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Citrate calcium complex. The distance between calcium's two positive charges corresponds to the distance between two citrate carboxylate radicals. A carboxylate radical remains unbound, providing residual anionic charge and a mild acidic effect. This acidifying effect would be much stronger in vitro, in the absence of ionized calcium
Source publication
Regional citrate anticoagulation (RCA) is now recommended over systemic heparin for continuous renal replacement therapy in patients without contraindications. Its use is likely to increase throughout the world. However, in the absence of citrate blood level monitoring, the diagnosis of citrate accumulation, the most feared complication of RCA, rem...
Context in source publication
Context 1
... pKa values of 5.21, 4.28, and 2.92 at 25 °C) [20]. However, in plasma, unless the cal- cium level is extremely low (to levels incompatible with life), citrate is only present in the form of CCC. In that form, its acidifying capacity is limited by the binding of ionized calcium to two adjacent carboxylates, leaving only one residual anionic charge (Fig. 3). Circulating CCC therefore lead to mild plasma acidification. Under normal conditions, this effect is negligible since CCC are rapidly cleared from the ...
Similar publications
Extracorporeal circuits used in renal replacement therapy (RRT) can develop thrombosis, leading to downtimes and reduced therapy efficiency. To prevent this, anticoagulation is used, but the optimal anticoagulant has not yet been identified. Heparin is the most widely used anticoagulant in RRT, but it has limitations, such as unpredictable pharmaco...
Citations
... In case of suspected citrate accumulation, the anticoagulation regimen was switched to antithrombin III supplementation. According to our local standard operating procedures, citrate accumulation is rigorously monitored at least 3 times daily in patients with liver failure using the total calcium to ionized calcium ratio 20 . Dialysis with low-molecular-weight heparin was not applied in our patient cohort, nor was dialysis without anticoagulation 21 . ...
... In our experience, the risk for citrate accumulation is highest during the first cycle of CVVHD when the patient is still in an unstable condition. In this situation, the already limited liver function is further compromised by circulatory/septic shock, resulting in the inability to metabolize citrate and ultimately leading to citrate accumulation 20 . In this regard, citrate accumulation might also represent a negative prognostic marker for outcome in ACLF patients 48 . ...
CytoSorb is a hemoadsorptive column used to remove high concentrations of proinflammatory cytokines in septic shock. Data on CytoSorb application in acute-on-chronic liver failure (ACLF) is lacking. This retrospective observational study analyzed 21 ACLF patients admitted to ICUs at the Vienna General Hospital who received CytoSorb adsorber therapy between 2017 and 2023. Median ICU length of stay was 8 days (IQR: 3–13), the ICU survival rate was 23.8% (n = 5). Significant decreases in bilirubin (median peak: 20.7 mg/dL to median post-treatment: 10.8 mg/dL; − 47.8%; p < 0.001), procalcitonin (1.34 to 0.74 pg/mL; − 44.6%; p < 0.001), interleukin-6 (385 to 131 ng/mL; − 66.0%; p = 0.0182)—but also of platelets (72 to 31 G/L; − 56.9%; p = 0.0014) and fibrinogen (230 to 154 mg/dL; − 33.0%; p = 0.0297) were detected. ICU survivors had a trend towards a stronger relative decrease in bilirubin (− 76.1% vs. − 48.2%), procalcitonin (− 90.6% vs. − 23.5%), and IL-6 (− 54.6% vs. − 17.8%) upon CytoSorb treatment. Moreover, no serious CytoSorb-attributed complications were detected. In conclusion, use of CytoSorb adsorber in ACLF patients results in a significant decrease in bilirubin and proinflammatory cytokines, while platelets and fibrinogen were also lowered. Prospective trials are warranted to investigate the impact of CytoSorb on clinical outcomes of ACLF patients with high proinflammatory cytokine levels.
... It is both a weak acid and a buffer, and its buffer capacity depends on the proportion of strong cations present in its solution, usually trisodium citrate. 6 The strong ion difference (SID) of trisodium citrate is zero, and its accumulation in humans can induce mild metabolic acidosis. Since the ionized calcium normally increases in acidosis, a low ionized calcium with acidosis suggest that citrate metabolism is impaired. ...
