Citrate: a different mental approach to extracorporeal circuit anticoagulation

Citrate anticoagulation (RCA) during continuous renal replacement therapy (CRRT) in intensive care units (ICUs) is a practical application of a regional technique in which anticoagulation is virtually restrained to the extracorporeal circuit. This technique involves a different mental approach to anticoagulation, which gives RCA an advantage over systemic anticoagulation. The efficacy of anticoagulation depends on the level of citratemia reached in the circuit (from 2 to 6 mmol/L) and the associated decrease in ionized calcium (from 0.5 to 0.1 mmol/L). Compared with heparin in ICU patients in terms of efficacy and safety, citrate is able to maintain circuit patency for the same time, if not longer. It also reduces the risk of bleeding and the need for blood transfusions. Metabolic alterations during RCA such as metabolic alkalosis, hypocalcemia and hypernatremia are rare and of little clinical impact; their incidence is similar to those reported during CRRT with heparin. In patients at risk of citrate accumulation due to liver metabolism failure, the citrate load returning to the patient can be reduced by increasing the dialysis effluent volume. The popularity of RCA worldwide is neither high nor uniform. Apart from clinical indications, its diffusion is influenced by local and logistic conditions, the level of staff skill, and economic factors. However, thanks to the availability of dedicated monitors, disposable materials, and easy-to-learn operative protocols fitting patients' needs the use of RCA is increasing. For these reasons, RCA is expected to become the ruling anticoagulation approach during CRRT in ICUs.     

Outcomes of Continuous Renal Replacement Therapy With Regional Citrate Anticoagulation in Small Children After Cardiac Surgery: Experience and Protocol From a Single Center

Patients after a cardiac surgery in cardiopulmonary bypass often present an acute kidney failure. Continuous renal replacement therapy (CRRT) is often required. The aim of this study was to present effectiveness and safety of CRRT with regional citrate anticoagulation (RCA‐CRRT) in small children after cardiac surgery. A retrospective analysis was conducted on 15 patients after cardiac surgery and who had RCA‐CRRT performed in 2014. The established protocol was followed. Mean time on the RCA‐CRRT was 192 h 40 min with the circuit mean lifetime of 43 h 33 min. Clotting was found to be a cause of shutdown in 29% of circuits. No severe electrolyte and metabolic disorders were observed. The RCA‐CRRT is a safe procedure for critically ill children with contraindications to the CRRT with heparin anticoagulation. To avoid adverse effects related to metabolic disorders a proper procedure protocol has to be followed.     

Regional Citrate Anticoagulation in Predilution Continuous Venovenous Hemofiltration Using Prismocitrate 10/2 Solution

Regional citrate anticoagulation (RCA) for continuous renal replacement therapy (CRRT) is associated with a longer filter life and fewer bleeding events. Complexity of the regimen is the major hurdle preventing widespread application. This study describes a simple predilution continuous venovenous hemofiltration (CVVH) protocol utilizing a commercially prepared replacement solution containing citrate (Prismocitrate 10/2). Ten patients with acute renal failure were evaluated. The Prismaflex system was used for predilution CVVH, with Prismocitrate 10/2 running at 2500 mL/h as the main predilution replacement. An 8.4% sodium bicarbonate solution was infused at 50 mL/h in the first 2 h followed by 30 mL/h; 10% calcium gluconate was given to achieve an ionized calcium (iCa) level of 1–1.2 mmol/L. The circuit was run for 72 h unless there was filter clotting, transportation was required, or the patient did not require further CRRT. Total treatment duration was 504.5 h. The post‐dilution equivalent ultrafiltration rate was 32.9 mL/kg/h (interquartile range [IQR] 31.6–38.2) and the median circuit life was 50.3 h (IQR 25.5–72.0). None of the circuit was changed due to circuit clotting. The median systemic iCa was 0.98 mmol/L (IQR 0.91–1.08). The total calcium‐to‐iCa ratio was 2.33 (IQR 2.21–2.45). None of the patients developed hypernatremia (Na ≥ 150 mmol/L) or citrate toxicity (total Ca‐to‐iCa ratio > 2.5 plus increasing metabolic acidosis), and metabolic alkalosis (pH ≥ 7.5) occurred in one patient. This simple RCA CVVH protocol using commercially‐prepared solution could be a feasible, relatively safe, and effective alternative to the conventional regimen for patients with a body weight up to 80 kg.     

