Is there evidence to guide the dosing of calcium (gluconate or chloride) to prevent or treat citrate toxicity during CRRT in pediatric patients?

Comment by InpharmD Researcher

There is a lack of established consensus on guiding the dosing of citrate anticoagulation for continuous renal replacement therapy (CRRT) among children. Dosing protocols employed in available studies vary; some adjusted calcium based on the desired systemic ionized calcium levels of 1.0-1.3 mmol/L. In general, the treatment protocol utilized for citrate-induced hypocalcemia prevention depends on the citrate solution used.

Background

A 2022 review article discusses the use of continuous renal replacement therapy (CRRT) in critically ill children, highlighting the importance of understanding the mechanisms of clearance, factors influencing these processes, and appropriate selection of treatment candidates for CRRT. One key aspect associated with CRRT management is the use of regional citrate anticoagulation (RCA). RCA utilizes citrate to prevent coagulation by binding and chelating free ionized calcium in the extracorporeal circuit, which is essential for the formation of fibrin and clots in the coagulation cascade. Citrate is infused into the circuit after the blood leaves the patient but before it enters the CRRT filter, resulting in hypercoagulability within the circuit. Calcium is then infused back into the patient via a central line, independent of the circuit, to reverse anticoagulation and prevent hypocalcemia caused by citrate administration. However, the treatment protocol utilized for citrate-induced hypocalcemia prevention depends on the citrate solution used; generally, the citrate infusion rate is titrated to target a circuit ionized calcium concentration of 0.25-0.4 mmol/L. Additionally, calcium in a normal saline solution is infused concurrently to maintain the desired systemic ionized calcium concentration of 1.1-1.3 mmol/L. Of note, a specific calcium formulation and dose for the prevention of citrate toxicity is not provided within the review. [1]

Literature Review

A search of the published medical literature revealed 5 studies investigating the researchable question:

Is there evidence to guide the dosing of calcium (gluconate or chloride) to prevent or treat citrate toxicity during CRRT in pediatric patients?

Level of evidence

D - Case reports or unreliable data  Read more→



Please see Tables 1-5 for your response.


Citrate anticoagulation and systemic heparin anticoagulation during continuous renal replacement therapy among critically ill children
Design

Retrospective comparative cohort study

N= 131 

Objective To evaluate the efficacy and safety of citrate versus heparin anticoagulation for continuous renal replacement therapy (CRRT) in critically-ill children
Study Groups

Regional citrate anticoagulation (RCA) group (n = 55)

Systemic heparin group (n = 76 participants)

Inclusion Criteria Critically-ill children admitted to pediatric intensive care unit (PICU) from April 2015 to January 2021 who received CRRT with either systemic anticoagulation (heparin) or RCA
Exclusion Criteria Insufficient data, received anticoagulation therapy for therapeutic purposes during CRRT or up to 24 h before CRRT, received an RRT modality other than CRRT, underwent RRT for other reasons before admission
Methods

Heparin was initiated at 10 IU/kg/hr pre-filter and adjusted to maintain a post-filter activated clotting time (ACT) of 180–220 seconds. Dialysis and replacement solutions included Dialisan and Prism0cal B22. Citrate flow, linked to blood flow, was adjusted by the device to deliver 3 mmol/L of blood. CRRT was conducted with pre-filter citrate and post-filter replacement fluid.

Citrate was neutralized with a continuous calcium infusion of calcium gluconate 10% mixed 50/50 with dextrose 5% (116 mmol/L), administered through a separate central venous line or, when unavailable, the return line of the circuit. The initial rate was 1 mL/kg/h, adjusted based on systemic ionized calcium (iCa++) levels to maintain patient iCa++ between 1 and 1.2 mmol/L and filter iCa++ between 0.25 and 0.35 mmol/L. iCa++ levels were monitored at 30 minutes, 1, 2, 4 hours, and then every 4 hours, with additional checks an hour after changes in blood flow, citrate concentration, or dialysis. Biochemical markers and electrolytes were assessed every 12–24 hours.

For citrate accumulation, adjustments included reducing blood or citrate flow rates, increasing dialysate flow for clearance, or increasing calcium infusion for ionized hypocalcemia. Metabolic alkalosis was managed with 0.9% sodium chloride as pre- or post-replacement fluid.

