Ionic homeostasis, acid-base balance and the risk of citrate accumulation in patients after cardiovascular surgery treated with continuous veno-venous haemofiltration with post-dilution regional citrate anticoagulation - An observational case-control study.

BACKGROUND: Patients after cardiovascular surgery, requiring renal replacement therapy, can benefit from adequate non-heparin circuit anticoagulation. Simplified regional citrate anticoagulation (RCA) protocol proposes the use of citric acid dextrose formula A (ACD-A) during post-dilutional continuous veno-venous hemofiltration (CVVH) with standard bicarbonate buffered calcium containing replacement solution. Citrate accumulation diagnosed upon total to ionized calcium ratio (tCa/iCa) and low ionized calcium (iCa) are considered as the biggest risks related to regional citrate accumulation. METHODS: This prospective observational case-control study evaluated electrolyte and acid-base homeostasis in cardiovascular surgery patients treated with post-dilution CVVH with a simplified RCA protocol with ACD-A. In total, 50 consecutive cardiovascular surgery patients were evaluated. Base excess, pH, bicarbonate, lactate, Na+, Cl-, Mg++, and inorganic phosphate concentrations, the total to ionized calcium ratio (tCa/iCa), and high anion gap metabolic acidosis were assessed during haemofiltration treatment in survivors and non-survivors. RESULTS: Thirty-three (66%) patients died. The therapies were very well balanced in sodium and chloride homeostasis. The lactate concentration and anion gap decreased during CVVH sessions lasting longer than 72 hours, but no inter-group difference was observed. The tCa/iCa ratio exceeded 4.5% and was significantly higher in non-survivors (p=0.037). Initial lactate concentration did not correlate with tCa/iCa ratio during haemofiltration. Magnesium and phosphate concentrations decreased and additional supplementation with magnesium was necessary. The magnesium concentration was lower in the non-survivors. CONCLUSIONS: The incidence of citrate accumulation exceeded 4% and was significantly higher in non-survivors. Supplementation with magnesium and phosphate ions is needed in CVVH with RCA.

Regional citrate anticoagulation "non-shock" protocol with pre-calculated flow settings for patients with at least 6 L/hour liver citrate clearance.

BACKGROUND: Regional citrate anticoagulation (RCA) for the prevention of clotting of the extracorporeal blood circuit during continuous kidney replacement therapy (CKRT) has been employed in limited fashion because of the complexity and complications associated with certain protocols. Hypertonic citrate infusion to achieve circuit anticoagulation results in variable systemic citrate- and sodium load and increases the risk of citrate accumulation and hypernatremia. The practice of "single starting calcium infusion rate for all patients" puts patients at risk for clinically significant hypocalcemia if filter effluent calcium losses exceed replacement. A fixed citrate to blood flow ratio, personalized effluent and pre-calculated calcium infusion dosing based on tables derived through kinetic analysis enable providers to use continuous veno-venous hemo-diafiltration (CVVHDF)-RCA in patients with liver citrate clearance of at least 6 L/h. METHODS: This was a single-center prospective observational study conducted in intensive care unit patients triaged to be treated with the novel pre-calculated CVVHDF-RCA "Non-shock" protocol. RCA efficacy outcomes were time to first hemofilter loss and circuit ionized calcium (iCa) levels. Safety outcomes were surrogate of citrate accumulation (TCa/iCa ratio) and the incidence of acid-base and electrolyte complications. RESULTS: Of 53 patients included in the study, 31 (59%) had acute kidney injury and 12 (22.6%) had the diagnosis of cirrhosis at the start of CVVHDF-RCA. The median first hemofilter life censored for causes other than clotting exceeded 70 h. The cumulative incidence of hypernatremia (Na > 148 mM), metabolic alkalosis (HCO3- > 30 mM), hypocalcemia (iCa < 0.9 mM) and hypercalcemia (iCa > 1.5 mM) were 1/47 (1%), 0/50 (0%), 1/53 (2%), 1/53 (2%) respectively and were not clinically significant. The median (25th-75th percentile) of the highest TCa/iCa ratio for every 24-h interval on CKRT was 1.99 (1.91-2.13). CONCLUSIONS: The fixed citrate to blood flow ratio, as opposed to a titration approach, achieves adequate circuit iCa (< 0.4 mm/L) for any hematocrit level and plasma flow. The personalized dosing approach for calcium supplementation based on pre-calculated effluent calcium losses as opposed to the practice of "one starting dose for all" reduces the risk of clinically significant hypocalcemia. The fixed flow settings achieve clinically desirable steady state systemic electrolyte levels.

