Predictors for poor daily weight gain in preterm neonates exposed to different dose regimens of caffeine in ICU- a retrospective cohort study.

BACKGROUND: With a wide therapeutic index, efficacy, ease of use, and other neuroprotective and respiratory benefits, caffeine citrate(CC) is currently the drug of choice for preterm neonates (PTNs). Caffeine-induced excessive energy expenditure, diuresis, natriuresis, and other CC-associated potential side-effects (CC-APSEs) result in lower daily-weight gain (WG) in premature neonates. This study aimed to evaluate the risk factors for daily-WG in neonates exposed to different dose regimens of caffeine in ICU. METHOD: This retrospective cohort study included neonates of ≤ 36weeks gestational age (GA) and received CC-therapy. The same participants were followed for data analysis in two postnatal phases: 15-28 and 29-42 days of life (DOL). Based on daily CC-dose, formed group-I (received; standard-doses = 5 mg/kg/day), group-II (received;>5-7 mg/kg/day), and group-III (received;>7 mg/kg/day). Prenatal and postnatal clinical characteristics, CC-regimen, daily-WG, CC-APSEs, and concomitant risk-factors, including daily-caloric intake, Parenteral-Nutrition duration, steroids, diuretics, and ibuprofen exposure, were analyzed separately for group-II and group-III using group-I as standard. Regression analysis was performed to evaluate the risk factors for daily-WG. RESULTS: Included 314 PTNs. During 15-28 DOL, the mean-daily-WG(MD-WG) was significantly higher in group-I than group-II [19.9 ± 0.70 g/kg/d vs. 17.7 ± 0.52 p = 0.036] and group-III [19.9 ± 0.70 g/kg/d vs. 16.8 ± 0.73 p < 0.001]. During 29-42 DOL the MD-WG of group-I was only significantly higher than group-III [21.7 ± 0.44 g/kg/d vs. 18.3 ± 0.41 g/kg/d p = 0.003] and comparable with group-II. During 15-28 DOL, observed CC-APSEs was significantly higher in group-II and III but during 29-42 DOL it was only significant in group-III. In the adjusted regression analysis for daily-WG during 15-28DOL, with respect to standard-dose, 5-7 mg/kg/day (ß=-1.04; 95%CI:-1.62,-0.93) and > 7-10 mg/kg/day (ß=-1.36; 95%CI:-1.56,-1.02) were associated with a lower daily-WG. However, during 29-42DOL, this association was present only for > 7-10 mg/kg/day (ß=-1.54; 95%CI:-1.66,-1.42). The GA ≤ 27weeks (ß=-1.03 95%CI:-1.24, -0.88) was associated with lower daily-WG only during 15-28DOL. During both periods of therapy, higher cumulative-caffeine dose and presence of culture proven sepsis, tachypnea, hyponatremia, and feeding intolerance were significantly associated with lower daily-WG. Conversely, daily kcal intake was found to be linked with an increase in daily-WG in both periods. CONCLUSION: In this study cohort exposure to higher caffeine daily and cumulative doses is associated with lower postnatal daily-WG in PTNs than standard-daily doses, which may be due to its catabolic effects and CC-APSEs.

Association of Caffeine Daily Dose With Respiratory Outcomes in Preterm Neonates: A Retrospective Cohort Study.

Apnea and poor respiratory drive increase the risk of extubation failure (EF) and prolonged invasive mechanical ventilation (IMV) in preterm neonates (pre-nates) with respiratory distress. Caffeine citrate (CC) is often prescribed for pre-nates in doses of 5-10 mg/kg in 24 h. This study aimed to evaluate the most effective dosage regimen (5 mg/kg/day vs >5-10 mg/kg/day) to prevent apnea and EF with minimal caffeine-associated potential side effects (CC-APSEs) in pre-nates. This one-year retrospective cohort study included all the eligible neonates admitted to NICU and received CC-therapy till 28 days of life (DOL) or discharge. Based on CC-daily dose formed LD-caffeine-group (5 mg/kg/day) and HD-caffeine-group (>5-10 mg/kg/day). Antenatal, prenatal, and postnatal characteristics, CC-regimen, comorbidities, and CC-APSEs were compared between the groups. Predictors of apnea and EF were analyzed through logistic regression. There were 181 and 72 neonates in the LD and HD-caffeine-groups respectively. In HD-caffeine-group daily CC-dose was 7 to 7.5 mg/kg/day in 93% of neonates and >7.5 to 10 mg/kg/day in only 7%. Significantly fewer neonates experienced apnea and EF in the HD-caffeine-group till 28DOL or discharge. This difference was even greater in the subgroup of ≤28 weeks GA (15.6% vs 40.0%; P < .01). In HD-caffeine-group the incidence of severe/moderate-BPD was significantly lower and the frequency of CC-APSEs was higher. Multivariate analysis showed that; the smaller the GA higher the risk of apnea (AOR = 0.510, 95% CI 0.483-0.999) and EF (AOR = 0.787, 95% CI 0.411-0.997). The HD-caffeine was inversely associated with developing apnea (AOR = 0.244, 95% CI 0.053-0.291) and EF (AOR = 0.103, 95% CI 0.098-2.976). IMV-duration before extubation (AOR = 2.229, 95% CI 1.672-2.498) and severe/moderate-BPD (AOR = 2.410, 95%CI 1.104-2.952) had a high risk of EF. Initiating early HD-caffeine may prevent apnea and extubation failure in preterm neonates. Optimization of caffeine initiation time and dosages can be a safe and feasible approach to decrease the burden of neonatal respiratory morbidities.