局部枸橼酸钠抗凝连续性肾替代治疗中可通过管路采血监测钙浓度

目的:探讨对重症医学科(ICU)行局部枸橼酸钠抗凝(RCA)的连续性肾替代治疗(CRRT)患者通过管路采血检测钙离子(i Ca2+)浓度的可行性。方法:回顾性分析2015年1月-2019年7月入住南通大学附属海安医院ICU患者100例,其中使用普通CRRT机器的患者50例,使用Ci-Ca专用仪器的患者50例。同时采集血滤管路内血液样本和动脉血,分别检测i Ca2+浓度,并采用Bland-Altman法分析2种采血方式血液i Ca2+浓度。观察患者一次性穿刺成功率和采血点不良反应发生率。结果:普通CRRT组和Ci-Ca专用CRRT组患者血滤管路采血和动脉采血,血液i Ca2+浓度差异无统计学意义[(1. 058±0. 083) mmol/L vs(1. 069±0. 085) mmol/L,(1. 069±0. 086) mmol/L vs(1. 076±0. 085) mmol/L,P均 0. 05]。绘制Bland-Altman散点图,2组患者血滤管路采血和动脉采血的血液i Ca2+浓度具有一致性(P=0. 0688,0. 0599)。普通CRRT组血管内采血一次穿刺成功率为94. 0%,穿刺位点渗血、淤青、血肿等不良反应发生率分别为10%、16%、8%,而血滤管路采血则未发生上述不良反应,且一次穿刺成功率均为100%。结论:对于行RCA-CRRT治疗的ICU高危患者,通过血滤管路采血检测的i Ca2+浓度与动脉血i Ca2+浓度具有一致性,在密切监测i Ca2+浓度的前提下可代替动脉穿刺采血。     

Antikoagulation bei der extrakorporalen Therapie des akuten Nierenversagens

Anticoagulation is of central importance for efficient continuous renal replacement therapy (CRRT). Premature clotting of the extracorporeal system leads to therapy interruption, is costly, and causes relevant blood loss. Unfractionated heparin is still the standard anticoagulant for CRRT. Disadvantages are increased bleeding risk, often suboptimal coagulation inhibition, and heparin-induced thrombocytopenia. Regional citrate anticoagulation (RCA) is in several aspects superior to heparin and is increasingly used for CRRT. It allows significantly longer filter running times, and a bleeding risk can be completely excluded due to its mode of action. In its modern form, RCA is safe and associated with a low rate of mostly mild metabolic changes. In case of severe liver insufficiency, RCA can lead to metabolic complications. In this special situation, CRRT without any anticoagulation can be successful. Patients with acute heparin-induced thrombocytopenia and need for CRRT should be treated with argatroban as the first choice, and combination with RCA may be useful. The use of RCA only is inadequate.     

Regional citrate anticoagulation: towards a first-choice treatment

Continuous renal replacement therapy (CRRT) is the most widely used technique for the treatment of severe acute kidney injury in the critically ill. The need for prolonged anticoagulation is the most important drawback of CRRT and clinically important bleeding significantly increases the risk of death. Therefore, alternative anticoagulation methods should be more widely adopted. Among the potential alternatives to systemic heparin anticoagulation, regional citrate anticoagulation (RCA) is the most promising. By reducing ionized calcium inside the extracorporeal circuit, citrate is able to block the coagulation cascade at different levels. Compared with unfractionated heparin, several studies reported better filter survival times and a marked reduction of transfusion rates with RCA. Despite the positive reports about the efficacy and safety of RCA, the use of this alternative method of anticoagulation appears to be relatively limited. Desirable future improvements in RCA should be focused on simplifying protocols, minimizing the need for calcium and magnesium supplementation, increasing the flexibility of buffer balance, and introducing customized dialysis systems able to deliver automated RCA. In particular, safe protocols with automated delivery of citrate and calcium can allow easy parameter settings that can be adapted to a wide range of clinical situations, facilitating the wider use of RCA in the coming years.     

Calcific degeneration as the main cause of porcine bioprosthetic valve failure

Sixty-seven glutaraldehyde-processed porcine bioprostheses (PBs), recovered at autopsy or reoperation from 65 patients, were evaluated by roentgenologic and pathologic examination. Seven patients with 8 PBs were younger than 20 years of age. The time interval of function was 2 to 138 months (average 62). Pathologically, 53 explants had signs of intrinsic dysfunction, which was ascribed to calcification in 36 (68%). By x-ray examination, calcific deposits were found in 55 of 67 PBs (82%). The mean duration of function was 70 ± 32 months in calcified PBs vs 27 ± 18 months in noncalcified PBs (p <0.001). All 26 PBs that had been in place for longer than 6 years were calcified. In 45 PBs the Ca⁺⁺ deposits were considered severe (mean time of function 76 ± 32 months) and mild in 10 (mean time of function 44 ± 22 months) (p <0.005). The Ca⁺⁺ deposits were located at the commissures in 54 PBs (98%), at the body of cusps in 41 (75 %), at the free margin in 37 (67 %) and at the aortic wall in 37 (67%). When mild, Ca⁺⁺ deposits involved the commissures in 90% of cases, the body of cusps in 30 % and the free margin only in 10%. Forty-seven calcified PBs were mounted on a flexible stent, and 8 had a rigid stent, with an average time of function of 63 ± 28 and 113 ± 18 months, respectively (p <0.00001). Ca⁺⁺ dysfunction occurred earlier in the aortic than in the mitral position (59 ± 19 vs 86 ± 35 months, p < 0.05). All the PBs explanted from young patients and 47 of 59 PBs removed from adult patients were calcified, with an average time of function of 50 ± 21 vs 73 ± 33 months, respectively (p < 0.05). The duration of PB in patients older than 35 years of age and in those aged 20 to 35 years was identical. Chronic anticoagulant therapy with warfarin did not influence the occurrence and severity of Ca⁺⁺ degeneration.     

