 (81%) completed the trial: 38 in the 30-minute flush group, 37 in the 2-hour flush group, and 42 in the no-flush group. The mean circuit lifespan was shorter in the 30-minute group (31.03 ± 20.26 h) than in the 2-hour (41.96 ± 18.26 h) and no-flush groups (42.10 ± 19.29 h)(p < 0.05). Significant differences were observed among the 30-minute flush, 2-hour flush, and no-flush groups in terms of delivered CRRT dose (89%, 95% vs. 98%, p < 0.001), filtration fraction (16.14%, 14.05% vs. 13.07%, p < 0.001), and nurse satisfaction (32.26, 62.04 vs. 93.93, p < 0.001). The 30-minute flush group had a higher hypotension incidence within 2 hours of CRRT initiation compared to the no-flush group (71.05% vs. 42.85%, p < 0.017, Bonferroni-adjusted). No significant differences were found in the number of clotting-free patients at 72 hours, hospital stay, or 28-day mortality (p > 0.05).
Conclusions
Frequent saline flushing does not appear to effectively prevent circuit clotting and may be associated with increased hypotension, reduced delivered CRRT dose, higher filtration fraction, and lower nurse satisfaction. These findings suggest that saline flushing should be used cautiously in anticoagulant-free CRRT.
Trial registration
Chinese Clinical Trial Registry:ChiCTR2400080111(01/20/2024).
Keywords: Continuous renal replacement treatment, Saline flushing, Circuit lifespan
Introduction
Continuous renal replacement therapy (CRRT) is a slower, continuous form of dialysis that maintains solute and fluid homeostasis [1]. Anticoagulants are typically required to ensure extracorporeal circuit patency and optimal filter performance [2]. Regional citrate anticoagulation(RCA) is recommended by the 2012 KDIGO AKI guidelines as the first-line anticoagulation for CRRT in patients without contraindications [3]. However, many critically ill patients have contraindications to anticoagulants due to severe liver failure, citrate accumulation or a higher risk of bleeding [4]. According to a global survey, approximately one-third of patients undergoing CRRT do not receive anticoagulants [5]. The KDIGO guidelines recommended CRRT proceed without anticoagulation in patients with contraindication to citrate and increased bleeding risk [3]. However, performing CRRT without anticoagulants poses significant challenges, primarily due to the increased risk of extracorporeal circuit clotting. Circuit clotting can lead to potential blood loss, compromises haemodynamic stability, necessitates frequent circuit changes [6], increases the workload for medical staff, and elevates treatment costs [7].
Saline flushing has been proposed as a simple and safe alternative for reducing clotting in heparin-free CRRT [8]. However, studies on its effectiveness have yielded mixed results. While some suggest that it may help prevent circuit clotting, others associate saline flushing with high rates of clotting events [9, 10]. Additionally, the frequency of saline flushing varies widely across studies, raising questions about its overall efficacy [11, 12]. A systematic review concluded that there is no evidence to support that intermittent saline flushing prolongs filter lifespan [13], and the mechanisms underlying its potential antithrombotic effects remain unproven.
To address these uncertainties, we conducted a prospective, single-center, three-arm randomized clinical trial (RCT) to evaluate the efficacy and safety of saline flushing for preventing circuit clotting during CRRT without anticoagulants.
Methods
Study design and ethics
This single-center, open-label, 3-arm randomized controlled trial was conducted between January 2022 and December 2023. ICU patients meeting the inclusion criteria were randomly assigned to the 30-minute saline flush group, 2-hour saline flush group, or non-saline flush group at a 1:1:1 ratio via a computer-generated randomization sequence. The study was reported in accordance with the Consolidated Standards of Reporting Trials (CONSORT) guidelines.
This study was approved by the Research Ethics Committee in accordance with the Declaration of Helsinki and was registered at the Chinese Clinical Trial Registry (ChiCTR2400080111). Informed consent was obtained from all participants or their guardians prior to randomization.
Patient recruitment
Consent was secured before patient enrollment. Eligible participants received a unique study ID and were allocated to a treatment group.