Citrate anticoagulation in plasma exchange followed by continuous renal replacement therapy in critically ill children.

OBJECTIVE: To investigate the effectiveness and safety of regional citrate-anticoagulated (RCA) plasma exchange (PE) and whether citrate-related metabolic disorders can be improved by sequential RCA continuous renal replacement therapy (CRRT). METHODS: This retrospective, single-center observational study included 79 critically ill children requiring PE followed by CRRT (June 2018 to June 2021) at the Pediatric Intensive Care Unit of Hunan Children's Hospital, China. Patients were divided into the RCA-PE (n = 30) and systemic heparin anticoagulation (SHA-PE) (n = 49) groups. Filter level comparison post-PE assessed RCA-PE efficacy, and metabolic changes occurring pre- and post-PE and CRRT were used to evaluate the effect of CRRT on RCA-based anticoagulation safety. RESULTS: The RCA-PE group had a better overall filter performance than the SHA-PE group. Two hours after PE, pH and HCO3- levels increased more significantly for the RCA-PE than the SHA-PE group. The RCA-PE incidence of metabolic alkalosis was 48.3%, higher by 4.2% (p < 0.001) compared to the SHA-PE group. In the RCA-PE group, pH and HCO3- decreased significantly 4 h after CRRT; the metabolic alkalosis caused by RCA-PE decreased to 13.8% (p = 0.005). No significant difference in pH, HCO3-, and metabolic alkalosis incidence was observed between the two groups 4 h after CRRT. CONCLUSIONS: The overall filtration performance of RCA-PE is superior to that of SHA-PE followed by CRRT. The metabolic complications associated with RCA-PE are mainly metabolic alkalosis that can be improved by using CRRT after RCA-PE and this is a better alternative for anticoagulation during PE in critically ill children.

Let's stop talking about 'citrate toxicity'.

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'.

Anticoagulation practices for continuous renal replacement therapy: a survey of physicians from the United States.

BACKGROUND: During continuous renal replacement therapy (CRRT), anticoagulants are recommended for patients at low risk of bleeding and not already receiving systemic anticoagulants. Current anticoagulants used in CRRT in the US are systemic heparins or regional citrate. To better understand use of anticoagulants for CRRT in the US, we surveyed nephrologists and critical care medicine (CCM) specialists. METHODS: The survey contained 30 questions. Respondents were board certified and worked in intensive care units of academic medical centers or community hospitals. RESULTS: 150 physicians (70 nephrologists and 80 CCM) completed the survey. Mean number of CRRT machines in use increased ∼30% from the pre-pandemic era to 2022. Unfractionated heparin was the most used anticoagulant (43% of estimated patients) followed by citrate (28%). Respondents reported 29% of patients received no anticoagulant. Risk of hypocalcemia (52%) and citrate safety (42%) were the predominant reasons given for using no anticoagulant instead of citrate in heparin-intolerant patients. 84% said filter clogging was a problem when no anticoagulant was used, and almost 25% said increased transfusions were necessary. Respondents using heparin (n = 131) considered it inexpensive and easily obtainable, although of moderate safety, citing concerns of heparin-induced thrombocytopenia and bleeding. Anticoagulant citrate dextrose solution was the most used citrate. Respondents estimated that 37% of patients receiving citrate develop hypocalcemia and 17% citrate lock. CONCLUSIONS: Given the increased use of CRRT and the lack of approved, safe, and effective anticoagulant choices for CRRT in the US, effective use of current and other anticoagulant options needs to be evaluated.

Calcium-Citrate Anticoagulation during Continuous Renal Replacement Therapy in Patients with Metformin Intoxication: A Case Series, Mathematical Estimation of Citrate Accumulation, and Literature Review.

