A controlled trial of low-molecular-weight heparin (dalteparin) versus unfractionated heparin as anticoagulant during continuous venovenous hemodialysis with filtration.

OBJECTIVE: To compare the efficacy, safety, and cost of fixed-dose low-molecular-weight heparin (dalteparin) with adjusted-dose unfractionated heparin as anticoagulant for continuous hemofiltration. DESIGN: Prospective, randomized, controlled clinical trial. SETTING: University-affiliated adult intensive care unit PATIENTS: All patients requiring continuous hemofiltration for acute renal failure or systemic inflammatory response syndrome (SIRS) were eligible. Fifty-seven patients were enrolled. Eleven were excluded, seven because of major protocol violations and four died before hemofiltration. INTERVENTIONS: Patients received continuous venovenous hemodialysis with filtration with prefilter replacement at 500 mL/hr and countercurrent dialysate at 1000 mL/hr. Filters were primed with normal saline containing anticoagulant. Dalteparin-treated patients received a commencement bolus of 20 units/kg and a maintenance infusion at 10 units/kg/hr. Heparin-treated patients received a commencement bolus of 2000-5000 units and a maintenance infusion at 10 units/kg/hr, titrated to achieve an activated partial thromboplastin time in the patient of 70-80 secs. MEASUREMENTS AND MAIN RESULTS: The primary outcome measure--time to failure of the hemofilter--was compared using survival analysis. Twenty-two patients (13 with acute renal failure and nine with SIRS; total, 41 filters) were randomized to heparin. Twenty-five patients (16 with acute renal failure and nine with SIRS; total, 41 filters) were randomized to dalteparin. Mean (SE) activated partial thromboplastin time in the heparin group was 79 (4.3) secs. Mean (SE) anti-factor-Xa activity in the six patients given dalteparin who were assayed was 0.49 (0.07). Mean (SE) prehemofiltration platelet count was 225 (35.5) x 10(9) for heparin and 178 (18.1) x 10(9) for dalteparin (p = .24, unpaired Student's t-test). Mean (SE) prehemofiltration hemoglobin was 11.4 (0.61) g/dL for heparin and 10.6 (0.38) g/dL for dalteparin (p = .31, unpaired Student's t-test). PRIMARY OUTCOME: There was no significant difference in the time to failure between the two groups (p = .75, log rank test). For dalteparin, Kaplan-Meier (K-M) mean (SE) time to failure of the hemofilter was 46.8 (5.03) hrs. For heparin, K-M mean (SE) time to failure was 51.7 (7.51) hrs. The 95% CI for difference in mean time to failure was -13 to 23 hrs. The power of this study to detect a 50% change in filter life was >90%. SECONDARY OUTCOMES: Mean (SE) reduction in platelet count during hemofiltration was 63 (25.8) x 10(9) for heparin and 41.8 (26.6) x 10(9) for dalteparin (p = .57, unpaired Student's t-test). Eight patients given dalteparin and four patients given heparin had screening for heparin-induced thrombocytopenia; three of the dalteparin patients and one of the heparin patients were positive (p = 1.0, Fisher's exact test). There were three episodes of trivial bleeding and two episodes of significant bleeding for dalteparin, and there were three episodes of trivial bleeding and four episodes of significant bleeding for heparin (p = .53, chi-square test). The mean (SE) decrease in hemoglobin concentration during hemofiltration was 0.51 (0.54) g/dL for heparin and 0.28 (0.49) g/dL for dalteparin (p = .75, unpaired Student's t-test). The mean (SE) packed-cell transfusion volume during hemofiltration was 309 (128) mL for heparin and 290 (87) mL for dalteparin (p = .90, unpaired Student's t-test). Daily costs, including coagulation assays, of hemofiltration were approximately 10% higher using dalteparin than with heparin. CONCLUSIONS: Fixed-dose dalteparin provided identical filter life, comparable safety, but increased total daily cost compared with adjusted-dose heparin. Unfractionated heparin remains our anticoagulant of choice for continuous hemofiltration in intensive care.     