The inclusion criteria included: (1) Initiation of CRRT for the first time during the ICU stay, (2) Aged between 18 and 70 years, and (3) Clinical indications for anticoagulant-free CRRT contraindications to citrate or systemic anticoagulation.
The exclusion criteria included: (1) Use of any form of systemic anticoagulation (e.g., unfractionated heparin, low molecular weight heparin, direct oral anticoagulants) within 24 hours before enrollment，(2) Hemodynamic instability before CRRT(systolic blood pressure ≤90 mmHg or mean arterial pressure below 60 mmHg), (3) Pregnant, or (4) Scheduled for surgery within 72 hours.
A total of 144 patients were screened for 7 eligibility criteria. Of these, 3 patients did not meet the inclusion criteria and 7 declined to participate. Ultimately, 134 patients were randomized into three study groups. During the study period, 17 patients were withdrawn: 9 due to flushing-related hypotension(saline flushing discontinued but CRRT continued), 5 were discharged within 24 hours, 2 discontinued CRRT due to scheduled surgery or testing, and 1 due to catheter dysfunction. Ultimately, 117 patients completed the study (Fig. 1).
Fig. 1.
Participant flow in the study
Procedures
Nurses skilled in CRRT techniques administered continuous veno-venous hemodiafiltration(CVVHDF) to all participants utilizing the Prismaflex system paired with AN69ST ST150 dialyzers (Baxter International, Inc.). Vascular access was established through the femoral or jugular vein using double-lumen catheters (13 Fr, 250 mm; GDHK-1325, Baxter International Inc., Deerfield, IL, USA). The prescribed dose of 25–35 mL/kg/h was followed, with a flow rate of 2 L/h (dialysate to replacement fluid ratio of 1:1) for critically ill patients. Calcium-containing replacement fluid (Qingshan Likang, Pharmaceutical Co. Ltd.) was used in a pre-post dilution mode (half before the filter and the other half after the filter) [14], with a blood flow rate of 200 mL/min, without anticoagulants.
First, before CRRT, the extracorporeal circuit was flushed with normal saline solution containing heparin, followed by flushing with clean normal saline solution. In all patients undergoing CRRT, the circuit was connected directly to the dual-lumen catheter at both the arterial and venous ends at the start of therapy, after which blood was withdrawn. Patients were randomized into three groups: the 30-minute saline flush group, the 2-hour saline flush group, or the non-saline flush group. The volume of saline infused each hour was included in fluid balance calculations. During saline flush intervals, the CRRT machine was switched to bag-change mode, with the blood pump running at 100 mL/h.
In the 30-minute saline flush group, 200 mL of 0.9% saline was infused into the arterial limb every 30 minutes, with an ultrafiltration rate adjustment of 400 mL per hour. In the 2-hour saline flush group, saline flushing occurred every 2 hours, with an ultrafiltration rate adjustment of 100 mL per hour.
The site of saline flushing is shown in Fig. 2. The extracorporeal circuit were replaced every 72 hours following the manufacturer’s instructions. The participant flow through the study is shown in Fig. 2.
Fig. 2.
The saline flushing site
Sample size
The sample size calculation was based on a preliminary experiment. According to that experiment [15], the mean circuit lifespans in the three groups were 24.4 ± 17.7 hours, 35.3 ± 19.3 hours, and 37.3 ± 18 hours, respectively. Using PASS15.0 with an α value of 0.05 and a power of 80%, it was determined that 111 patients (37 per group) would be needed. To account for a 10% loss to follow-up, the minimum sample size required at baseline was 123 patients (41 per group).
Data collection
Demographic and clinical data were collected at the start of CRRT. Key characteristics, including age, sex, disease diagnosis, mechanical ventilation,vasopressor, illness severity, and organ failure, were assessed. The Acute Physiology and Chronic Health Evaluation (APACHE) score and Sequential Organ Failure Assessment (SOFA) score were recorded on the day CVVHDF began. Laboratory tests were conducted to measure activated partial thromboplastin time (aPTT), prothrombin time (PT), fibrinogen (FIB), platelet count (PLT), hematocrit (HCT), serum creatinine (Scr), blood urea nitrogen (BUN) levels.