INTRODUCTION: Metformin intoxication causes lactic acidosis by inhibiting Krebs' cycle and oxidative phosphorylation. Continuous renal replacement therapy (CRRT) is recommended for metformin removal in critically ill patients. According to current guidelines, regional citrate anticoagulation (RCA) is the first-line strategy. However, since metformin also inhibits citrate metabolism, a risk of citrate accumulation could be hypothesized. In the present study, we monitored the potential citrate accumulation in metformin-associated lactic acidosis (MALA) patients treated with CRRT and RCA using the physical-chemical approach to acid-base interpretation. METHODS: We collected a case series of 3 patients with MALA. Patients were treated with continuous venovenous hemofiltration (CVVH), and RCA was performed with diluted citrate solution. Citrate accumulation was monitored through two methods: the ratio between total and ionized plasma calcium concentrations (T/I calcium ratio) above 2.5 and the strong ion gap (SIG) to identify an increased concentration of unmeasured anions. Lastly, a mathematical model was developed to estimate the expected citrate accumulation during CVVH and RCA. RESULTS: All 3 patients showed a resolution of MALA after the treatment with CVVH. The T/I calcium ratio was consistently below 2.5, and SIG decreased, reaching values lower than 6 mEq/L after 48 h of CVVH treatment. According to the mathematical model, the estimated SIG without citrate metabolism should have been around 21 mEq/L due to citrate accumulation. CONCLUSIONS: In our clinical management, no signs of citrate accumulation were recorded in MALA patients during treatment with CVVH and RCA. Our data support the safe use of diluted citrate to perform RCA during metformin intoxication.

Evaluation of the efficacy and associated complications of regional citrate anticoagulation in neonates: experience from a fourth level neonatal intensive care unit.

Continuous kidney replacement therapy (CKRT) use has increased in recent years, but anticoagulation is a challenge for neonates. Regional citrate anticoagulation (RCA) is rarely preferred in neonates because of citrate accumulation (CA) and metabolic complications. We aimed to demonstrate the efficacy and safety of RCA in neonates. We retrospectively analyzed the medical records of 11 neonates treated with RCA-CKRT between 2018 and 2023. The initial dose of RCA was 2.1-3 mmol/l, and then, its dose was increased according to the level of ionized calcium (iCa+2) in the circuit and patients. The total/iCa+2 ratio after-treatment > 2.5 was indicated as CA. We evaluated to citrate dose, CA, circuit lifespan, and dialysis effectivity. The median gestational age was 39 (36.4-41.5) weeks, the median body weight (BW) was 3200 (2400-4000) grams, and the mean postnatal age was 4 (2-24) days. The most common indication for CKRT was hyperammonemia (73%). All neonates had metabolic acidosis and hypocalcemia during CKRT. Other common metabolic complications were hypophosphatemia (90%), hypokalemia (81%), and hypomagnesemia (63%). High dialysate rates with a median of 5765 ml/h/1.73 m2 allowed for a rapid decrease in ammonia levels to normal. Four patients (36.3%) had CA, and seven (63.7%) did not (non-citrate accumulation, NCA). Mean BW, median postnatal age, biochemical parameters, coagulation tests, and ammonia levels were similar between the CA and NCA groups. Low pH, low HCO3, high lactate, and SNAPPE-II scores could be associated with a higher T/iCa ratio. CONCLUSION:  RCA was an efficient and safe anticoagulation for neonates requiring CKRT. Metabolic complications may occur, but they could be managed with adequate supplementation. WHAT IS KNOWN: • Continuous kidney replacement therapy (CKRT) has become popular in recent years due to its successful treatment of fluid overload, electrolyte imbalance, metabolic acidosis, multi-organ failure, and hyperleucinemia/hyperammonemia associated with inborn errors of metabolism. • The need for anticoagulation is the major difficulty in neonatal CKRT. In adult and pediatric patients, regional citrate anticoagulation has been shown to be effective. WHAT IS NEW: • RCA is an effective and safe anticoagulation method for neonates who require CKRT. • Electrolyte imbalances and metabolic acidosis could be managed with adequate supplementation and appropriate treatment parameters such as citrate dose, blood flow rate, and dialysate flow rate.

Regional Citrate Anticoagulation or Heparin Anticoagulation for Renal Replacement Therapy in Patients With Liver Failure: A Systematic Review and Meta-Analysis.