Recurring Extracorporeal Circuit Clotting During Continuous Renal Replacement Therapy in Fungal Sepsis: Successful Treatment With Argatroban

The relative effectiveness of anticoagulation strategies during continuous renal replacement therapy (CRRT) may vary according to the clinical circumstances. In this study, the case of a 46-year-old man who developed fungal mediastinitis with the pathogen Scedosporium prolificans after coronary bypass surgery is reported. Numerous debridements and multiple antifungal agents were not effective in this patient. Miltefosine, a non-Food and Drug Administration-approved agent, was started after institutional review board request and approval. CRRT was initiated with regional citrate anticoagulation (RCA) for clinical sepsis with acute kidney injury. Subsequently, crescendo clotting of the extracorporeal circuit (ECC) occurred. Multiple interventions, including escalating RCA, adding increasing heparin to RCA and exchanging the dialysis catheter, were not effective. Argatroban anticoagulation was started without further ECC clotting, and the patient recovered from both acute kidney injury and septic shock, despite continued miltefosine administration. Sepsis may contribute to recurrent ECC clotting. Argatroban, a direct thrombin inhibitor, had a disproportionate effectiveness to maintain ECC patency in this patient.     

Regional Citrate Anticoagulation for High Volume Continuous Venovenous Hemodialysis in Surgical Patients With High Bleeding Risk

Acute kidney injury requiring renal replacement therapy occurs in up to 10% of all intensive care unit patients. Those who are hemodynamically unstable are often treated with continuous renal replacement therapy requiring continuous anticoagulation of the extracorporeal circuit. This is usually achieved by infusion of unfractionated heparin, which subsequently increases the risk of bleeding. To avoid systemic anticoagulation for continuous renal replacement therapy, regional anticoagulation with citrate has been introduced. We studied safety and efficacy of regional citrate anticoagulation for continuous venovenous hemodialysis in surgical patients requiring high dialysis doses. This was an observational prospective study in a 40‐bed surgical intensive care unit at a university hospital. During a 12‐month study period, all consecutive critically ill patients with high risk of bleeding requiring continuous renal replacement therapy continuous renal replacement therapy were treated with citrate anticoagulation for continuous venovenous hemodialysis. Prescribed dialysis dose was 45 mL/kg per h with a 10% increase for expected downtime. We studied filter lifetime, delivered dialysis dose, control of acid–base status, bleeding episodes, and adverse effects, that is, citrate intolerance. The total number of filters analyzed in 75 patients was 100. Mean (± standard deviation) filter running time was 78 ± 25 h. Fifty‐one circuits had to be renewed because of extended filter running time (96 ± 18 h), 33 discontinued for reasons not related to renal replacement therapy (62 ± 19 h), and 13 due to filter clotting (58 ± 18 h). The mean dialysis dose during the first 72 h was 49 ± 14 mL/kg per h. Overall, acid–base status after 72 h was well controlled in 62% of patients, metabolic alkalosis (pH > 7.45) occurred in 29%, and metabolic acidosis (pH < 7.35) in 9%. In one patient, treatment was stopped because of citrate accumulation. Citrate intoxication or overt bleeding episodes were not observed. Regional citrate anticoagulation for continuous venovenous hemodialysis is a safe and effective method to deliver a high dialysis dose in critically ill patients with a high risk of bleeding. Filter patency was excellent, acid–base status was well controlled, and clinically relevant adverse effects were not observed. Therefore, citrate anticoagulated continuous venovenous hemodialysis is a useful treatment option for patients with acute kidney injury requiring high dialysis doses and at risk of bleeding.     