... However, CCC can escape into the circulation, where citrate is metabolized to bicarbonate releasing sodium, which further increases the SID and may cause metabolic alkalosis and hypernatremia. 6 Although citrate accumulation is the most frequent complication of RCA, its most feared side effect is hypocalcemia, which can induce hypotension, convulsions, arrhythmias, respiratory muscle weakness and death. Citrate also chelates magnesium, which should be monitored. ...
... Citrate associated toxicity is suspected by the presence of low ionized calcium, a total/ionized calcium ratio >2.5, a high anion gap metabolic acidosis, or whenever more calcium is needed to maintain the desired blood calcium levels. 6 However, recent studies suggested that the Total/ionized calcium ratio is not a reliable indicator to either confirm or rule out citrate accumulation, since changes in albumin, phosphate, lactate, and circulating unmeasured anions can affect this ratio. 7 Although RCA is avoided in children with liver failure, some pediatric studies showed that after proper adjustments and close monitoring it could be used safely in children with liver injury. ...
... Further, the researchers selected 20 ICU medical staff members meeting the inclusion criteria were selected as a sample. Two [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32], moderate [33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51], and high [52][53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68][69][70]; the attitude component into: low , moderate [36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55], and high [56][57][58][59][60][61][62][63][64][65][66][67][68][69][70][71][72][73][74][75]; and the practice component into: low [10][11][12][13], moderate [14][15][16], and high [17][18][19][20] [28,29]. ...
... Further, the researchers selected 20 ICU medical staff members meeting the inclusion criteria were selected as a sample. Two [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32], moderate [33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51], and high [52][53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68][69][70]; the attitude component into: low , moderate [36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55], and high [56][57][58][59][60][61][62][63][64][65][66][67][68][69][70][71][72][73][74][75]; and the practice component into: low [10][11][12][13], moderate [14][15][16], and high [17][18][19][20] [28,29]. ...
... The regulation of citrate infusion rate is intricate and cannot rely on a single index for monitoring. Incorrect monitoring regulation may lead to poisoning or inadequate anticoagulation [59], thus contributing to ICU staff 's lack of confidence in this practice. Similarly, 23.29 of the participants disagreed with allowing nurses to independent regulate the ultrafiltration rate. ...
Background
Continuous renal replacement therapy (CRRT) is a commonly utilized form of renal replacement therapy (RRT) in the intensive care unit (ICU). A specialized CRRT team (SCT, composed of physicians and nurses) engage playing pivotal roles in administering CRRT, but there is paucity of evidence-based research on joint training and management strategies. This study armed to evaluate the knowledge, attitude, and practice (KAP) of ICU staff toward CRRT, and to identify education pathways, needs, and the current status of CRRT implementation.
Methods
This study was performed from February 6 to March 20, 2023. A self-made structured questionnaire was used for data collection. Descriptive statistics, T-tests, Analysis of variance (ANOVA), multiple linear regression, and Pearson correlation coefficient tests (α = 0.05) were employed.
Results
A total of 405 ICU staff from 66 hospitals in Central and South China participated in this study, yielding 395 valid questionnaires. The mean knowledge score was 51.46 ± 5.96 (61.8% scored highly). The mean attitude score was 58.71 ± 2.19 (73.9% scored highly). The mean practice score was 18.15 ± 0.98 (85.1% scored highly). Multiple linear regression analysis indicated that gender, age, years of CRRT practice, ICU category, and CRRT specialist panel membership independently affected the knowledge score; Educational level, years of CRRT practice, and CRRT specialist panel membership independently affected the attitude score; Education level and teaching hospital employment independently affected the practice score. The most effective method for ICU staff to undergo training and daily work experience is within the department.
Conclusion
ICU staff exhibit good knowledge, a positive attitude and appropriately practiced CRRT. Extended CRRT practice time in CRRT, further training in a general ICU or teaching hospital, joining a CRRT specialist panel, and upgraded education can improve CRRT professional level. Considering the convenience of training programs will enhance ICU staff participation. Training should focus on basic CRRT principles, liquid management, and alarm handling.