Effects of early high-volume continuous venovenous hemofiltration on survival and recovery of renal function in intensive care patients with acute renal failure: a prospective,randomized trial

OBJECTIVE: To study the effects of the initiation time of continuous venovenous hemofiltration and of the ultrafiltrate rate in patients with circulatory and respiratory insufficiency developing early oliguric acute renal failure. The primary end points were mortality at 28 days and recovery of renal function. DESIGN: A randomized, controlled, two-center study. SETTING: The closed-format multidisciplinary intensive care units of a university hospital (30 beds) and a teaching hospital (18 beds). PATIENTS AND INTERVENTIONS: A total of 106 ventilated severely ill patients who were oliguric despite massive fluid resuscitation, inotropic support, and high-dose intravenous diuretics were randomized into three groups. Thirty-five patients were treated with early high-volume hemofiltration (72-96 L per 24 hrs), 35 patients with early low-volume hemofiltration (24-36 L per 24 hrs), and 36 patients with late low-volume hemofiltration (24-36 L per 24 hrs). RESULTS: Median ultrafiltrate rate was 48.2 (42.3-58.7) mL.kg(-1).hr(-1) in early high-volume hemofiltration, 20.1 (17.5-22.0) mL.kg(-1).hr(-1) in early low-volume hemofiltration, and 19.0 (16.6-21.1) mL.kg(-1).hr(-1) in late low-volume hemofiltration. Survival at day 28 was 74.3% in early high-volume hemofiltration, 68.8% in early low-volume hemofiltration, and 75.0% in late low-volume hemofiltration (p =.80). On average, hemofiltration started 7 hrs after inclusion in the early groups and 42 hrs after inclusion in the late group. All hospital survivors had recovery of renal function at hospital discharge, except for one patient in the early low-volume hemofiltration group. Median duration of renal failure in hospital survivors was 4.3 (1.4-7.8) days in early high-volume hemofiltration, 3.2 (2.4-5.4) days in early low-volume hemofiltration, and 5.6 (3.1-8.5) days in late low-volume hemofiltration (p =.25). CONCLUSIONS: In the present study of critically ill patients with oliguric acute renal failure, survival at 28 days and recovery of renal function were not improved using high ultrafiltrate volumes or early initiation of hemofiltration.     

A phase II randomized, controlled trial of continuous hemofiltration in sepsis

OBJECTIVE: To study the effect of early and continuous venovenous hemofiltration (CVVH) on the plasma concentrations of several humoral mediators of inflammation and subsequent organ dysfunction in septic patients. DESIGN: Randomized, controlled trial. SETTING: Intensive care unit of a tertiary hospital. PATIENTS: Twenty-four patients with early septic shock or septic organ dysfunction. INTERVENTIONS: Random allocation to receive 48 hrs of isovolemic CVVH at 2 L/hr of fluid exchange or no hemofiltration. MEASUREMENTS AND MAIN RESULTS: We measured the plasma concentrations of complement fractions C3a and C5a, interleukins 6, 8, and 10, and tumor necrosis factor alpha at baseline and 2, 24, 26, 48, and 72 hrs. A multiple organ dysfunction score (MODS) was calculated daily for each patient until death or discharge from the intensive care unit. The concentrations of most mediators decreased between baseline and 72 hrs. Some significant falls in concentration could be identified between specific time points, but CVVH was not associated with an overall reduction in any plasma cytokine concentrations. There was also no difference between the mean cumulative MODS for control survivors (43.3 +/- 19.7) and CVVH survivors (33.2 +/- 19.0; p = .30), and no difference between the average MODS calculated for all controls (4.1 +/- 1.9) and all CVVH subjects (3.3 +/- 1.7; p = .26). CVVH did not improve oxygenation, lower the platelet count, or reduce the duration of vasopressor support and mechanical ventilation. CONCLUSIONS: Early use of CVVH at 2 L/hr did not reduce the circulating concentrations of several cytokines and anaphylatoxins associated with septic shock, or the organ dysfunction that followed severe sepsis. CVVH using current technology cannot be recommended as an adjunct to the treatment of septic shock unless severe acute renal failure is present.     