In patients with liver failure complicated by acute kidney injury, renal replacement therapy (RRT) is often required to improve the internal environment. The use of anticoagulants for RRT in patients with liver failure remains controversial. We searched the PubMed, Embase, Cochrane Library, and Web of Science databases for studies. The methodological quality of the included studies was assessed using the Methodological Index for Nonrandomized Studies. A meta-analysis was performed using R software (version 3.5.1) and Review Manager (version 5.3.5). During RRT, 348 patients from 9 studies received regional citrate anticoagulation (RCA), and 127 patients from 5 studies received heparin anticoagulation (including heparin and LMWH). Among patients who received RCA, the incidence of citrate accumulation, metabolic acidosis, and metabolic alkalosis were 5.3% (95% confidence interval [CI]: 0%-25.3%), 26.4% (95% CI: 0-76.9), and 1.8% (95% CI: 0-6.8), respectively. The potassium, phosphorus, total bilirubin (TBIL), and creatinine levels were lower, whereas the serum pH, bicarbonate, base excess levels, and total calcium/ionized calcium ratio were higher after treatment than before treatment. Among patients who received heparin anticoagulation, the TBIL levels were lower, whereas the activated partial thromboplastin clotting time and D-dimer levels were higher after treatment than before treatment. The mortality rates in the RCA and heparin anticoagulation groups were 58.9% (95% CI: 39.2-77.3) and 47.4% (95% CI: 31.1-63.7), respectively. No statistical difference in mortality was observed between the 2 groups. For patients with liver failure, the administration of RCA or heparin for anticoagulation during RRT under strict monitoring may be safe and effective.

Heparin anticoagulation versus regional citrate anticoagulation for membrane therapeutic plasma exchange in patients with increased bleeding risk.

Background Heparin anticoagulation (HA) is commonly employed for membrane therapeutic plasma exchange (mTPE). However, for patients with increased bleeding risk, there were controversial opinions on the use of HA versus regional citrate anticoagulation (RCA) for mTPE. Our present study aimed to evaluate the efficacy and safety of HA vs. RCA for mTPE in patients with increased bleeding risk.Methods Patients with increased bleeding risk who underwent mTPE between 2014 and 2021 in our center were screened. Observations of anticoagulation efficacy and safety were used as the study endpoints.Results A total of 108 patients with 368 mTPE sessions were included. Of the included patients, 38 and 70 received HA and RCA mTPE, respectively. There was no significant difference in the clotting of extracorporeal circuits between the HA and RCA groups (4.1% vs. 4.4%, p = 0.605). More bleeding episodes were observed in the HA group compared to the RCA group (16.4% vs. 4.4% mTPE sessions, p < 0.001). The frequency of postoperative transfusion within 24 h (11% vs. 3.4%, p = 0.007) was significantly different in the HA and RCA group. Anticoagulation strategy (HA vs. RCA; OR 5.659, 95%CI 2.266-14.129; p < 0.001), and mean arterial pressure (prior treatment, OR 1.052, 95%CI 1.019-1.086; p = 0.002) were independent risk factors of bleeding episodes. At the end of mTPE treatment, the incidence of metabolic alkalosis (16.7% vs. 54.1%, p = 0.027) and hypocalcemia (41.7% vs. 89.2%, p = 0.001) was significantly different in the HA (n = 5, 12 sessions) and RCA (n = 22, 74 sessions) groups, respectively.Conclusion RCA is as effective as HA for mTPE. However, for patients with increased bleeding risk, RCA is associated with a lower risk of bleeding, compared with HA. With careful monitoring and timely adjustment, RCA most likely is a safe and effective anticoagulation option for mTPE in patients with increased bleeding risk.

Simplified regional citrate anticoagulation protocol for CVVH, CVVHDF and SLED focused on the prevention of KRT-related hypophosphatemia while optimizing acid-base balance.

BACKGROUND: Hypophosphatemia is a common electrolyte disorder in critically ill patients undergoing prolonged kidney replacement therapy (KRT). We evaluated the efficacy and safety of a simplified regional citrate anticoagulation (RCA) protocol for continuous venovenous hemofiltration (CVVH), continuous venovenous hemodiafiltration (CVVHDF) and sustained low-efficiency dialysis filtration (SLED-f). We aimed at preventing KRT-related hypophosphatemia while optimizing acid-base equilibrium. METHODS: KRT was performed by the Prismax system (Baxter) and polyacrylonitrile AN69 filters (ST 150, 1.5 m2, Baxter), combining a 18 mmol/L pre-dilution citrate solution (Regiocit 18/0, Baxter) with a phosphate-containing solution (HPO42- 1.0 mmol/L, HCO3- 22.0 mmol/L; Biphozyl, Baxter). When needed, phosphate loss was replaced with sodium glycerophosphate pentahydrate (Glycophos™ 20 mmol/20 mL, Fresenius Kabi Norge AS, Halden, Norway). Serum citrate measurements were scheduled during each treatment. We analyzed data from three consecutive daily 8-h SLED-f sessions, as well as single 72-h CVVH or 72-h CVVHDF sessions. We used analysis of variance (ANOVA) for repeated measures to evaluate differences in variables means (i.e. serum phosphate, citrate). Because some patients received phosphate supplementation, we performed analysis of covariance (ANCOVA) for repeated measures modelling phosphate supplementation as a covariate. RESULTS: Forty-seven patients with acute kidney injury (AKI) or end stage kidney disease (ESKD) requiring KRT were included [11 CVVH, 11 CVVHDF and 25 SLED-f sessions; mean Acute Physiology and Chronic Health Evaluation II (APACHE II) score 25 ± 7.0]. Interruptions for irreversible filter clotting were negligible. The overall incidence of hypophosphatemia (s-P levels <2.5 mg/dL) was 6.6%, and s-P levels were kept in the normality range irrespective of baseline values and the KRT modality. The acid-base balance was preserved, with no episode of citrate accumulation. CONCLUSIONS: Our data obtained with a new simplified RCA protocol suggest that it is effective and safe for CVVH, CVVHDF and SLED, allowing to prevent KRT-related hypophosphatemia and maintain the acid-base balance without citrate accumulation. TRIAL REGISTRATION: NCT03976440 (registered 6 June 2019).