Safety and Efficacy of Regional Citrate Anticoagulation During 8-Hour Sustained Low-Efficiency Dialysis

Background and objectives: Patients who may benefit from sustained low-efficiency dialysis therapy are often at risk for bleeding. A safe and simple “regional” anticoagulation strategy would be beneficial. The modification of existing regional citrate anticoagulation protocols to typically performed 8-h sustained low-efficiency dialysis is necessary.Design, setting, participants, & measurements: Sustained low-efficiency dialysis was performed at blood and dialysate rates of 250 and 300 ml/min, respectively. The circuit was anticoagulated with 4% sodium citrate (citrate 136, sodium 408 mmol/L) and reversed with CaCl₂. Every 2 h, electrolytes, ionized circuit, and patient calcium were monitored during the first two versions. The second version differed by an increased infusion of CaCl₂ and lower infusion of citrate, both by 10%. The third version measured only laboratory values before and after sustained low-efficiency dialysis.Results: There were 41 treatments in the first iteration, 42 in the second, and 34 in the final iteration. All versions were titrated to maintain patient ionized calcium of 4.0 to 4.8 mg/dl (1.0 to 1.2 mmol/L) and the circuit ionized calcium between 0.8 and 1.6 mg/dl (0.2 and 0.4 mmol/L). The final protocol infusion was 31 mmol/h citrate and 41 mmol/h elemental calcium, which kept circuit and patient ionized calcium at targets. No unexpected metabolic complications occurred.Conclusions: Compared with continuous renal replacement therapy, one must increase the calcium infusion because of the more efficient removal of the calcium citrate complex. Safe and effective regional citrate anticoagulation can be performed in 8-h sustained low-efficiency dialysis without metabolic complications with laboratory surveillance only before and after sustained low-efficiency dialysis treatment; however, certain safeguards are mandatory.Since regional citrate anticoagulation (RCA) for hemodialysis (HD) was first introduced in 1961, it has been modified throughout the world to apply to many dialysis modalities (1–4). It is an ideal alternative to heparin in patients who are at increased risk for bleeding (5,6). The technical application and concentration of citrate does vary (7,8). The pharmacokinetics of citrate anticoagulation are well understood as citrate chelates free calcium in the blood, essentially removing Ca²⁺ from its role as a co-factor in the coagulation cascade. To date, the main application of citrate has been to continuous renal replacement therapy (CRRT), including continuous sustained low-efficiency dialysis (SLED), but it has not been shown to have a role or application in intermittent hybrid therapies such as 8-h SLED, as performed in the United States.The major metabolic complications of RCA are due to excess retained sodium and citrate ions (hypernatremia and metabolic alkalosis) (9,10). Trisodium citrate (TSC) is metabolized to bicarbonate in skeletal muscle and liver and, when metabolism is complete, results in the generation of three molecules of bicarbonate from one citrate molecule. Because TSC contains on a molar basis three times as many sodium ions as citrate ions, the sodium load can increase the serum sodium concentration. Thus, hypernatremia has been observed in our experience, as well as others using RCA during continuous venovenous HD. The correction often requires the addition of hemodiafiltration with 0.45% NaCl replacement fluid to remove excess sodium and bicarbonate (HCO₃⁻) (11). Other metabolic complications and adverse effects of RCA have been due to the difficulty of correcting the decalcification and impaired citrate metabolism that accompany liver failure (12–14). Thus, RCA is not without potential problems. Developing a protocol that is safe and effective is in itself time-consuming and will not be undertaken unless there is a significant demand for SLED for patients who are at high risk for bleeding. Thus, we believe that describing the protocol that we developed for this population will have broad utility. Furthermore, the development of the protocol itself is instructive.Finkel and Foringer (15) described the use of RCA during continuous SLED (C-SLED), demonstrating that in >2200 h of therapy, none of the 20 patients had significant derangements in serum sodium concentration or acid base status to require cessation of RCA during this therapy. Their explanation for the lack of hypernatremia and metabolic alkalosis was that the higher dialysis dosage delivered by C-SLED likely corrected the problems as they developed and the problems never became clinically evident. Finkel and Foringer used different blood flow (Qb) and dialysate flow (Qd) than are used in our 8-h SLED, so the RCA regimen was only theoretically applicable. Marshall et al. (16) simulated RCA during SLED using a crystalloid solution instead of blood. Again, this is only of theoretical benefit as applied to 8-h SLED. RCA was also applied to a hybrid therapy similar to 8-h SLED using the Genius system (17); however, the Genius system is not available worldwide, and 8-h SLED with the operating conditions that we apply is available almost everywhere.Thus, because of the unique properties of 8-h SLED therapy and its widespread use, we proposed an RCA protocol to fit this expanding modality. We used standard commercially available solutions and implemented a step-wise evolution of titration and safety monitoring of RCA adverse effects. We now are convinced that RCA can be applied to our 8-h SLED therapies in a safe and efficacious manner without the measurement of intradialytic ionized calcium, sodium, or bicarbonate concentrations.     