Prospective evaluation of short-term, high-volume isovolemic hemofiltration on the hemodynamic course and outcome in patients with intractable circulatory failure resulting from septic shock

OBJECTIVE: To evaluate the effects of short-term, high-volume hemofiltration (STHVH) on hemodynamic and metabolic status and 28-day survival in patients with refractory septic shock. DESIGN: Prospective, interventional. SETTING: Intensive care unit (ICU), tertiary institution. PATIENTS: Twenty patients with intractable cardiocirculatory failure complicating septic shock, who had failed to respond to conventional therapy. INTERVENTIONS: STHVH, followed by conventional continuous venovenous hemofiltration. STHVH consisted of a 4-hr period during which 35 L of ultrafiltrate is removed and neutral fluid balance is maintained. Subsequent conventional continuous venovenous hemofiltration continued for at least 4 days. MEASUREMENTS AND MAIN RESULTS: Cardiac index, systemic vascular resistance, pulmonary vascular resistance, oxygen delivery, mixed venous oxygen saturation, arterial pH, and lactate were measured serially. Fluid and inotropic support were managed by protocol. Therapeutic endpoints were as follows during STHVH: a) by 2 hrs, a > or =50% increase in cardiac index; b) by 2 hrs, a > or =25% increase in mixed venous saturation; c) by 4 hrs, an increase in arterial pH to >7.3; d) by 4 hrs, a > or =50% reduction in epinephrine dose. Patients who attained all four goals (11 of 20) were considered hemodynamic "responders"; patients who did not (9 of 20) were considered hemodynamic "nonresponders." There were no differences in baseline hemodynamic, metabolic, and Acute Physiology and Chronic Health Evaluation and Simplified Acute Physiology Scores between responders and nonresponders. Survival to 28 days was better among responders (9 of 11 patients) than among nonresponders (0 of 9). Factors associated with survival were hemodynamic-metabolic response status, time interval from ICU admission to initiation of STHVH, and body weight. CONCLUSIONS: These data suggest that STHVH may be of major therapeutic value in the treatment of intractable cardiocirculatory failure complicating septic shock. Early initiation of therapy and adequate dose may improve hemodynamic and metabolic responses and 28-day survival.     

Pharmacokinetics of meropenem in intensive care unit patients receiving continuous veno-venous hemofiltration or hemodiafiltration

OBJECTIVE: To evaluate an intravenous meropenem dosage regimen in adult intensive care patients with acute renal failure treated by continuous renal replacement therapy. DESIGN: A prospective, clinical study. SETTING: General intensive care unit of a university hospital. PATIENTS: Ten critically ill adult patients being treated with meropenem and receiving continuous veno-venous hemofiltration (hemofiltration rates, 1-2 L/hr) (n = 5) or continuous venovenous hemodiafiltration (hemofiltration rates, 1-1.5 L/hr; dialysis rates, 1-1.5 L/hr) (n = 5) via a polyacrylonitrile hollow fiber 0.9-m2 filter. INTERVENTIONS: Patients received a meropenem dose of 1 g iv every 12 hrs as a 5-min bolus. MEASUREMENTS AND MAIN RESULTS: Meropenem concentrations were measured by high-performance liquid chromatography in serum taken at timed intervals and in ultrafiltrate/dialysate to determine serum concentration-time profiles, derive pharmacokinetic variable estimates, and determine sieving coefficients and filter clearances. The serum concentrations were examined to see whether they were above the minimum inhibitory concentrations (MICs) for pathogens that may be encountered in intensive care patients. Serum concentrations exceeded 4 mg/L (MIC90 for Pseudomonas aeruginosa) during 67% of the dosage period in all patients. Sub-MIC90 concentrations were obtained in three patients immediately before treatment and in one patient 12 hrs after treatment. Mean (SD) (n = 10) pharmacokinetic variable estimates were as follows: elimination half-life, 5.16 hrs (1.83 hrs); volume of distribution, 0.35 L/kg (0.10 L/kg); and total clearance, 4.30 L/hr (1.38 L/hr). A sieving coefficient of 0.93 (0.06) (n = 9) indicated free flow across the filter. The fraction cleared by the extracorporeal route was 48% (13%) (n = 9), which is clinically important. CONCLUSIONS: A meropenem dose of 1g iv every 12 hrs provides adequate serum concentrations in the majority of patients receiving continuous veno-venous hemofiltration or continuous venovenous hemofiltration with a 0.9-m2 polyacrylonitrile filter at combined ultrafiltrate/dialysate flow rates of up to 3 L/hr. A lower dose would not be sufficient for the empirical treatment of potentially life-threatening infections in all patients.     

