Retrospective comparative cohort study

N= 131 

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

Systemic heparin group (n = 76 participants)

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.

April 2015 to January 2021

Primary: Hemofilter survival time

Secondary: Comparison of complications and metabolic disorders

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

Citrate Anticoagulation for CRRT in Children: Comparison with Heparin

Retrospective cohort study based on a prospective observational registry

N= 36

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

Citrate (n= 12)

Heparin (n= 24)

Critically ill children undergoing CRRT

Patients requiring ECMO at the time of hemofiltration

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.

January 2011 to February 2013

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

Primary: Circuit survival

Secondary: Incidence of metabolic complications and bleeding

Heparin (n= 24)

Age, months (IQR)

Weight, kg (IQR)

MOF (IQR)

Lactic acid (IQR)

Inotropic score (IQR)

Mechanical ventilation

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

Citrate (n= 12)

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

Extraction rate, mL/h

Dialysis, mL/h

Postfilter substitution, mL/h

Total CRRT doses, mL/kg/h

CRRT duration, h

Mortality

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

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.

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.

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

Retrospective study

N= 75

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

Liver failure (LF; n= 42)

Liver dysfunction (LD; n= 33)

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

Not disclosed

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.

January 2015 to October 2019

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

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

LD (n= 33)

RCA-CRRT sessions

Age, months

Weight, kg

Female

Child-Pugh Score

PRISM III Score

LD (n= 33)

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.

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.

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.

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.

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

Retrospective, observational, single-center review

N= 51

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

Study cohort (N= 51)

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

Not disclosed

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.

30 months of data collection

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

Secondary: Citrate accumulation (CA) recognition and intervention

Age, years (IQR)

Female

Mechanical ventilation, n (%)

Length of mechanical ventilation, days

Inotrope use, n (%)

Length of hospital stay, days

Length of PICU stay, days

Primary liver disease

Hospital mortality

Endpoint

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

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

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. 

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. 

Prospective observational study;

N= 7

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.

BUN and creatinine reduction, calcium level, metabolic complications

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