Hepatic sinusoidal endothelial fenestrae express plasma membrane Ca++pump and Ca++Mg++‐ATPase

Abstract: Background/Aim: In general, intracytoplasmic free calcium ions (Ca⁺⁺) are maintained at a very low concentration in mammalian tissue by extruding Ca⁺⁺ against a high concentration of extracellular Ca⁺⁺, mainly through the activity of the plasma membrane Ca⁺⁺pump‐ATPase. The aim of the present study was to demonstrate by electron cytochemical and immunogold methods the ultrastructural localization of two different types of plasma membrane Ca⁺⁺‐ATPase, i.e. Ca⁺⁺Mg⁺⁺‐ATPase and Ca⁺⁺pump‐ATPase in the hepatic sinusoidal endothelium. Methods: Liver tissues and the isolated hepatic sinusoidal endothelial cell (SEC)s were subjected to the following procedures. The ultrastructural localizations of Ca⁺⁺Mg⁺⁺‐ATPase were examined by an electron cytochemical method. The ultrastructural localization of Ca⁺⁺pump‐ATPase was identified by an electron immunogold method. Results: The cytochemical reaction of Ca⁺⁺Mg⁺⁺‐ATPase was found to be localized on the outer sites of the plasma membrane of sinusoidal endothelial fenestrae (SEF). The immunogold particles indicating the presence of Ca⁺⁺ pump‐ATPase were identified on the inner sites (cytoplasmic) of the invaginated plasma membrane of SEF. Conclusions: Both Ca⁺⁺Mg⁺⁺‐ATPase and Ca⁺⁺pump‐ATPase demonstrated on the SEF plasma membrane may be involved in the regulation of intracytoplasmic Ca⁺⁺ concentration.     

Real‐world experience with the all‐oral,interferon‐free regimen of ombitasvir/paritaprevir/ritonavir and dasabuvir for the treatment of chronic hepatitis C virus infection in the German Hepatitis C Registry

Real‐world studies are relevant to complement clinical trials on novel antiviral therapies against chronic hepatitis C; however, clinical practice data are currently limited. This study investigated effectiveness and safety of ombitasvir/paritaprevir/ritonavir (OBV/PTV/r)±dasabuvir (DSV)±ribavirin (RBV) for treatment of HCV genotype (GT) 1 and GT4 infection in a large real‐world cohort. The German Hepatitis C Registry is an observational cohort study prospectively collecting clinical practice data on direct‐acting antiviral therapies. Patients with GT1/4 infection treated with OBV/PTV/r±DSV±RBV were analysed. Effectiveness was assessed by sustained virologic response in 558 patients who reached post‐treatment week 12 (SVR12). Safety is reported in 1017 patients who initiated treatment. Of the patients, 892 (88%) had GT1 and 125 (12%) had GT4 infection. Prior treatment experience and cirrhosis were reported in 598 (59%) and 228 (22%) patients, respectively. Overall, SVR12 (mITT) was 96% (486/505) in GT1‐ and 100% (53/53) in GT4 patients. SVR12 rates were high across subgroups including patients with cirrhosis (95%, 123/129), patients with moderate to severe renal impairment (100%, 34/34), and subgroups excluded from registrational trials like patients ≥70 years (96%, 64/67) and failures to prior protease inhibitor treatment (96%, 46/48). Adverse events (AEs) and serious AEs were reported in 52% (525/1017) and 2% (21/1017) of patients, respectively, and led to treatment discontinuation in 1.5% (15/1017) of patients. OBV/PTV/r±DSV±RBV was effective and generally well tolerated for treatment of HCV infection in clinical practice.     

Real‐world safety and effectiveness of ombitasvir/paritaprevir/ritonavir ± dasabuvir ± ribavirin in hepatitis C virus genotype 1‐ and 4‐infected patients with diverse comorbidities and comedications: A pooled analysis of post‐marketing observational studies from 13 countries

Ombitasvir/paritaprevir/ritonavir ± dasabuvir ± ribavirin (OBV/PTV/r ± DSV ± RBV) regimens show high efficacy and good tolerability in clinical trials for chronic hepatitis C virus (HCV) genotypes (GT) 1 or 4. To evaluate whether these results translate to clinical practice, data were pooled from observational studies across 13 countries. Treatment‐naïve or ‐experienced patients, with or without cirrhosis, received OBV/PTV/r ± DSV ± RBV according to approved local labels and clinical practice. Sustained virologic response at post‐treatment Week 12 (SVR12), adverse events (AEs) and comedication management were assessed for patients initiating treatment before 1 June 2017. The safety population included 3850 patients who received ≥1 dose of study drug. The core population (N = 3808) further excluded patients with unknown GT or cirrhosis status, or who received off‐label treatment. Patients had HCV GT1a (n = 732; 19%), GT1b (n = 2619; 69%) or GT4 (n = 457; 12%). In 3546 patients with sufficient follow‐up data at post‐treatment Week 12, the SVR12 rate was 96% (n/N = 3401/3546 [95% CI 95.2‐96.5]). In patients with or without cirrhosis, SVR12 was comparable (96%). In patients with HCV GT1a, GT1b or GT4, SVR12 rates were 93%, 97% and 94%. In GT1b‐infected patients with planned treatment for 8 weeks, SVR12 was 96%. In patients with ≥1 comorbidity (67%), SVR12 was 95%. 58% of patients received ≥1 comedication, and there was minimal impact on SVR12 rates using comedications for peptic ulcers and gastro‐esophageal reflux disease, statins, antipsychotics or antiepileptics. Most comedications were maintained during treatment although 58% of patients changed their statin medication. AEs and serious AEs occurred in 26% and 3% of patients. Post‐baseline Grade 3‐4 laboratory abnormalities were rare (<3%), and discontinuation rates were low (<4%). Real‐world evidence confirms the effectiveness of OBV/PTV/r ± DSV ± RBV in patients with HCV GT1 or GT4, regardless of common comorbidities or comedications, and is consistent with clinical trial results. Adverse safety outcomes may be limited by underreporting in the real‐world setting.     