Optimized calcium supplementation approach in post-dilution CVVHDF using regional citrate anticoagulation.

BACKGROUND: Regional citrate anticoagulation has been recommended as first choice for anticoagulation of continuous renal replacement therapy. Precise calcium supplementation is important for the safety of regional citrate anticoagulation. In this study we aimed to provide an optimized calcium supplementation approach for regional citrate anticoagulation in post-dilution continuous venous-venous hemodiafiltration. METHODS: Twenty-seven patients receiving post-dilution continuous venous-venous hemodiafiltration anticoagulated by citrate were included in this study. The ionized calcium levels were monitored and maintained in the targeted range. After linear regression analysis of the clearance of non-protein bound calcium and calculating the ratio of the non-protein bound calcium concentration to total calcium concentration, we concluded the mathematical model for calcium supplementation. RESULTS: Positive correlations were found between the clearance of non-protein bound calcium and both dialysate flow rates (r = 0.647, p < 0.001) and ultrafiltration plus substitution fluid flow rates (r = 0.525, p = 0.005). The ratio of the non-protein bound calcium concentration to total calcium concentration values at the pre-filter point after infusion of citrate were constant about 0.83. Based on the clearance and the calcium ratio, the amount of extracorporeal calcium removal can be estimated with a simplified equation. CONCLUSIONS: We provided an optimized calcium supplementation approach for post-dilution continuous venous-venous hemodiafiltration anticoagulated by citrate which may help to estimate the amount of extracorporeal circuit removal of calcium with regard to different dosages of regional citrate anticoagulation.

Meropenem dosing recommendations for critically ill patients receiving continuous renal replacement therapy.

PURPOSES: To gather available meropenem pharmacokinetics and define drug dosing regimens for Asian critically ill patients receiving CRRT. METHODS: All necessary pharmacokinetic and pharmacodynamic data from Asian population were gathered to develop mathematic models with first order elimination. Meropenem concentration-time profiles were calculated to evaluate efficacy based on the probability of target attainment (PTA) of 40%fT>4MIC. A group of 5000 virtual patients was created and tested using Monte Carlo simulations for each dose in the models. The optimal dosing regimens were defined as the doses achieved at least 90% of the PTA. RESULTS: The recommended meropenem dosing regimen for Asian critically ill patients receiving CRRT with standard (20-25 mL/kg/h) and high (35 mL/kg/h) effluent rates was 750 mg q 8 h to manage Gram negative infections with expected MIC < 2 mg/L in virtual Asian patients. Some meropenem dosages from available clinical resources could not achieve the aforementioned target. The volume of distribution, body weights and nonrenal clearance significantly contributed to drug dosing adaptation especially in the specific population. CONCLUSIONS: A meropenem regimen of 750 mg q 8 h was recommended for Asian critically ill patients receiving 2 different CRRT modalities with standard and high effluent rates. Clinical validation of these results is needed.

Serum glucose and phosphorus concentrations during continuous renal replacement therapy using commercial replacement solutions with or without phosphorus.