Customized Citrate Anticoagulation versus No Anticoagulant in Continuous Venovenous Hemofiltration in Critically Ill Patients with Acute Kidney Injury: A Prospective Randomized Controlled Trial.

INTRODUCTION: The use of anticoagulants during continuous renal replacement therapy (CRRT) is essential. Regional citrate anticoagulation (RCA) is recommended rather than systemic heparinization to prolong the filter's lifespan in patients at high risk of bleeding. However, commercial citrate is expensive and may not be available in resource-limited areas. The objective of this study is comparing filter life between our locally made customized RCA and no anticoagulation. The primary outcomes were the first circuit life in hours and the number of filters used within the first 72 h of therapy. METHODS: We conducted a single-center prospective randomized controlled trial in critically ill patients requiring CRRT. The participants were randomized to receive continuous venovenous hemofiltration (CVVH) with either customized RCA or no anticoagulant. RESULTS: Of 76 patients, 38 were randomized to receive customized RCA and 38 to receive CVVH without anticoagulant. There was no significant difference in baseline characteristics between the two groups. Compared to anticoagulant-free group, the median circuit life of customized RCA group was significantly longer [44.9 (20.0, 72.0) vs. 14.3 (7.0, 22.0) hours; p < 0.001]. The number of filters used within 72 h was significant lower [2.0 (1.0, 2.0) vs. 2.5 (1.0, 3.0); p < 0.015]. RCA was prematurely discontinued in 5 patients due to citrate accumulation (2 cases) and severe metabolic acidosis requiring higher dose of CVVH (3 cases). No differences in bleeding complications were observed (p = 0.99). CONCLUSION: Customized citrate-based replacement solution improved filter survival in CVVH compared to anticoagulant-free strategy. This regimen is safe, feasible, and suitable for low- to middle-income countries.

Negative calcium balance despite normal plasma ionized calcium concentrations during citrate anticoagulated continuous venovenous hemofiltration (CVVH) in ICU patients.

BACKGROUND: Supplementation of calcium during continuous venovenous hemofiltration (CVVH) with citrate anticoagulation is usually titrated using a target blood ionized calcium concentration. Plasma calcium concentrations may be normal despite substantial calcium loss, by mobilization of calcium from the skeleton. Aim of our study is to develop an equation to calculate CVVH calcium and to retrospectively calculate CVVH calcium balance in a cohort of ICU-patients. METHODS: This is a single-center retrospective observational cohort study. In a subcohort of patients, all calcium excretion measurements in patients treated with citrate CVVH were randomly divided into a development set (n = 324 in 42 patients) and a validation set (n = 441 in 42 different patients). Using mixed linear models, we developed an equation to calculate calcium excretion from routinely available parameters. We retrospectively calculated calcium balance in 788 patients treated with citrate CVVH between 2014 and 2021. RESULTS: Calcium excretion (mmol/24 h) was - 1.2877 + 0.646*[Ca]blood,total * ultrafiltrate (l/24 h) + 0.107*blood flow (ml/h). The mean error of the estimation was - 1.0 ± 6.7 mmol/24 h, the mean absolute error was 4.8 ± 4.8 mmol/24 h. Calculated calcium excretion was 105.8 ± 19.3 mmol/24 h. Mean daily CVVH calcium balance was - 12.0 ± 20.0 mmol/24 h. Mean cumulative calcium balance ranged from - 3687 to 448 mmol. CONCLUSION: During citrate CVVH, calcium balance was negative in most patients, despite supplementation of calcium based on plasma ionized calcium levels. This may contribute to demineralization of the skeleton. We propose that calcium supplementation should be based on both plasma ionized calcium and a simple calculation of calcium excretion by CVVH.