27 Citrate Anticoagulation for Single‐Needle Hemodialysis: Safety and Efficacy

Background Single‐needle (SN) hemodialysis can be the only option for selected patients with difficulties with vascular access. Full heparinization is required to avoid clotting in the circuit. In patients at risk of bleeding, citrate could be the alternative anticoagulant. The aim of our retrospective clinical study was to evaluate safety and efficacy of regional citrate anticoagulation (RCA) during SN hemodialysis. Patients and methods Regional citrate anticoagulation was performed using 4% trisodium citrate, 1 m CaCl₂ and dialysate with 0 mmol/L Ca, 0.5 mmol/L Mg and 0 g/L glucose, Na was set at 138 mmol/L and HCO₃ at 28 mmol/L. Safety was assessed by percent of procedures that were terminated prematurely or changed to another modality due to RCA‐related complications and by incidence of important hypocalcemia, defined as decrease of iCa from start of dialysis > 0.2 mmol/L or decrease > 0.05 mmol/L to a value of < 0.8 mmol/L. Efficacy was evaluated by visual assessing of clot formation in arterial and venous bubble traps and dialyzer, after completing dialysis, by scoring: grade 5 (<10 fibers clotted) to 0 (>20% fibers clotted). It was considered insufficient if the grade was ≤ 3 or a significant clot in bubble traps occurred. Results In retrospective analysis of 41 protocols, important hypocalcemia was recorded in 34% of cases. 5% of procedures were terminated prematurely. Median dialyzer grade was 5 (interquartile range 4–5, N = 36). Anticoagulation was insufficient in 17% (6/36) of procedures, in these cases neither citrate infusion rate was lower nor coagulation time shorter. None of the systems clotted. Thirty protocols were filled in completely; average parameters are shown in the table below. In the first hour iCa decreased in 67% of procedures for 0.08 ± 0.05 mmol/L, those procedures had significantly lower starting calcium rate (6.4 ± 0.9 vs. 7.3 ± 1.1 mmol/L, P = 0.02) and higher starting iCa (1.02 ± 0.13 vs. 0.89 ± 0.14 mmol/L, P = 0.02). Over the entire procedure iCa decreased in 80% of cases for 0.17 ± 0.09 mmol/L, there was significant but small increase in Na (135 ± 4 vs. 137 ± 4 mmol/L, P ≤ 0.01) and no increase in HCO₃ at the end of hemodialysis ( Table A27 ).

Super High‐Flux Continuous Venovenous Hemodialysis Using Regional Citrate Anticoagulation: Long‐Term Stability of Middle Molecule Clearance

Continuous renal replacement therapy is a standard treatment in critically ill patients with acute kidney injury. All CRRT techniques provide a high low‐molecular weight clearance but even with hemofiltration, clearance of middle molecules is low. We investigated whether a new super high‐flux hemofilter provides effective and sustained middle molecule clearance during citrate‐anticoagulated continuous venovenous hemodialysis for up to 72 h. We included 14 critically ill patients with AKI‐KDIGO‐III in a prospective observational trial. We measured/calculated blood and urine concentrations, clearances and sieving coefficients of eight molecules with molecular weights from 60 to 66 kDa, hemodynamic parameters and SAPS‐II scores. All filters were patent at 72 h. Clearance and sieving coefficients of small solutes were high and sustained over time, those for larger solutes decreased over 72 h but remained high enough to decrease blood concentrations of solutes up to 25 kDa. Albumin serum levels remained unaffected. Catecholamine doses and SAPS‐II scores decreased significantly. This new hemofilter may improve blood purification in critically ill patients with AKI.     