Duration

April 2015 to January 2021

Outcome Measures

Primary: Hemofilter survival time

Secondary: Comparison of complications and metabolic disorders

Baseline Characteristics Variable All Patients (n = 131) Citrate group (n = 55) Heparin group (n = 76) p-value
Age, years 3.9 (1.3–11.0) 5.2 (1.3–11.3) 3.0 (1.3–7.3) 0.089
Male  65 (49.6%) 28 (50.9%) 37 (48.7%) 0.941
Weight, kg 16 (11–32) 21 (11–42) 13.3 (10.8–23) 0.051
Weight < 10 kg 24 (18.3%) 9 (16.4%) 15 (19.7%) 0.792
PRISM III score, 15 (9–24) 14 (10–24) 17 (9–24) 0.976
PRISM Pediatric risk of mortality score
Results Variables All Patients (n = 131) Citrate group (n = 55) Heparin group (n = 76) p-value
Total CRRT time, hr 11992 5762 6230 --
CRRT time per patient, hr 64 (32–115) 70 (40–144) 56 (30–96) 0.187
Total number of hemofilters 280 115 165 --
Number of filters per patient 2 (1–3) 2 (1–3) 2 (2–2) 1.000
Median circuit lifetime, hr 40 (20–57) 51 (24–67) 29.5 (17–48) 0.024
Calcium infusion flow rate, mmol/h 3.08 (1.32–5.78) 3.08 (1.32–5.78) -- --
Calcium infusion flow rate per kg, mmol/kg/h 0.85 (0.08–0.10) 0.85 (0.08–0.10) -- --
Citrate dose, mmol/L 4.0 (3.5–4.0) 4.0 (3.5–4.0) -- --
Total calcium/Ionized calcium ratio 2.04 (1.88–2.20) 2.04 (1.88–2.20) -- --
Adverse Events Hypocalcemia (35.7% in RCA vs 15.2% in heparin), Metabolic alkalosis (33% in RCA vs 19.4% in heparin), Citrate accumulation in 4 (3.5%) of 115 RCA sessions.
Study Author Conclusions RCA is a safe and effective anticoagulation method for CRRT in critically-ill children, prolonging hemofilter survival with manageable side effects.
Critique

Strengths: Large sample size for pediatric CRRT studies, comprehensive analysis of metabolic complications

Limitations: Single-center, retrospective design, potential bias due to non-use of RCA in hepatic failure patients, and evolving experience with CRRT over study period

References:

Atis SK, Duyu M, Karakaya Z, Yilmaz A. Citrate anticoagulation and systemic heparin anticoagulation during continuous renal replacement therapy among critically-ill children. Pediatr Res. 2024;96(3):702-712. doi:10.1038/s41390-024-03163-x

Citrate Anticoagulation for CRRT in Children: Comparison with Heparin

Design

Retrospective cohort study based on a prospective observational registry

N= 36

Objective

To assess the efficacy and safety of citrate anticoagulation compared to heparin in continuous renal replacement therapies (CRRT) in critically ill children

Study Groups

Citrate (n= 12)

Heparin (n= 24)

Inclusion Criteria

Critically ill children undergoing CRRT

Exclusion Criteria

Patients requiring ECMO at the time of hemofiltration

Methods

CRRT was performed using a Prismaflex device. Citrate solution was administered prefilter, and calcium was infused postfilter. The continuous calcium infusion was comprised of calcium gluconate 10% 50/50 with glucose 5% in a 50 mL syringe (0.22 mEq/mL), with an initial infusion rate of 0.5 mL/kg/h used to maintain serum calcium between 1.1-1.3 mmol/L. Heparin was administered with a bolus and continuous infusion. Median citrate dose was 2.6 mmol/L, and median heparin dose was 15 IU/kg/h.