INTRODUCTION: Continuous venovenous hemofiltration (CVVH) is a common practice in the intensive care unit often associated with electrolyte derangements. Recently, our institution added a phosphate dialysis solution, Phoxillum®, to our formulary as an option for CVVH fluid in addition to the bicarbonate-based Prismasol® products available. We sought to evaluate the impact of Phoxillum in patients who required CVVH when compared to Prismasol with regard to phosphate and glucose management. METHODS: This was a single-center, retrospective, observational cohort analysis approved by Partners Health Care System Institutional Review Board that included patients who received a minimum of 24 hours of either Prismasol 4/2.5 or Phoxillum for CVVH from February 2017 to November 2017. Phosphate and glucose levels were monitored daily while on CVVH. Prevalence of hypoglycemia (glucose <70 mg/dL), hyperglycemia (glucose >180 mg/dL), hypophosphatemia (phosphate <2.5 mg/dL), and hyperphosphatemia (phosphate >4.3 mg/dL) were collected in terms of days of occurrence while on CVVH. Oral and intravenous phosphate repletion requirements were collected for all patients. FINDINGS: Hypophosphatemia occurred more frequently while patients were receiving Prismasol as compared to Phoxillum (130 [24.9%] vs. 13 [6.2%], rate ratio [RR] 0.20 [95% confidence interval-CI = 0.10-0.42, P < 0.0001]), and consequently there was a numerically lower need for intravenous phosphorous repletion in the Phoxillum group (RR = 0.58, 95% CI [0.26, 1.30], P = 0.19]. There was a numerically higher incidence of hyperphosphatemia while patients were on Phoxillum therapy as compared to Prismasol (78 [37%] vs. 145 [27.7%], RR 1.25 [95% CI = 0.84, 1.86, P = 0.27]). There was no difference between the Phoxillum and Prismasol groups in terms of hypoglycemia or hyperglycemia. There was no notable difference in the cost found between the two therapies. DISCUSSION: The findings suggest that the use of Phoxillum for CVVH may be associated with decreased incidence of hypophosphatemia and a potentially decreased need for phosphate repletion in patients who require CVVH.

Predictors of Hypophosphatemia and Outcomes during Continuous Renal Replacement Therapy.

INTRODUCTION: Hypophosphatemia occurs in up to 80% of patients undergoing continuous renal replacement therapy (CRRT) and has been associated with poor outcomes. Whether preemptive phosphate supplementation is warranted in select patients has not been adequately explored. This single-center, retrospective cohort study evaluates predictors of hypophosphatemia and characterizes treatment approaches in adult patients undergoing at least 12 h of CRRT. METHODS: Patients were divided into 2 groups based on the presence or absence of hypophosphatemia as defined by serum phosphorus <2.5 mg/dL. Select laboratory values at baseline and during CRRT, medications and nutritional sources affecting phosphorus, and CRRT parameters were compared. Patient outcomes including resolution of acute kidney injury (AKI), freedom from renal replacement therapy at hospital discharge, duration of intensive care unit (ICU) and hospital stay, duration of mechanical ventilation, and ICU mortality were evaluated. RESULTS: Seventy-two patients were included. The group was 43% female and 51% African American. CRRT was ordered for AKI in 83% and for end-stage renal disease in 15%. Hypophosphatemia occurred in 45 patients (63%). Mean time to development of hypophosphatemia was 34 ± 22 h. Patients who developed hypophosphatemia received a longer duration of CRRT (p = 0.001), were more likely to have a diet ordered (p = 0.005), less likely to have received calcium infusions (p = 0.045), and had lower phosphorus (p = 0.017) and potassium levels (p = 0.038) and higher calcium levels at baseline (p = 0.048). Development of hypophosphatemia was associated with an increased duration of ICU stay (p = 0.014) but not with the other patient outcomes evaluated. Twenty-seven of the 45 patients (60%) who developed hypophosphatemia received phosphorus supplementation with near equal use of intravenous, oral, and combination routes. Only 17 patients (38%) achieved resolution of hypophosphatemia while on CRRT. CONCLUSION: Hypophosphatemia is common, difficult to correct, and contributes to longer ICU stays in patients requiring CRRT. A preemptive approach to address hypophosphatemia including aggressive supplementation strategies to correct phosphorus is warranted in patients requiring CRRT.

Population Pharmacokinetics of Vancomycin Under Continuous Renal Replacement Therapy Using a Polymethylmethacrylate Hemofilter.