... Citrate accumulation (CA) was defined as a ratio of total calcium (totCal ++ )-toionized calcium (iCal + +) of > 2.5 for longer than 48 h with high anion gap metabolic acidosis. 29 The volume of packed red cells transfused during CRRT (and after circuit clotting) was recorded for each circuit. Transfusions were initiated in response to hemoglobin concentration measurements obtained from regular blood sampling, with a threshold of 7.0 g/dL during CRRT. ...
... In case of metabolic alkalosis, in addition to the interventions performed for CA, we administered 0.9% sodium chloride infusion as pre-or post-replacement fluid. 29,33 Statistical analysis ...
... This can be addressed by administering 0.9% sodium chloride infusion as pre-or post-replacement fluid, in addition to the conservative methods used for CA. 29,33,39 Hypocalcemia, one of the most dangerous metabolic complications associated with RCA, occurs through two mechanisms. The first is the elevation of dialyzable calcium fraction due to the citrate-calcium complex. ...
Bakcground
The aim of this study was to evaluate the efficacy and safety of citrate versus heparin anticoagulation for CRRT in critically-ill children.
Methods
This retrospective comparative cohort reviewed the clinical records of critically-ill children undergoing CRRT with either RCA or systemic heparin anticoagulation. The primary outcome measure was hemofilter survival time. Secondary outcomes included the comparison of complications and metabolic disorders.
Results
A total of 131 patients (55 RCA and 76 systemic heparin) were included, in which a cumulative number of 280 hemofilters were used (115 in RCA with 5762 h total CRRT time, and 165 in systemic heparin with 6230 h total CRRT time). Hemofilter survival was significantly longer for RCA (51.0 h; IQR: 24–67 h) compared to systemic heparin (29.5 h; IQR, 17–48 h) ( p = 0.002). Clotting-related hemofilter failure occurred in 9.6% of the RCA group compared to 19.6% in the systemic heparin group ( p = 0.038). Citrate accumulation occurred in 4 (3.5%) of 115 RCA sessions. Hypocalcemia and metabolic alkalosis episodes were significantly more frequent in RCA recipients (35.7% vs 15.2%, p < 0.0001; 33.0% vs 19.4%, p = 0.009).
Conclusion
RCA is a safe and effective anticoagulation method for CRRT in critically-ill children and it prolongs hemofilter survival.
Impact
RCA is superior to systemic heparin for the prolongation of circuit survival (overall and for clotting-related loss) during CRRT.
These data indicate that RCA can be used to maximize the effective delivery of CRRT in critically-ill patients admitted to the PICU.
There are potential cost-saving implications from our results owing to benefits such as less circuit downtime and fewer circuit changes.
... Sixty percent of these are eliminated directly through the dialysis membrane. Residual components enter the systemic circulation and are metabolized to bicarbonate within the Krebs cycle of hepatic, muscular and renal tissue [12]. Manifestation of clogging along the filter reduces the amount of removed calcium-citrate complexes with a consecutive higher load within the systemic circulation, resulting in a typical triad of metabolic alkalosis with hypercalcemia and hypernatremia [13]. ...
Background
Clogging is characterized by a progressive impairment of transmembrane patency in renal replacement devices and occurs due to obstruction of pores by unknown molecules. If citrate-based anti-coagulation is used, clogging can manifest as a metabolic alkalosis accompanied by hypernatremia and hypercalcemia, primarily a consequence of Na 3 Citrate infusion. An increased incidence of clogging has been observed during the COVID-19 pandemic. However, precise factors contributing to the formation remain uncertain. This investigation aimed to analyze its incidence and assessed time-varying trajectories of associated factors in critically ill patients on continuous renal replacement therapy (CRRT).
Methods
In this retrospective, single-center data analysis, we evaluated COVID-19 patients undergoing CRRT and admitted to critical care between March 2020 and December 2021. We assessed the proportional incidence of clogging surrogates in the overall population and subgroups based on the specific CRRT devices employed at our institution, including multiFiltrate (Fresenius Medical Care) and Prismaflex System (Baxter). Moderate and severe clogging were defined as Na > 145 or ≥ 150 mmol/l and HCO 3 ⁻ > 28.0 or ≥ 30 mmol/l, respectively, with a total albumin-corrected calcium > 2.54 mmol/l. A mixed effect model was introduced to investigate factors associated with development of clogging.