Outcomes
The primary outcomes of our study were the lifespan of the circuit and the number of filters used during the first 72 hours of CVVHDF therapy. The circuit lifespan was defined as the duration, in hours, until the first filter was disconnected nonelectively due to filter clotting, extracorporeal coagulation, a transmembrane pressure (TMP) exceeding 250 mmHg, or visible clotting in the air trap chamber [16].
The secondary outcomes included the effective delivered dose, which was calculated as the ratio of the actual delivered dose per 24 hours to the prescribed dose per 24 hours [17], the mean filtration fraction, nurse satisfaction, the length of stay, the 28-day mortality rate, and the occurrence of hypotension within two hours of starting CRRT. Hypotension was defined as a mean arterial pressure (MAP) less than 60 mmHg, systolic blood pressure (SBP) less than 90 mmHg, a reduction in SBP greater than 40 mmHg from baseline, or an increased need for vasopressors [18]. Each participant was assigned to a single treatment group.
Statistical analysis
All the statistical analyses were performed using SPSS for Windows (IBM SPSS Statistics 21, Chicago, IL, USA). Categorical variables are shown as counts and percentages, while continuous variables are presented as either mean (SD) or median with interquartile range (IQR), depending on their distribution. Group comparisons for categorical data were made using χ2 tests, and for continuous data, one-way ANOVA or Mann–Whitney U tests were used based on distribution. Pairwise comparisons among the three groups were conducted using the Student–Newman–Keuls (SNK) method. Kaplan‒Meier(K-M) analysis was applied to compare circuit lifespans across groups using R software (version 4.3.1). Statistical significance was defined as a two-tailed p value < 0.05 or < 0.017 after Bonferroni adjustment for multiple comparisons.
Results
Participants and recruitment
A total of 117 patients completed the study and were assigned to the 30-minute saline flush group (n = 38), 2-hour saline flush group (n = 37), or control group (n = 42) (Fig. 1). Baseline clinical and demographic characteristics are shown in Table 1, with no significant differences observed among the groups (p > 0.05), ensuring comparable starting conditions.
Table 1.
Baseline characteristics of the patients enrolled in the study (n = 117)
| Characteristic | 30-minute saline flush group (n = 38) | 2-hour saline flush group (n = 37) | Non saline flush group (n = 42) | Statistic | P-value |
|---|---|---|---|---|---|
| Demographics | |||||
| Sex, no. (%) |
 = 0.086 |
0.958 | |||
| Men | 30（78.95） | 30（81.08） | 33（78.57） | ||
| Women | 8（21.05） | 7（18.92） | 9（21.43） | ||
| Age, mean (SD), y | 57.03(15.23) | 59.78 (12.97) | 56.17 (13.90) | t = 0.674 | 0.512 |
| Weight, mean (SD), kg | 68.90(12.95) | 64.36(10.31) | 67.15(11.04) | t = 1.376 | 0.257 |
| Vascular access, n (%) |
 = 2.496 |
0.287 | |||
| Femoral vein | 30(78.94) | 34 (91.89) | 35 (83.33) | ||
| Jugular vein | 8(21.06) | 3 (8.11) | 7(16.67) | ||
| Main diagnose, no. (%) |
 = 5.230 |
0.998 | |||
| Sepsis | 9(23.68) | 8(21.62) | 8(19.05) | ||
| Brain haemorrhage | 2 (5.26) | 4(10.81) | 4(9.52) | ||
| Alimentary tract haemorrhage | 2 (5.26) | 3(8.11) | 3(7.14) | ||