Duration

January 2011 to February 2013

Median treatment duration: 155 hours citrate group and 166 hours heparin group

Outcome Measures

Primary: Circuit survival

Secondary: Incidence of metabolic complications and bleeding

Baseline Characteristics   Citrate (n= 12)

Heparin (n= 24)

 

Age, months (IQR)

36.0 (5.6-103.7) 33.0 (5.6-84.0)  

Weight, kg (IQR)

13.4 (6.8-28.8) 9.8 (6.3-19.8)  

MOF (IQR)

3 (3-3.75) 3 (3-4)  

Lactic acid (IQR)

2.5 (1.3-6.8) 1.4 (1.0-2.4)  

Inotropic score (IQR)

40 (18-54) 38 (4-53)  

Mechanical ventilation

91.7% 81.8%  

Abbreviations: IQR= interquartile range; MOF= multi-organ failure

Results Endpoint

Citrate (n= 12)

Heparin (n= 24) p-value

Blood flow/weight, (mL/min)/kg

3.2 (2-3.8) 5.0 (3.8-5.6) 0.008

Extraction rate, mL/h

75 (50-97.5) 60 (50-90) 0.526

Dialysis, mL/h

325 (50-600) 400 (200-750) 0.289

Postfilter substitution, mL/h

50 (0-50) 300 (140-500) 0.026

Total CRRT doses, mL/kg/h

69 (52-85) 59 (44-70) 0.154

CRRT duration, h

155 (92-204) 166 (92-271) 0.736

Mortality

25% 25% 1.000
Adverse Events

Mild metabolic alkalosis in 66.6% of citrate patients, hypochloremia in 45.5%, hypomagnesemia in 27.3%, and hypophosphatemia in 27.8% of heparin patients

Study Author Conclusions

Citrate is a safe and effective anticoagulation method for CRRT in children, achieving longer circuit survival than heparin with a lower incidence of bleeding complications.

Critique

The study provides valuable insights into the use of citrate in pediatric CRRT, highlighting its advantages over heparin. However, the study's limitations include its retrospective design, small sample size, and lack of randomization. Additionally, the use of two different citrate solutions may have impacted the results.

References:

Fernández SN, Santiago MJ, López-Herce J, et al. Citrate anticoagulation for CRRT in children: comparison with heparin. Biomed Res Int. 2014;2014:786301. doi:10.1155/2014/786301

Clinical application of regional citrate anticoagulation for continuous renal replacement therapy in children with liver injury

Design

Retrospective study

N= 75

Objective

To evaluate the clinical safety and efficacy of regional citrate anticoagulation (RCA)-continuous renal replacement therapy (CRRT) in children with liver injury and explore RCA-CRRT management strategies

Study Groups

Liver failure (LF; n= 42)

Liver dysfunction (LD; n= 33)

Inclusion Criteria

Children with liver injury who received RCA-CRRT in the Pediatric Intensive Care Unit

Exclusion Criteria

Not disclosed

Methods

RCA-CRRT was performed using PlasautoΣ equipment. Initial treatment parameters included blood flow rate (QB) of 5 ml/kg/min, dose of 4% sodium citrate (QCi) of 9 ml/kg/h, dose of 10% calcium gluconate QCa of 0.5 ml/kg/h, dialysate flow rate (Qd) of 25 ml/kg/h, replacement fluid flow rate (Qf) of 35 ml/kg/h, and dose of 5% sodium bicarbonate (QSB) of 0.6 ml/kg/h. Adjustments were made based on blood gas analysis and electrolytes.

Duration

January 2015 to October 2019

Outcome Measures

Primary: Incidence of bleeding, clotting, citrate accumulation (CA), acid-base imbalance, electrolyte disturbance

Secondary: Filter lifespans, changes in biochemical indicators, CRRT parameters adjustment

Baseline Characteristics   LF (n= 42)

LD (n= 33)

 

RCA-CRRT sessions

83 68  

Age, months

37 49  

Weight, kg

18.84 ± 13.76 24.16 ± 18.73  

Female

16 9  

Child-Pugh Score

12.83 ± 1.90 6.24 ± 0.78  

PRISM III Score

20.81 ± 5.65 26.88 ± 6.03  
Results   LF (n= 42)

LD (n= 33)

p-value

28-day mortality

28.6%

18.2%

0.60

In-hospital mortality

4.8%

6.1%

1.00

Average filter lifespan, h

Filter lifespan <24 h

35.63 ± 17.41

25.3%

31.94 ± 16.92

32.4%

0.18

0.68

PT and APTT in the LF group were significantly higher than those in the LD group both before and after treatment, but no significant difference in PT and APTT before and after treatment in either LF or LD groups. Changes in biochemical indicators after treatment varied in range and significance between groups.