Chronic hepatitis C infection and liver disease in HIV‐coinfected patients in Asia

Data on markers of hepatitis C virus (HCV) disease in HIV‐HCV‐coinfected patients in resource‐limited settings are scarce. We assessed HCV RNA, HCV genotype (GT), IL28B GT and liver fibrosis (FibroScan^®) in 480 HIV‐infected patients with positive HCV antibody in four HIV treatment centres in South‐East Asia. We enrolled 165 (34.4%) patients in Jakarta, 158 (32.9%) in Bangkok, 110 (22.9%) in Hanoi and 47 (9.8%) in Kuala Lumpur. Overall, 426 (88.8%) were male, the median (IQR) age was 38.1 (34.7‐42.5) years, 365 (76.0%) reported HCV exposure through injecting drug use, and 453 (94.4%) were on combination antiretroviral therapy. The median (IQR) CD4 count was 446 (325‐614) cells/mm³ and 208 (94.1%) of 221 patients tested had HIV‐1 RNA <400 copies/mL. A total of 412 (85.8%) had detectable HCV RNA, at a median (IQR) of 6.2 (5.4‐6.6) log₁₀ IU/mL. Among 380 patients with HCV GT, 223 (58.7%) had GT1, 97 (25.5%) had GT3, 43 (11.3%) had GT6, eight (2.1%) had GT4, two (0.5%) had GT2, and seven (1.8%) had indeterminate GT. Of 222 patients with IL28B testing, 189 (85.1%) had rs12979860 CC genotype, and 199 (89.6%) had rs8099917 TT genotype. Of 380 patients with FibroScan^®, 143 (37.6%) had no/mild liver fibrosis (F0‐F1), 83 (21.8%) had moderate fibrosis (F2), 74 (19.5%) had severe fibrosis (F3), and 79 (20.8%) had cirrhosis (F4). One patient (0.3%) had FibroScan^® failure. In conclusion, a high proportion of HIV‐HCV‐coinfected patients had chronic HCV infection. HCV GT1 was predominant, and 62% of patients had liver disease warranting prompt treatment (≥F2).     

Thromboelastography Parameters in Patients with Acute on Chronic Liver Failure

Introduction and aim. Patients with acute on chronic liver failure (ACLF) have abnormal conventional coagulation tests- platelet count and international normalized ratio (INR). Thromboelastography (TEG) is a rapid, point-of-care assay, more comprehensive than platelet count and INR as it assesses for platelet adequacy(number and function), coagulation factors and clot retraction. The aim of the study was to evaluate the TEG parameters in patients with ACLF, chronic liver disease having acute decompensation (AD) and healthy subjects (HC).Material and methods. TEG parameters were assessed in patients with ACLF and AD within 24 h of admission. Consecutive patients were included in the study over 12 months. Healthy subjects were recruited as controls.Results. 179 patients were included- 68 ACLF, 53 AD and 58 HC. The mean values of INR in ACLF, AD and HC groups were 2.9 ± 1.4, 1.6 ± 0.4 and 1.1 ± 0.2; P < 0.001. Among TEG parameters - maximum amplitude (MA) was low in ACLF and AD patients as compared with HC (53.8 ± 15, 58.3 ± 13.9 mm and 67.2 ± 12.1 mm, respectively; P < 0.001). Lysis at 30 min (LY30) was high in ACLF patients, as compared to AD and HC (8.6 ± 14.1%, 5.0 ± 9.5% and 4.9 ± 9.8%, respectively; P = 0.060). There were no differences in r time, k time, and alpha angle between groups; normal in >90% patients. There was no difference in TEG parameters between different ACLF grades, whereas CCTs were more deranged with increasing grades of ACLF.Conclusion. Despite abnormal conventional coagulation tests, TEG parameters in ACLF patients are essentially normal, except reduced maximum amplitude. Future studies are needed to explore the utility of TEG in clinical management of ACLF patients.     