| SAP | 5(13.16) | 4(10.81) | 4(9.52) | ||
| MODS | 2 (5.26) | 1(2.70) | 1(2.38) | ||
| Hepatic failure | 3 (7.89) | 4(10.81) | 4(9.52) | ||
| Severe pneumonia | 2 (5.26) | 3(8.11) | 6(14.29) | ||
| Multiple injury | 6 (15.80) | 5(13.51) | 4(9.52) | ||
| Post-cardiac surgery | 2 (5.26) | 2(5.41) | 3(7.14) | ||
| Others | 5 (13.16) | 3(8.11) | 4(9.52) | ||
| Laboratory indexes | |||||
| Hb, mean (SD), g/L | 76.00(15.24) | 75.82 (16.89) | 74.83(26.40) | t = 0.045 | 0.956 |
| WBC, mean (SD),109/L | 13.72（8.12） | 15.62（8.69） | 13.97（7.26） | t = 0.564 | 0.570 |
| APTT, median (IQR), s | 39.20 (35.90,50.70) | 46.10 (38.05,52.00) | 39.10 (34.60,45.50) | Z = 4.078 | 0.130 |
| PT, median (IQR), s | 15.00 (13.70, 17.10) | 14.05 (13.40,24.05) | 15.80 (13.70,20.20) | Z = 1.139 | 0.566 |
| PLT, median (IQR), 109/L | 35.00 (19.00,80.00) | 58.50 (38.75,87.00) | 54 (32.00,89.00) | Z = 1.273 | 0.529 |
| FIB, median (IQR), (g/L) | 2.21(1.36,3.35) | 2.10(1.25,2.89) | 2.10(1.41,3.39) | Z = 0.425 | 0.808 |
| HCT, mean (SD), % | 25.26 (4.79) | 24.56 (5.73) | 24.59 (5.42) | t = 0.200 | 0.819 |
| TG, median (IQR), mmol/L | 2.47 (1.52,2.80) | 1.68 (1.24,2.69) | 1.71 (1.25,2.52) | Z = 3.154 | 0.207 |
| BUN，median (IQR), mmol/L | 13.20 (8.20,20.28) | 12.95 (10.58,19.88) | 14.30(8.75,17.55) | Z = 0.620 | 0.733 |
| Scr, median (IQR), µmol/L | 110.00 (74.50,257.00) | 153.00 (77.25,258.25) | 151.00 (83.00,241.50) | Z = 0.105 | 0.949 |
| Reasons for CRRT, no. (%) |
 = 1.597 |
0.809 | |||
| AKI | 31(81.58) | 30(81.08) | 33(78.57) | ||
| CKD | 4(10.53) | 2(5.41) | 5(11.91) | ||
| Others | 3(7.89) | 5(13.51) | 4(9.52) | ||
| Mechanical ventilation, no. (%) | 34(89.47) | 32(86.49) | 39(92.86) |
 = 0.872 |
0.647 |
| Vasopressor dependency, no. (%) | 30(78.95) | 28(75.68) | 30(71.43) |
 = 0.611 |
0.737 |
| APACHE, mean (SD) | 19.86(6.37) | 18.27(7.04) | 21.70(7.52) | t = 1.369 | 0.261 |
| SOFA, mean (SD) | 15.33（3.63） | 14.89（4.18） | 15.14（2.21） | t = 0.082 | 0.921 |
Abbreviations: Hb: haemoglobin; WBC: white blood cell; APTT: activated partial thrombin time; PT: prothrombin time; PLT: platelet; FIB: fibrinogen; HCT: haematocrit; TG: total triglycerides; BUN: blood urea nitrogen; Scr: serum creatinine; AKI: acute kidney disease; SAP: severe acute pancreatitis; MODS: multiple organ dysfunction syndrome; CKD: chronic kidney disease; IQR: interquartile range
Primary outcomes: circuit lifespan
The circuit lifespan was significantly shorter in the 30-minute saline flush group (31.03 ± 20.26 hours) than in both the 2-hour saline flush group (41.96 ± 18.26 hours) and the control group (42.10 ± 19.29 hours) (p < 0.05). No significant difference was found between the 2-hour saline flush group and the control group (p > 0.05). Kaplan-Meier survival analysis revealed no overall difference in circuit lifespan among the groups (log-rank p = 0.059), but the lifespan in the 30-minute saline flush group was significantly shorter than that in the control group (log-rank p = 0.042) (Fig. 3).
Fig. 3.
The Kaplan–Meier survival curve for circuit lifespan. Note: Group1 (30-minute saline flush group), Group 2 (2-hour saline flush group), Group 3 (non-saline group)
The incidence of circuits remaining clot-free within 72 hours did not differ significantly among the groups (p = 0.509).