Adverse Events

Hypocalcemia-related hypotension (6.0% LF vs 5.9% LD), hypocalcemia-related convulsions (2.4% LF vs 1.5% LD), bleeding (9.5% LF vs 9.1% LD). There were 2 deaths in each group, but deaths were not related to RCA-CRRT.

Study Author Conclusions

RCA-CRRT can be safely and effectively used in children with liver dysfunction and even liver failure, with proper protocol adjustments to manage risks of citrate accumulation and hypocalcemia.

Critique

The study provides valuable insights into the use of RCA-CRRT in pediatric patients with liver injury, highlighting the importance of protocol adjustments. However, the retrospective nature and small sample size may limit the generalizability of the findings. Additionally, not all laboratory examinations were available for all patients, which could impact the results.

References:

Hu F, Sun Y, Bai K, Liu C. Clinical application of regional citrate anticoagulation for continuous renal replacement therapy in children with liver injury. Front Pediatr. 2022;10:847443. Published 2022 Oct 11. doi:10.3389/fped.2022.847443

Regional citrate anticoagulation for continuous renal replacement therapy in pediatric patients with liver failure

Design

Retrospective, observational, single-center review

N= 51

Objective

To establish the safety and efficacy of regional citrate anticoagulation (RCA) in pediatric liver failure patients on continuous renal replacement therapy (CRRT)

Study Groups

Study cohort (N= 51)

Inclusion Criteria

Pediatric patients with acute and acute-on-chronic liver failure receiving CRRT

Exclusion Criteria

Not disclosed

Methods

Data were compiled from CRRT patients receive hemodiafiltration (CVVHDF) at Texas Children’s Hospital. All patients also received calcium chloride (8 mg/ml) or calcium gluconate (20 mg/ml) infusions into the return line of CRRT circuit or via separate central line. Calcium values were measured at least q8h and adjusted per the attending nephrologist.

Duration

30 months of data collection

Outcome Measures

Primary: Safety (frequency of AEs), ffficacy (filter life)

Secondary: Citrate accumulation (CA) recognition and intervention

Baseline Characteristics

 

Study cohort (N= 51)

Age, years (IQR)

3.5 (0.75-14.2)

Female

36 (71%)

Mechanical ventilation, n (%)

49 (96.1%)

Length of mechanical ventilation, days

17 (7-29)

Inotrope use, n (%)

48 (94%)

Length of hospital stay, days

40 (25-97)

Length of PICU stay, days

27 (14-55)

Primary liver disease

30 (61.2%)

Hospital mortality

29 (56.9%)
Results

Endpoint

Study cohort (N= 51)

Adverse event types

Hemodynamic instability/hypotension

Bleeding

Metabolic alkalosis

Metabolic acidosis

Arrhythmia

 

29 (56.9%)

18 (39.1%)

9 (17.6%)

9 (17.6%)

1 (1.9%)

Hypocalcemia episodes

613 (6%)

Hospital mortality

29 (57%)

Citrate accumulation, days

3 (0-8)
Adverse Events

79 adverse events in 34 patients; 92 events per 1,000 CRRT days; included bleeding, hypotension, arrhythmias.

Study Author Conclusions

RCA is effective for CRRT in pediatric liver failure, with adequate filter life and no increase in adverse events. Standardized CA definition could improve recognition and management. 

Critique

Limitations of this study includes its retrospective design and data compiled from a single-center study, which introduces confounding. Additionally, there is potential observer bias in adverse event reporting. 

References:

Rodriguez K, Srivaths PR, Tal L, et al. Regional citrate anticoagulation for continuous renal replacement therapy in pediatric patients with liver failure. PLoS One. 2017;12(8):e0182134. Published 2017 Aug 8. doi:10.1371/journal.pone.0182134

Regional citrate anticoagulation for pediatric CRRT using integrated citrate software and physiological sodium concentration solutions
Design

Prospective observational study;

N= 7

Objective To assess the safety and efficacy of regional citrate anticoagulation for pediatric continuous renal replacement therapy (CRRT) using integrated citrate software and physiological sodium concentration solutions
Study Groups All study subjects (n = 7)
Inclusion Criteria Children with a body weight >15 kg, critically ill with acute kidney injury, requiring CRRT
Exclusion Criteria Children already receiving heparin, body weight <10 kg, liver failure with prothrombin activity <40%
Methods

CRRT was performed with pre-filter citrate anticoagulation, utilizing an 18 mmol/L citrate solution and post-filter replacement fluid. Citrate and calcium flow rates were automatically regulated by integrated software.