BACKGROUND: Although continuous hemodiafiltration (CHDF) is often performed in critically ill patients during sepsis treatment, the pharmacokinetics of vancomycin (VCM) during CHDF with a polymethylmethacrylate hemofilter (PMMA-CHDF) have not been revealed. In this study, the authors aimed to describe the population pharmacokinetics of VCM in critically ill patients undergoing PMMA-CHDF and clarify its hemofilter clearance (CLhemofilter). METHODS: This single-center, retrospective study enrolled patients who underwent intravenous VCM therapy during PMMA-CHDF at the intensive care unit of Chiba University Hospital between 2008 and 2016. A population analysis was performed, and CLhemofilter was assessed. RESULTS: Twenty-five patients were enrolled. Median body weight (BW) and Sequential Organ Failure Assessment (SOFA) score were 63 kg and 15, respectively. Mean conditions for CHDF were 107.5 ± 18.3 mL/min for blood flow rate and 26.3 ± 6.3 mL/kg/h for effluent flow rate. The mean parameter estimates were distribution volume of the central compartment (V1), 59.1 L; clearance of the central compartment (CL1), 1.35 L/h; distribution volume of the peripheral compartment (V2), 56.1 L; and clearance of the peripheral compartment (CL2), 3.65 L/h. BW and SOFA score were significantly associated with V1 (P < 0.05) and CL1 (P < 0.05), respectively, and were thus selected as covariates in the final model. The estimated dosage of VCM to achieve a target area under the concentration-time curve/minimum inhibitory concentration ≥400 was 27.1 mg/kg for loading and 9.7 mg/kg every 24 hours for maintenance; these dosages were affected by BW and SOFA score. Mean CLhemofilter obtained from 8 patients was 1.35 L/h, which was similar to CL1. CONCLUSIONS: The authors clarified the pharmacokinetics and CLhemofilter of VCM in PMMA-CHDF patients. The PK of VCM in patients undergoing CHDF appeared to vary not only with the CHDF setting and BW but also with SOFA score.

[Nutrition in children with continuous renal replacement therapy]. / Nutrición en niños tratados con técnicas de depuración extrarrenal continua.

INTRODUCTION: The aim of this study was to analyse the nutritional state, diet and gastrointestinal complications of children that require continuous renal replacement therapy (CRRT). MATERIAL AND METHODS: A retrospective analysis of a database, which included the information about patients who required CRRT between the years 2013 and 2017. Data were collected on the replacement technique, type of nutrition, calorie and protein intake, gastrointestinal complications, and clinical course. RESULTS: A total of 65 children (61.5% male) were treated with CRRT, and 24 patients (37%) also needed ECMO support. Just over one-quarter (27.7%) of patients had a weight less than P3, and 48.4% of them a height less than P3. At the beginning of the technique, 31 children (47.7%) received enteral nutrition, at the end, there were 52 patients receiving enteral nutrition (80%). The transpyloric tube was used to provide nutrition in 76% of the cases. The median caloric intake was 63kcal/kg/day, and the protein intake was 1.6g/kg/day. There were gastrointestinal difficulties during the process in 48 patients (73.8%), with 29 (44.6%) patients being diagnosed with gastric distension or excessive gastric remains, 22 (33.8%) with constipation, 8 (12.3%) with vomiting, and 4 (6.1%) diarrhoea. One patient treated with ECMO presented with intestinal ischaemia. Enteral nutrition was cancelled in 3 patients (4.6%) due to the complications. There was no relationship between complications and type of diet or ECMO assistance. CONCLUSIONS: A high percentage of children treated with CRRT showed undernutrition but they had adequate tolerance to the enteral nutrition. Although the gastrointestinal complications percentage was high in few subjects, these complications are the reason why enteral nutrition was stopped.

Continuous venovenous hemodiafiltration using cytokine-adsorbing hemofilters as adjuvant therapy for anaerobic descending necrotizing mediastinitis: a case report.

BACKGROUND: We describe a combinatorial intensive care approach and discuss the critical factors that allowed us to successfully manage a life-threatening case of acute anaerobic septic shock triggered by descending necrotizing mediastinitis. CASE PRESENTATION: We admitted a 38-year-old critically ill Kosovar Albanian man to our intensive care unit because of clinical manifestations of severe sepsis. His condition had worsened in the previous 2 weeks following unsuccessful antibiotic therapy for tonsillitis complicated by retropharyngeal abscesses. Computed tomography and intraoperative observations identified abscesses in the anterior and middle mediastinum regions and the distal part of the neck, directly on the border with the left lobe of the thyroid gland. Cultures indicated infections with α-hemolytic Streptococcus and Clostridium species: High procalcitonin and lactate levels, blood gas analysis, poor peripheral capillary oxygen saturation, and severe hemodynamic instability pointed to a case of acute septic shock. The entire treatment consisted of an aggressive antibiotic regimen, transthoracic and mediastinal surgical evacuation of the abscess, vacuum sealing drainage with a pleural chest tube, continuous venovenous hemodiafiltration using cytokine-adsorbing hemofilters, and extracorporeal blood hyperoxygenation. CONCLUSIONS: Efficient treatment of severe anaerobic sepsis resulting from descending necrotizing mediastinitis should build on a multidisciplinary approach. In support of first-line therapies with targeted antibiotics and surgical debridement, clinicians should consider alternative therapies such as continuous venovenous hemodiafiltration with cytokine-adsorbing hemofilters and hyperoxygenation.