Application of regional citrate anticoagulation in patients at high risk of bleeding during intermittent hemodialysis: a prospective multicenter randomized controlled trial.

OBJECTIVES: Safe and effective anticoagulation is essential for hemodialysis patients who are at high risk of bleeding. The purpose of this trial is to evaluate the effectiveness and safety of two-stage regional citrate anticoagulation (RCA) combined with sequential anticoagulation and standard calcium-containing dialysate in intermittent hemodialysis (IHD) treatment. METHODS: Patients at high risk of bleeding who underwent IHD from September 2019 to May 2021 were prospectively enrolled in 13 blood purification centers of nephrology departments, and were randomly divided into RCA group and saline flushing group. In the RCA group, 0.04 g/mL sodium citrate was infused from the start of the dialysis line during blood draining and at the venous expansion chamber. The sodium citrate was stopped after 3 h of dialysis, which was changed to sequential dialysis without anticoagulant. The hazard ratios for coagulation were according to baseline. RESULTS: A total of 159 patients and 208 sessions were enrolled, including RCA group (80 patients, 110 sessions) and saline flushing group (79 patients, 98 sessions). The incidence of severe coagulation events of extracorporeal circulation in the RCA group was significantly lower than that in the saline flushing group (3.64% vs. 20.41%, P<0.001). The survival time of the filter pipeline in the RCA group was significantly longer than that in the saline flushing group ((238.34±9.33) min vs. (221.73±34.10) min, P<0.001). The urea clearance index (Kt/V) in the RCA group was similar to that in the saline flushing group with no statistically significant difference (1.12±0.34 vs. 1.08±0.34, P=0.41). CONCLUSIONS: Compared with saline flushing, the two-stage RCA combined with a sequential anticoagulation strategy significantly reduced extracorporeal circulation clotting events and prolonged the dialysis time without serious adverse events.

Reevaluation of lock solutions for Central venous catheters in hemodialysis: a narrative review.

BACKGROUND: A significant proportion of incident and prevalent hemodialysis patients have central venous catheters for vascular access. No consensus is available on the prevention of catheter dysfunction or catheter-related bloodstream infections in patients undergoing hemodialysis by means of catheter lock solutions. METHOD: We reviewed the effects of single and combined anticoagulants with antibacterial catheter lock solutions or other antimicrobials for the prevention of thrombosis or infections in hemodialysis patients. Relative risks with 95% confidence intervals for trials of the same type of catheter locking solution were pooled. SOURCES OF INFORMATION: We included original research articles in English from PubMed, EMBASE, SpringerLink, Elsevier and Ovid using the search terms 'hemodialysis,' 'central venous catheter,' 'locking solution,' 'UFH,' 'low molecular weight heparin,' 'EDTA,' 'citrate,' 'rt-PA,' 'urokinase,' 'gentamicin,' 'vancomycin', 'taurolidine,' 'sodium bicarbonate,' 'hypertonic saline' and 'ethanol' and 'catheter'. FINDINGS: Low-dose heparin lock solution (< 5000 U/ml) can efficiently achieve anticoagulation and will not increase the risk of bleeding. Low-concentration citrate (< 5%) combined with rt-PA can effectively prevent catheter infection and dysfunction. Catheter-related infections may be minimized by choosing the appropriate antibiotic and dose. LIMITATIONS: There is a lack of follow-up validation data for LMWH, EDTA, taurolidine, sodium bicarbonate, ethanol, and other lock solutions. IMPLICATIONS: Since catheterization is common in hemodialysis units, studies on long-term treatment and preventative strategies for catheter dysfunction and catheter-related infection are warranted.

Continuous Renal Replacement Therapy with Regional Citrate Anticoagulation in Children with Liver Dysfunction/Failure.

Regional citrate anticoagulation (RCA) is an option but citrate accumulation is risk and it is a giving up cause for this situation. This retrospective study was conducted in the pediatric intensive care unit (PICU) between May 2019 and April 2021. We investigated 47 patients with liver failure (LF) in our PICU, and RCA during continuous renal replacement therapy (CRRT) was applied to 10 (21.3%) of them. Half of them were male (n: 5/10), their mean age was 104.7 ± 66.20 months. Nine of them needed vasoactive support during follow-up. The most common indication for CRRT was hepatorenal syndrome (40%). There was no significant difference between liver transaminases and liver function tests before and after CRRT (p > 0.05). In terms of citrate toxicity of the patients, there was no significant difference between total calcium/ionized calcium, lactate level, pH and bicarbonate values before and after CRRT (p > 0.05). The mean total CRRT time was 110.2 ± 118.2 h, and the mean circuit lifespan was 43.8 ± 48.7 h; the mean number of circuits was 2.7 ± 2.4. Total Ca/ionized Ca >2.5 was a clinically relevant endpoint, but no patient interrupted dialysis for this cause. There was no complication about RCA. This study did not observe any adverse effects on acid-base status, transaminases, an increase in bilirubin during RCA-CRRT treatment in pediatric patients with LF. Total calcium/ionized calcium ratio, serum lactate level and prothrombin time level should be closely monitored daily in terms of citrate accumulation in this patient group.