Results
Fifty-three patients with 240 CRRT runs were analyzed. Moderate and severe clogging occurred in 15% (8/53) and 19% (10/53) of patients, respectively. Twenty-seven percent (37/136) of CRRTs conducted with a multiFiltrate device met the criteria for clogging, whereas no clogging could be observed in patients dialyzed with the Prismaflex System. Occurrence of clogging was associated with elevated triglyceride plasma levels at filter start ( p = 0.013), amount of enteral nutrition ( p = 0.002) and an increasing white blood cell count over time ( p = 0.002).
Conclusions
Clogging seems to be a frequently observed phenomenon in critically ill COVID-19 patients. The presence of hypertriglyceridemia, combined with systemic inflammation, may facilitate the development of an impermeable secondary membrane within filters, thereby contributing to compromised membrane patency.
... A recent review states that with impaired metabolism of citrate there would be excess of circulating calcium-citrate, somehow causing metabolic acidosis [15]. However, this is incorrect if the citrate first entered the circulation as trisodium citrate, in which case an increase in pH is actually expected, as one carboxyl binds protons, given its pK of 6.4. ...
... In summary, the study did not show a clear relationship of liver function to tolerance of citrate anticoagulation. As highlighted in a recent review, the ability of patients with acute or acute-on-chronic liver failure to metabolize citrate is not null but simply decreased [15]. ...
Purpose of review
Continuous renal replacement therapy (CRRT) is a vital medical intervention used in critically ill patients with acute kidney injury (AKI). One of the key components of adequate clearance with CRRT is the use of anticoagulants to prevent clotting of the extracorporeal circuit. Regional citrate anticoagulation is the most often recommended modality. The term ‘citrate toxicity’ is used to describe potential adverse effects of accumulation of citrate and subsequent hypocalcemia. However, citrate is itself not inherently toxic. The term and diagnosis of citrate toxicity are questioned in this review.
Recent findings
Citrate is being increasingly used for regional anticoagulation of the CRRT circuit. Citrate accumulation is infrequent and can cause hypocalcemia and metabolic alkalosis, which are potential adverse effects. Citrate itself, however, is not a toxic molecule. The term ‘citrate toxicity’ has been used to denote hypocalcemia and metabolic acidosis. However, citrate administration is well known to cause systemic and urinary alkalinization and under certain circumstances, metabolic alkalosis, but is not associated itself with any ‘toxic’ effects.
We review the existing literature and debunk the perceived toxicity of citrate. We delve into the metabolism and clearance of citrate and question current data suggesting metabolic acidosis occurs as the result of citrate accumulation.
Summary
In conclusion, this article calls into question prevailing concerns about ‘citrate toxicity’. We emphasize the need for a more nuanced understanding of its safety profile. We recommend discarding the term ‘citrate toxicity’ in favor of another frequently used, but more meaningful term: ‘citrate accumulation’.
... The percentage of children with at least one episode of citrate accumulation (38.1%) was significantly lower than those reported by Ma et al. (20) for adults who had undergone RCA-mTPE (67%) and by Keila et al. (33) (70%) for children with LF who had undergone RCA-CRRT. Citric acid is a non-toxic physiological organic acid associated with the primary risks of hypocalcemia and moderate metabolic acidosis (34). Thus, the evaluation of the safety of RCA based on the presence of these conditions may be more reasonable. ...
Background
Regional citrate anticoagulation (RCA) is being used more commonly in children for continuous renal replacement therapy. Few reports describe the application of membrane-based therapeutic plasma exchange (mTPE) with RCA in children with liver failure (LF).
Aims
To explore the application of RCA-mTPE in children with LF.
Methods
We retrospectively analyzed data from children with LF who underwent RCA-mTPE in the Children's Hospital of Chongqing Medical University's pediatric intensive care unit. We used the total to ionized calcium ratio (T/iCa) > 2.5 as the diagnostic criteria for citrate accumulation (CA). The patients were divided into two groups according to the occureence of CA at the end of RCA-mTPE (CA group: T/iCa > 2.5; NCA group: T/iCa ≤ 2.5). To evaluate the clinical safety and efficacy of RCA-mTPE, the following data from medical records were assessed and compared between groups: clinical characteristics, reasons for LF, RCA-mTPE parameters and duration, laboratory findings, and complications.