New modes of continuous renal replacement therapy using a refiltering technique to reduce micronutrient loss.

INTRODUCTION: Micronutrient depletion is a major drawback of high-dose continuous renal replacement therapy (CRRT). We tested two novel CRRT modes, double-filtration hemofiltration (DHF) and dialysate-recycling hemodiafiltration (DHDF), aimed at reducing micronutrient loss while maintaining a high clearance rate of midsized solutes comparable to that of high-volume hemofiltration (HVHF). METHODS: Forty patients with renal failure requiring CRRT were randomly assigned to receive predilutional standard-volume hemofiltration (SVHF, effluent rate 35 mL/kg/h), predilutional HVHF (100 mL/kg/h), DHF (35 mL/kg/h), and DHDF (30 mL/kg/h). In the two novel modes of CRRT, part of the high-volume primary effluent fluid produced by a high-flux filter (AV600S) was refiltered by two low-flux filters (15 L) for recycling as replacement fluid in DHF and dialysate in DHDF, while the remainder was discarded as final effluent fluid. Specimens were collected for measurement of trace elements, folic acid, amino acids (AAs), ß2-microglobulin, cystatin C, and creatinine and for calculation of solute clearance. FINDINGS: The clearance of 17 AAs, phosphorus, folic acid, copper, and zinc by DHF and DHDF was much lower than that by HVHF and comparable to that by SVHF. The estimated amount of AA loss by SVHF, HVHF, DHF, and DHDF was 10.3 (7.2-13.4) g/d, 22.1 (17.8-24.0) g/d, 10.6 (8.6-14.0) g/d, and 10.0 (8.6-11.4) g/d, respectively. Clearance of cystatin C and ß2-microglobulin by DHF and DHDF was much greater than that by SVHF and equal to that by HVHF. DISCUSSION: Compared to HVHF, DHF, and DHDF have an equal capacity for removal of large solutes but show substantially reduced micronutrient loss.

Calcium supplementation in CVVH using regional citrate anticoagulation.

INTRODUCTION: Calcium supplementation is one of the most important factors in maintaining the safety and efficacy of regional citrate anticoagulation (RCA) during continuous renal replacement therapy (CRRT). The aims of this study were to assess the determinants of calcium requirements in RCA-CVVH and to simplify the calcium supplementation approach. METHODS: Our study consisted of two parts. The first part was a discovery phase to determine the key factors of calcium supplementation. Twenty critically ill patients who required RCA-CVVH were enrolled in this part. Systemic citrate, total calcium, protein-bound calcium, and ionized calcium concentrations were serially measured using the traditional RCA protocol. A two-phase calcium supplementation protocol was then proposed, and algorithms were developed for calcium supplementation. The second part of the study was the validation phase. Another 97 critically ill patients were enrolled and were treated with RCA-CVVH using the new version of the calcium supplementation protocol. FINDINGS: The loss of calcium flux in the extracorporeal circuit and the increase in citrate-calcium complexes in vivo were the main determinants of the required calcium supplementation. In the CVVH mode, the rate of calcium infusion had to be reduced after systemic citrate level reached a steady state. With the aid of mathematical models, systemic calcium levels could be stably maintained in the normal range, and the frequencies of calcium monitoring were reduced. DISCUSSION: Calcium supplementation during RCA-CVVH undergoes two phases. We propose mathematical models to quantify the need for calcium supplementation, which enable individualization of the RCA prescription and simplify the management of RCA in the CVVH mode.