Secondary outcomes
No significant differences were observed in hospital length of stay or 28-day all-cause mortality among the three groups (p > 0.05) (Table 2).
Table 2.
Clinical outcomes in the study
| Characteristic | Total (n = 117) |
30-minute saline flush group (n = 38) | 2-hour saline flush group (n = 37) | Non saline flush group (n = 42) | Statistic | P-value |
|---|---|---|---|---|---|---|
| Primary outcome | ||||||
| Circuit life span, mean (SD), h | 38.46(19.82) | 31.03(20.26) | 41.96(18.26)1 | 42.10 (19.29)2 | t = 4.177 | 0.018 |
| Without clotting (72 hours) (n, %) | 19(16.24) | 4（10.53） | 7（18.92） | 8（19.05） |
 = 1.351 |
0.509 |
| Secondary outcomes | ||||||
| Effective delivered dose, mean (SD) | 94.34(4.15) | 88.88（1.65） | 95.47（1.13） | 98.28（0.70） | t = 628.60 | ＜0.001 |
| Early hypotension, no. (%) | 64(54.70) | 27(71.05)a | 20(54.05)a,b | 17(42.85)b |
 = 6.473 |
0.039 |
| Filtration fraction, mean (SD), % | 14.36(2.95) | 16.14（3.99） | 14.05（1.96） | 13.07（1.57） | t = 13.19 | ＜0.001 |
| Nurse satisfaction, mean (SD), score | 62.74(36.39) | 32.26(11.93) | 62.04（30.40） | 93.93（12.49） | t = 36.691 | ＜0.001 |
| Length of stay, median (IQR), d | 23.00(14.00,42.00) | 23.00(18.00,42.00) | 21.00 (14.00,41.00) | 25.00(11.00,44.00) | Z = 0.467 | 0.792 |
| 28-day mortality rate, no. (%) | 71(60.68) | 22 (57.89) | 25 (67.57) | 24 (57.14%) |
 = 1.079 |
0.583 |
Note: Compared with the 30-minute flush group, P1 = 0.016, P2 = 0.012
a vs b: significant difference between group a and group b
ab: no statistically significant differences from either group a or group b
However, significant differences were observed between groups in terms of effective delivery dose, filtration fraction, and nurse satisfaction (p < 0.05 for all pairwise comparisons; Table 2). Specifically, the no-flush group had the highest effective CRRT dose delivery (98%) and the lowest filtration fraction (13.07%), while the 30-minute flush group had the lowest effective dose (89%) and the highest filtration fraction (16.14%). In terms of nurse satisfaction, scores were highest in the no-flush group (93.93), followed by the 2-hour flush group (62.04), and lowest in the 30-minute flush group (32.26).
Adverse events
The incidence of hypotension within two hours of CRRT initiation was significantly greater in the 30-minute saline flush group compared to the control group (71.05% vs. 42.85%, p < 0.017; Bonferroni-adjusted) (Table 2).
Discussion
The findings of the randomized controlled trial suggest that high-frequency saline flushing during CVVHDF without anticoagulants may not significantly extend the circuit lifespan and could increase the risk of hypotension. Additionally, the results indicate that saline flushing appeared to reduce the effective delivered dose and increase the filtration fraction, with these effects being observed across different flushing frequencies.
A prior study suggested that heparin-free dialysis with high blood flow and without saline flushing is preferable for patients at elevated risk of bleeding [8]. Research has shown that hemodilution with saline may promote a hypercoagulable state by reducing the levels of natural anticoagulants such as antithrombin, anti-FXa, and α2-macroglobulin [12, 19, 20]. Our findings align with studies showing that altering the saline flush frequency and volume does not effectively prevent extracorporeal circuit clotting [21, 22]. Notably, both intermittent saline flushing (ISF) and continuous saline infusion (CSI) are associated with high clotting rates, undermining their efficacy [22]. Additionally, saline flushing has been linked to elevated filtration fractions, which increase postfiltration hematocrit levels, promote clot formation and impair filter performance [23]. Consistent with these findings, our study revealed no improvement in circuit lifespan with saline flushing, regardless of its frequency.