A Comparison of the Commonly Used Surrogate Markers for Citrate Accumulation and Toxicity during Continuous Renal Replacement Therapy with Regional Citrate Anticoagulation.

INTRODUCTION: Continuous renal replacement therapy using regional citrate anticoagulation is commonly used as a modality of organ support in the critically ill population. Currently, citrate accumulation or toxicity is assessed using surrogate markers, notably the uncorrected total-to-ionized calcium ration. The accuracy and utility of this method have been questioned. OBJECTIVES/AIMS: The aim of this study was to compare the surrogate markers used for assessing citrate accumulation or toxicity using the measurement of plasma citrate as the gold standard. METHODS: Blood was sampled from 20 patients before, during, and after episodes of filtration with citrate concentration measured using spectrophotometry. Demographic and other clinical and biochemical data were also collected. According to protocol, a 15 mmol/L solution of trisodium citrate was used as the prefilter anticoagulant. Results were analyzed using STATA (v16.0) and presented as mean (SD), median (IQR), or simple proportion. Univariate linear regression using citrate concentration as the dependent variable was performed with all surrogate markers. RESULTS: Twenty patients (17 males) were enrolled in the study with a mean (SD) age of 62.7 (9.9) years. The uncorrected calcium ratio had the best fit to the citrate data with an R2 value of 0.39. The albumin-corrected calcium ratio, pH, anion gap (AG), albumin-corrected AG, standard base excess, and strong ion gap all had R2 values less than 0.05. CONCLUSION(S): In the absence of direct measurement of citrate concentration, uncorrected total-to-ionized calcium ratio is superior to other surrogate markers, though not ideal, in assessing citrate accumulation or toxicity.

Regional citrate versus heparin anticoagulation for continuous renal replacement therapy in critically ill patients: A meta-analysis of randomized controlled trials.

INTRODUCTION: This study aimed to compare the efficacy and safety of citrate and heparin in continuous renal replacement therapy (CRRT) for critically ill patients. METHODS: Searched in PubMed, Embase, and Cochrane Library databases. RESULTS: Analyses showed that there no difference existed in mortality, metabolic alkalosis, circuit loss, and the number of transfused between the two groups (RR = 0.95, p = 0.40; RR = 1.73, p = 0.40; RR = 0.64, p = 0.09; RR = 1.05, p = 0.70). The filter life of the citrate group was longer than the heparin group (MD = 16.98, p < 0.0001). The risk of bleeding and heparin-induced thrombocytopenia was significantly lower in the citrate (RR = 0.32, p < 0.00001; RR = 0.55, p = 0.04). The citrate group was more susceptible to hypocalcemia (RR = 4.85, p = 0.0004). CONCLUSION: Citrate anticoagulant therapy should have priority for CRRT in most critically ill patients.

Comparison of nafamostat mesilate to citrate anticoagulation in pediatric continuous kidney replacement therapy.

BACKGROUND: Regional citrate anticoagulation (RCA) is the preferred continuous kidney replacement therapy (CKRT) anticoagulation strategy for children in the USA. Nafamostat mesilate (NM), a synthetic serine protease, is used widely for CKRT anticoagulation in Japan and Korea. We compared the safety and efficacy of NM to RCA for pediatric CKRT. METHODS: Starting June 2019, the most recent 100 medical records of children receiving CKRT with either RCA or NM were reviewed retrospectively, at one children's hospital in Japan (NM) and one in the USA (RCA). The number of hours a single CKRT filter was in use, was the primary outcome. Safety was assessed by bleeding complications for the NM group and citrate toxicity leading to RCA discontinuation or electrolyte imbalance in the RCA group. RESULTS: Eighty patients received NM and 78 patients received RCA. Median filter life was longer for the NM group (NM: 38 [22, 74] vs. RCA: 36 [17, 66] h, p = 0.02). When filter life was censored for discontinuation other than clotting, the 60-h survival rate was higher for RCA (71% vs. 54%). The hazard ratio comparing NM over RCA varied over time (HR 0.7; 0.2-1.5, p = 0.33 at 0 h to HR 5.5; 1.3-23.7, p = 0.334 at 72 h). The lack of difference in filter survival persisted controlling for filter surface area, catheter diameter, and pre-CKRT platelet count. Major bleeding rates did not differ between groups (NM: 5% vs. RCA: 9%). CONCLUSIONS: RCA and NM provide satisfactory anticoagulation for CKRT in children with no difference in major bleeding rates. A higher resolution version of the Graphical abstract is available as Supplementary information.