Results
In total, 92 RCA-mTPE treatments were administered to 21 children with LF over 3.8 ± 0.9 h. The following mean values were determined: blood flow rate (QB) = 2.8 ml/kg/min, 4% sodium citrate dose/blood flow rate ratio (QCi/QB) = 1.1(QCi,ml/kg/h); plasma dose/body weight ratio(QP/BW) = 18.5 (QP, ml/kg/h); 10% calcium gluconate dose/blood flow rate ratio (QCa/QB) = 0.2(QCa, ml/kg/h). The mean concentration of iCa in vitro was 0.38 ± 0.07 mmol/L. Citrate accumulation was recorded after 34 (37%) treatments. Hypocalcemia occurred in 11 (12%) and 7 (7.6%) treatments, during and after mTPE, respectively. Three hypotensive and one convulsive events, related to hypocalcemia, and two clotting events occurred during RCA-mTPE. After RCA-mTPE, the patients' pH, HCO 3 ⁻ and Na ⁺ levels, and T/iCa were significantly increased and the total bilirubin (TB), conjugated bilirubin (DB), prothrombin time (PT), activated partial thromboplastin time (APTT), alanine aminotransferase (ALT), aspartate aminotransferase (AST),and ammonia levels were significantly decreased. The TB, DB, and lactic acid levels, before RCA-mTPE, were significantly higher in the CA group than in the NCA group, but there were no significance between the two groups in QB/BW, QCi/QB, and QP/BW, mTPE duration, and estimated amount of citrate metabolized.
Conclusions
Children with LF undergoing RCA-mTPE are at risk of hypocalcemia. With proper protocol adjustment, however, RCA-mTPE can be used safely and effectively in these patients.
... RCA protocols during CRRT are diverse, and there is currently no universally recommended protocol [8][9][10][11][12]. Moreover, RCA-related complications have raised concerns [13][14][15], including acid-base metabolic disorders, citrate accumulation, and ionization abnormalities, especially in patients with severe liver failure or shock who suffer malfunction in citrate metabolism. Most patients with renal failure present with metabolic acidosis, while patients undergoing CRRT can develop metabolic alkalosis. ...
Background
Metabolic alkalosis has raised concerns in patients receiving continuous renal replacement therapy (CRRT) via regional citrate anticoagulation (RCA). This study searched for alkalosis-related factors and mechanisms.
Measurements
We conducted a retrospective cross-sectional study of alkalosis in patients who received CRRT for at least 12 hours with RCA at an emergency department in a tertiary hospital between April 2017 and April 2020.
Main Results
The 59 patients meeting the inclusion criteria were 49% male, with a mean age of 55 ± 18 years old, and 42% had alkalosis by 12 hours after CRRT. Patients were divided into 4 groups based on whether they received NaHCO3 and alkalosis after 12 hours of CRRT. No significant differences in demographic features or laboratory results were observed among the groups. CRRT metrics, including blood flow rate, PBP rate, replacement fluid rate and total effluent rate, were significantly different among groups (p < 0.01). Multivariable logistic regression analysis indicated that the citrate rate was a risk factor for alkalosis (OR 1.088, 95% CI 1.020–1.161, p = 0.010). In patients receiving no NaHCO3 and without alkalosis, the linear regression analysis described the relationships of citrate with replacement fluid rate (citrate rate = 0.090 × replacement fluid rate + 56.581; R² = 0.6918) and total effluent rate (citrate rate = 0.099 × total effluent rate + 2.449).
Conclusions
This retrospective observational study demonstrated that CRRT metrics are highly associated with alkalosis after 12 hours of CRRT. Without NaHCO3 infusion, a 10-fold linear correlation was observed between citrate and total effluent rate in patients without metabolic alkalosis.