Saline flushing significantly reduced the effective delivered dose (89% in the 30-minute flush group, 95% in the 2-hour flush group, and 98% in the no-flush group, p < 0.001). The interruption of CRRT during saline flush intervals, when the CRRT machine is switched to bag-change mode with only the blood pump running, likely contributed to this reduction. Frequent interruptions, whether due to circuit clotting, machine alarms, or solution changes, can significantly impact the delivered dose [24]. Furthermore, saline flushing negatively impacted nurse satisfaction (32.26, 62.04 vs. 93.93, p < 0.001). Compared with the RCA, the saline flushing method is more time-consuming, complex, and labor-intensive [25, 26]. In clinical practice, saline flushing takes up the operating time of CRRT nurses and increases the frequency of balance alarms of the CRRT machine. For critically ill patients at risk of bleeding, close monitoring of the RCA may represent an optimal anticoagulation strategy [27].
At our institution, pre- and postdilution replacement fluids without saline flushing are utilized to prevent circuit clotting in patients with contraindications to RCA, such as severe hepatic failure, citrate accumulation, or active bleeding [14].
The incidence of hypotension within two hours of starting CRRT was 71.05%, 54.05%, and 42.85% in the 30-minute flush, 2-hour flush, and control groups, respectively. Saline flushing likely contributes to fluid overload and elevated ultrafiltration rates, leading to hypotension. The reported incidence of intradialytic hypotension during CRRT varies between 12.5 and 45% [28, 29], with some studies indicating even higher rates with aggressive ultrafiltration [30]. Hypotension is a recognized independent risk factor for in-hospital mortality among CRRT patients, with higher ultrafiltration rates and early net fluid removal associated with increased mortality [31, 32]. Nine patients in the saline flush group discontinued the study due to hypotension, reinforcing the heightened risk with high-frequency saline flushing.
Limitations
This study has several limitations. First, as a single-centre trial with a relatively small sample size, generalizability is limited. Future multicentre randomized controlled trials with larger populations are warranted. Second, patients with unstable haemodynamics were excluded, limiting the feasibility of saline flushing in this subgroup. Third, blinding of nursing staff and physicians was not possible due to the visible nature of the saline flushing intervention. Nevertheless, the rigorous methodology employed and the findings offer valuable evidence for anticoagulant-free CRRT, influencing clinical practices in our institution.
Conclusion
In this single-center randomized study, saline flushing during anticoagulant-free CVVHDF did not improve filter lifespan and was associated with a greater incidence of hypotension. These findings suggest that routine saline flushing may not be advisable as part of anticoagulant-free CVVHDF protocols, although further multicenter studies are needed to confirm these results.
Acknowledgements
The authors have none to declare.
Author contributions
Fang Wang and Li Lin contributed equally to this study. FW, LL,PYL: Conceived and designed the experiments, performed the experiments, analyzed and interpreted the data, and wrote the manuscript. XLH,TY, XKS,TX: Performed the experiments, analyzed and interpreted the data. MZ,SZ: Performed the experiments and collected the data. LZ, ZWC, YLZ: Conceived and designed the experiments, revised the paper. All authors reviewed the manuscript. Yuliang Zhao, Ling Zhang and Zhiwen Chen contributed equally to this work.
Funding
This work is financially supported by the National Key R&D Program of China (2023YFC2411800).
Data availability
The data that support the findings of this study are included in this article and are available from the corresponding author upon reasonable request.
Declarations
Ethical approval
This study was approved by the Research Ethics Committee of West China Hospital, Sichuan University(No.2021-742).
Consent for publication
Not applicable.
Conflict of interest
The authors declare no competing interests.
Footnotes
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Fang Wang and Li Lin contributed equally to this work.
Contributor Information
Yuliang Zhao, Email: 309444318@qq.com.
Ling Zhang, Email: zhangling_crrt@163.com.
Zhiwen Chen, Email: kiyuhot@163.com.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are included in this article and are available from the corresponding author upon reasonable request.