Application of simplified regional citrate anticoagulation in hemodialysis patients with high risk of bleeding.

AIM: To explore the safety, effectiveness, and dialysis adequacy of simplified regional citrate anticoagulation hemodialysis (SRCA-HD) in hemodialysis patients with high risk of bleeding. MATERIALS AND METHODS: From 64 hemodialysis patients, 400 cases of low blood flow (150 mL/min, dialysate flow 300 mL/min) SRCA-HD were retrospectively analyzed and subsequently referred to as the LBF-SRCA group. Then, a prospective cross-over study was performed in 24 hemodialysis patients with normal blood flow (200 mL/min, dialysate flow 500 mL/min) SRCA-HD, which was called the NBF-SRCA group. Citrate was pumped at the artery pipeline, and calcium-containing dialysate (A group: 1.25 mmol/L, B group: 1.5 mmol/L) was used. The differences in laboratory tests, pipeline and dialyzer clotting, adequacy of dialysis, and adverse events of the groups were compared. RESULTS: 1) In the LBF-SRCA study, the correlation between citrate dosage and serum Ca2+ level at 2 hours post-filter during dialysis was negative (r = -0.228, p < 0.05). Compared with the LBF-SRCA and NBF-SRCA-A group, the pump speed of citrate in the NBF-SRCA-B group was the highest, with 355.0 ± 19.5 mL/h, 396.3 ± 11.9 mL/h, and 407.7 ± 13.0 mL/h, respectively, p < 0.001. 2) The serum Ca2+ at 2 and 4 hours post-filter during dialysis in the NBF-SRCA-B group was closer to the physiological level and significantly higher than in the A group, with 0.80 ± 0.06 vs. 0.68 ± 0.12 mmol/L, p < 0.001; 1.03 ± 0.11 vs. 0.93 ± 0.10 mmol/L, p = 0.005, respectively. 3) Both Kt/V of the NBF-SRCA-A (1.17 ± 0.24) and B (1.22 ± 0.23) group were significantly higher than that of the LBF-SRCA group (0.94 ± 0.02), p = 0.024 and p = 0.005, respectively. 4) The efficiency of anticoagulation was higher than 95% LBF-SRCA, NBF-SRCA-A and NBF-SRCA-B groups. The total clotting in the NBF-SRCA-B group (5/24) was significantly higher than that in the A group (3/24), p = 0.005. CONCLUSION: SRCA is safe, simple, and effective in hemodialysis. The dosage of citrate can be adjusted by monitoring serum Ca2+ at 2 hours post-filter during dialysis. BFR of 200 mL/min, dialysate flow rate of 500 mL/min, and 1.5 mmol/L calcium dialysate are much safer in hemodialysis patients with a high-risk of bleeding.

Comparison Between Same-Day and Split-Dose Preparations with Sodium Picosulfate/Magnesium Citrate: A Randomized Noninferiority Study.

BACKGROUND: Sodium picosulfate/magnesium citrate (SPMC) is a small-volume bowel cleansing agent with similar efficacy to and better tolerability than polyethylene glycol. However, we found no data on which SPMC preparation (same-day vs. split-dose) provides better bowel cleansing efficacy for afternoon colonoscopy. AIMS: To compare bowel cleansing efficacy of different timing of the regimen. METHODS: This randomized, single-center, endoscopist-blinded, noninferior study compared same-day and split-dose SPMC preparations for afternoon colonoscopy in 101 and 96 patients, respectively. We also included a prospective observation group of 100 patients receiving morning colonoscopy to compare bowel preparation between morning and afternoon colonoscopies. Bowel cleansing efficacy was then evaluated by the Aronchick Scale, Ottawa Bowel Preparation Scale (OBPS), Boston Bowel Preparation Scale (BBPS), and the Bubble Scale. RESULTS: Same-day and split-dose preparations were similar in efficacy in all four scales. In the Aronchick Scale, the success rate (excellent and good cleanliness) was higher in same-day preparation than in split-dose preparation (100% vs. 92.8%). The same-day preparation also obtained a better OBPS score (1.4 vs. 2.1), but BBPS showed no difference between such groups (7.7 vs. 7.4). CONCLUSION: Same-day preparation with SPMC is not inferior to split-dose preparation for afternoon colonoscopy.