小剂量利尿剂对胱素C的影响

目的：分析小剂量利尿剂对胱素C的影响。方法：随机选取2014年3月至2016年3月期间在我院重症医学科就诊接受CRRT的AKI患者。试验组为利尿剂组,患者数为40例,对照组为非利尿剂组,患者数为40例,应用连续肾脏替代治疗急性肾损伤,对机械通气及血管活性药应用、平均动脉压(MAP)、血乳酸、血钾、尿量(均取开始CRRT后起初3d的平均值),开始CRRT前1d、治疗后起初3d肾功能[胱素 C(Cys-C)、SCr、尿素氮(BUN)],CRRT时间、住ICU时间和住院时间等指标进行分析,采用SPSS20.0软件进行统计学分析。结果：(1)性别、年龄、入院至入ICU间隔时间、APACHE Ⅱ评分、SOFA评分、基础疾病、AKI的病因和诊断分类等指标在两组之间无统计学差异,符合试验要求。(2)需血管活性药和有创机械通气指标在两组之间有统计学差异(P<0.05);MAP指标在利尿剂组和非利尿剂组之间比为72.53±7.68 VS 88.54±15.87,两组之间有显著统计学差异(P<0.01);乳酸指标在利尿剂组和非利尿剂组之间比为2.21±1.17 VS 2.92±2.74,两组之间有统计学差异(P<0.05);血钾指标在利尿剂组和非利尿剂组之间比为4.13±1.26 VS 4.83±1.25,两组之间有统计学差异(P<0.05);CRRT时间指标在利尿剂组和非利尿剂组之间比为5.12±3.53 VS 7.92±5.95,两组之间有显著统计学差异(P<0.01);住ICU时间指标在利尿剂组和非利尿剂组之间比为15.71±9.56 VS 23.24±17.82,两组之间有显著统计学差异(P<0.01);住院时间指标在利尿剂组和非利尿剂组之间比为20.57±13.34 VS 27.38±19.83,两组之间有显著统计学差异(P<0.01)。(3)开始CRRT治疗前1d、CRRT治疗后1d和2d,Cys-C、BUN、SCr和尿量在利尿剂组和非利尿剂组之间无统计学差异(P>0.05);CRRT治疗后3d,Cys-C指标在利尿剂组和非利尿剂组之间比为1.83±1.05 VS 2.45±1.87,两组之间有统计学差异(P<0.05);BUN指标在利尿剂组和非利尿剂组之间比为12.36±7.87 VS 16.39±7.94,两组之间有统计学差异(P<0.05);SCr指标在利尿剂组和非利尿剂组之间比为180.25±77.79 VS 205.53±134.83,两组之间有统计学差异(P<0.05);尿量指标在利尿剂组和非利尿剂组之间比为679.12±643.54 VS 796.49±1608.35,两组之间有统计学差异(P<0.05)。(4)28d内存活指标在利尿剂组和非利尿剂组之间比为32(80.0%)VS 26(65.0%),两组之间有统计学差异(P<0.05);28d内死亡指标在利尿剂组和非利尿剂组之间比为8(20.0%)VS 14(35.0%),两组之间有统计学差异(P<0.05)。结论：连续肾脏替代治疗急性肾损伤过程中,小剂量利尿剂能降低需血管活性药和有创机械通气的患者数,明显降低MAP,降低血液中乳酸和血钾含量,减少CRRT时间、住ICU时间和住院时间,小剂量利尿剂治疗有助于改善患者的肾功能,治疗后3d,小剂量利尿剂能降低患者血液中Cys-C、BUN和SCr含量,同时减少患者尿量,小剂量利尿剂治疗能提高患者28d内存活数,降低28d内死亡数。     

Transition From Heparin to Citrate Anticoagulation for Continuous Renal Replacement Therapy: Safety,Efficiency, and Cost

Regional citrate anticoagulation (RCA) for continuous renal replacement therapy (CRRT) has recently been recommended as first‐line over heparin. Evidence suggests that RCA prolongs filter life and may reduce bleeding risk, but there is little research on the benefits to dialysis dose delivery or cost, or the effectiveness of transitioning to RCA first‐line. The aim of the present study was to assess the effect on dialysis delivery, cost and safety when transitioning from systemic heparin to RCA for first‐line anticoagulation for CRRT. A single‐center, retrospective observational study was conducted from 2006 to 2012, during which a transition from heparin to a simplified RCA protocol occurred. Demographic and dialysis data, pathology results and costs were obtained. Data were analyzed for both heparin and RCA, and for before and after the transition. 166 patients had 992 dialysis days (heparin 334 vs. RCA 658); demographics were well matched; RCA used less filters per day (P = 0.03), had more days when prescribed dialysis was achieved (85% vs. 60%, P < 0.001), and less filter “down‐time” per day (2.4 vs. 6.1 h, P = 0.02). RCA was estimated to cost AU$487 per day, compared to heparin at $479 per day. When the data were analyzed, comparing before and after the transition, these results remained statistically significant. There was no statistical difference in clinical safety events. Transition to first‐line RCA was safe, provided more time on filter and consumed less filter circuits using a simple and user friendly protocol. The adjusted cost difference appears negligible.     

局部枸橼酸抗凝在肝衰竭患者连续性肾脏替代治疗中的应用

体外抗凝是连续性肾脏替代治疗(CRRT)的一项关键技术,肝素曾是CRRT首选的抗凝剂,但由于出血风险高,临床使用受限。枸橼酸作为一种新型局部抗凝剂,近年来受到越来越多的关注和推荐,但对于肝衰竭患者的应用一直存在争议。通过阅读近年来国内外相关文献,就局部枸橼酸抗凝在肝衰竭患者中的代谢特点、监测方法及其在CRRT应用中的安全性进行综述。