The initial citrate dose was set at 2.2 mmol/L and adjusted to achieve a circuit ionized calcium level below 0.5 mmol/L. Citrate solution was delivered via the preblood pump line of the Prismaflex machine. Beyond the filter, calcium was infused through the return line of the hemofiltration catheter to maintain blood calcium levels within the normal range in children. Software calculated calcium loss in the effluent based on therapy flow rates and anticoagulation settings. Calcium compensation was defined as the percentage of supplemented calcium compared to the loss and was initially set at 100%. Infusions used either 10% calcium gluconate (223 mmol/L) or 10% calcium chloride (456 mmol/L), depending on the hemofilter size (calcium gluconate for filters up to 0.6 m²). The lower concentration (223 mmol/L) allowed precise calcium delivery, especially at low blood flow rates, while meeting the machine’s minimum flow rate (2 mL/h). The higher concentration (456 mmol/L) provided greater calcium delivery with fewer syringe changes.

Duration December 2011 to December 2012
Outcome Measures

BUN and creatinine reduction, calcium level, metabolic complications

Baseline Characteristics Patient Age (years) Weight (kg) PIM2 (%) Disease Duration of CRRT (days) Venous access AST/ALT levels (UI/L) Prothrombin time (percentage of activity)
1 15 45 10.5 Postsurgical septic shock with MODS 4 Jugular, 11Fr 75/193 63
2 11 66 3.9 HUS with colitis 5 Femoral, 8Fr 291/244 80
3 13 45 13.0 Septic shock (Group A Streptococcus) 4 Jugular, 11Fr 146/62 90
4 6 20 1.2 HUS with kalemia >6.5 mmol/L 2 Femoral, 8Fr 35//38 76
5 9 31 2.8 HUS with severe enterocolitis 4 Jugular, 11Fr 134/68 45
6 12 45 1.5 HUS with pancreatitis 4 Jugular, 13.5Fr 127/59 74
7 3 15 2.8 Atypical HUS 2 Femoral, 8Fr 194/41 62
  PIM2, Revised version of the Pediatric Index of Mortality; MODS, multiple organ dysfunction syndrome; HUS, hemolytic-uremic syndrome; AST aspartate aminotransferase, ALT, alanine aminotransferase
Results Patient BUN at H0 (mmol/L) BUN at H24 (mmol/L) Percentage of decrease in BUN during first 24 h (%) Creatininemia at H0 (μM)/L Creatininemia at H24 (μM)/L Percentage of decrease in creatininemia during first 24 h (%) Total/ionized calcium ratio (%)
1 8.5 7.2 15 100 78 22 2.09
2 26.0 17.0 35 647 318 51 2.07
3 31.4 14.3 54 448 217 52 1.95
4 81.4 31.0 62 1358 492 64 2.00
5 31.9 15.7 51 431 218 49 1.89
6 32.1 18.4 43 875 477 45 1.79
7a 28.1 24.8 12 244 228 7 1.89
BUN, Blood urea nitrogen; H0, Baseline (before initiation of continuous renal replacement therapy (CRRT); H24, 24 h after initiation of CRRT
Adverse Events One transient metabolic alkalosis with spontaneous resolution; no citrate accumulation; no bleeding complications
Study Author Conclusions Regional citrate anticoagulation can be used safely and effectively in children over 15 kg using integrated citrate software and physiological sodium concentration solutions.
Critique

Strengths: Automated system reduces risk of human error, effective in reducing BUN and creatinine levels, safe with minimal adverse events

Limitations: Small sample size, single-center study, limited to children over 15 kg, short filter life

References:

Liet JM, Allain-Launay E, Gaillard-LeRoux B, et al. Regional citrate anticoagulation for pediatric CRRT using integrated citrate software and physiological sodium concentration solutions. Pediatr Nephrol. 2014;29(9):1625-1631. doi:10.1007/s00467-014-2770-2