... Citrate is a small (298 Dalton) water-soluble organic acid that is used in two forms: sodium citrate and dextrose citrate [39]. Its anticoagulant properties are secondary to its great affinity for divalent ionic calcium, forming citrate-calcium complexes in the blood, and thus decreasing the levels of ionic calcium (Fig. 5). ...
... Post-filter ionic calcium measurement is used to monitor an adequate degree of circuit anticoagulation, with goals of 0.2-0.35 mmol/L [39]. In parallel, a systemic ionic calcium measurement should be performed since citrate-calcium complexes are eliminated through the dialyzer in a variable proportion depending on the technique (30-60%) and administer intravenous calcium in order to maintain normal serum levels and thus avoid adverse effects secondary to hypocalcaemia [39]. ...
... mmol/L [39]. In parallel, a systemic ionic calcium measurement should be performed since citrate-calcium complexes are eliminated through the dialyzer in a variable proportion depending on the technique (30-60%) and administer intravenous calcium in order to maintain normal serum levels and thus avoid adverse effects secondary to hypocalcaemia [39]. Generally, dialysis and substitution solutions do not content calcium, since this way less citrate is used, which is intended only to chelate calcium from the blood. ...
Extracorporeal circuits used in renal replacement therapy (RRT) can develop thrombosis, leading to downtimes and reduced therapy efficiency. To prevent this, anticoagulation is used, but the optimal anticoagulant has not yet been identified. Heparin is the most widely used anticoagulant in RRT, but it has limitations, such as unpredictable pharmacokinetics, nonspecific binding to plasma proteins and cells, and the possibility of suboptimal anticoagulation or bleeding complications, specifically in critically ill patients with acute renal failure who are already at high risk of bleeding. Citrate anticoagulation is a better alternative, being considered a standard for continuous renal replacement therapy, since it is associated with a lower risk of bleeding complications and better efficacy, even in patients with acute renal failure or liver disease. The aim of this article is to provide an updated review of the different strategies of anticoagulation in renal replacement therapies that can be implemented in critical scenarios, focusing on the advantages and disadvantages of each one and the beneficial aspects of using citrate over heparin in critical ill patients.
... Citrate is a small (298 Dalton) water-soluble organic acid that is used in two forms: sodium citrate and dextrose citrate [39]. Its anticoagulant properties are secondary to its great affinity for divalent ionic calcium, forming citrate-calcium complexes in the blood, and thus decreasing the levels of ionic calcium (Fig. 5). ...
... Post-filter ionic calcium measurement is used to monitor an adequate degree of circuit anticoagulation, with goals of 0.2-0.35 mmol/L [39]. In parallel, a systemic ionic calcium measurement should be performed since citrate-calcium complexes are eliminated through the dialyzer in a variable proportion depending on the technique (30-60%) and administer intravenous calcium in order to maintain normal serum levels and thus avoid adverse effects secondary to hypocalcaemia [39]. ...
... mmol/L [39]. In parallel, a systemic ionic calcium measurement should be performed since citrate-calcium complexes are eliminated through the dialyzer in a variable proportion depending on the technique (30-60%) and administer intravenous calcium in order to maintain normal serum levels and thus avoid adverse effects secondary to hypocalcaemia [39]. Generally, dialysis and substitution solutions do not content calcium, since this way less citrate is used, which is intended only to chelate calcium from the blood. ...
Extracorporeal circuits used in renal replacement therapy (RRT) can develop thrombosis, leading to downtimes and reduced therapy efficiency. To prevent this, anticoagulation is used, but the optimal anticoagulant has not yet been identified. Heparin is the most widely used anticoagulant in RRT, but it has limitations, such as unpredictable pharmacokinetics, nonspecific binding to plasma proteins and cells, and the possibility of suboptimal anticoagulation or bleeding complications, specifically in critically ill patients with acute renal failure who are already at high risk of bleeding. Citrate anticoagulation is a better alternative, being considered a standard for continuous renal replacement therapy, since it is associated with a lower risk of bleeding complications and better efficacy, even in patients with acute renal failure or liver disease. The aim of this article is to provide an updated review of the different strategies of anticoagulation in renal replacement therapies that can be implemented in critical scenarios, focusing on the advantages and disadvantages of each one and the beneficial aspects of using citrate over heparin in critical ill patients.