Effect of filtration volume of continuous venovenous hemofiltration in the treatment of patients with acute renal failure in intensive care units

OBJECTIVE: We evaluated the variable Kt/V, which has become established in the therapy of end-stage renal disease in acute renal failure, to assess the influence of the filtration volume of continuous venovenous hemofiltration on Kt/V. We measured the variables of acid-base balance and uremia control. DESIGN: Prospective interventional pilot study. SETTING: Medical intensive care unit of a university hospital. PATIENTS: Fifty-six patients with acute renal failure and continuous venovenous hemofiltration treatment. INTERVENTIONS: The patients were consecutively treated with a filtration volume of either 1 L/hr (group 1) or 1.5 L/hr (group 2). MEASUREMENTS AND MAIN RESULTS: Patients with a filtration volume of 1.5 L/hr achieved a Kt/V of 0.8 per day, which was significantly higher than in the patient group treated with 1 L/hr (0.53, p <.05). The filtration volume of 1.5 L/hr led to a markedly better control of blood urea nitrogen concentrations, 69.3 +/- 6.6 mg/dL vs. 52.1 +/- 5.2 (p <.05), and to a much quicker and longer lasting compensation of acidosis. Both groups had acidotic pH at the beginning of therapy (group 1, 7.29 +/- 0.02; group 2, 7.29 +/- 0.02, nonsignificant). In group 2, a significantly higher pH value than in group 1 was measured after 24 hrs of continuous venovenous hemofiltration (p < .001; 7.39 +/- 0.02 vs. 7.31 +/- 0.02). The pH values in group 1 did not normalize until after 4 days. The filtration volume of 1.5 L/hr led to a quicker increase in bicarbonate concentrations after 24 hrs of therapy (group 1, 2.8 +/- 3.2 mmol/L; group 2, 6.5 +/- 3.1 mmol/L, p <.001). CONCLUSIONS: The standardized urea clearance Kt/V is a valuable tool in the treatment of acute renal failure. Higher Kt/V levels were associated with a better control of uremia and acid-base balance. However, there were no differences in the clinical course, patient survival, percentage of patients with or without renal failure who were transferred from the intensive care unit, or Acute Physiology and Chronic Health Evaluation III scores.     

Removal of linezolid by conventional intermittent hemodialysis, sustained low-efficiency dialysis, or continuous venovenous hemofiltration in patients with acute renal failure

OBJECTIVE: To study the removal of linezolid, a new oxazolidinone antibiotic, by renal replacement therapy in patients with acute renal failure. DESIGN: Prospective, single-dose pharmacokinetic study. SETTING: Renal intensive care unit of a tertiary university hospital. PATIENTS: Fifteen critically ill patients with oliguric acute renal failure on renal replacement therapy (seven males, mean age 72.3 yrs, range 60-94; Acute Physiology and Chronic Health Evaluation II score 24.9, range 18-36; mechanical ventilation ten of 15). INTERVENTIONS: All patients received 600 mg of intravenous linezolid before starting renal replacement therapy, which consisted of intermittent hemodialysis lasting 3-4 hrs in eight patients, sustained low-efficiency dialysis lasting 8 hrs in five patients, and continuous venovenous hemofiltration lasting 10.5-12 hrs in two patients. MEASUREMENTS AND MAIN RESULTS: Linezolid concentrations were measured by liquid chromatography/mass spectrometry methods on serum and dialysate/ultrafiltrate samples. At the start of renal replacement therapy, serum levels averaged 11.91 mg/L (range 5.49-21.52) and dropped at the end to levels <4 mg/dL (90% minimum inhibitory concentration values for Staphylococcus aureus) in three of eight patients on hemodialysis, three of five patients on sustained low-efficiency dialysis, and two of two patients on continuous venovenous hemofiltration. Mean removal of the drug was 193.7 mg with hemodialysis (32.3% of the dose administered), 205 mg with sustained low-efficiency dialysis (33.9%), and 74.8 mg (12.4%) and 105 (17.5%) mg following a continuous venovenous hemofiltration session lasting 10.5 and 12 hrs, respectively. CONCLUSIONS: In patients with acute renal failure, serum levels of linezolid can be reduced to the subtherapeutic range following renal replacement therapy.     

Prophylactic anticoagulation with enoxaparin: Is the subcutaneous route appropriate in the critically ill?

BACKGROUND: Subcutaneously administered low-molecular-weight heparins are widely used for prevention of venous thromboembolism. The appropriateness of the subcutaneous route in critically ill patients has never been established. OBJECTIVE: To determine anti-Xa activities in critically ill patients and in noncritically ill patients receiving prophylactic doses of subcutaneous enoxaparin. DESIGN: Prospective, controlled, open-labeled study. SETTING: Tertiary medical-cardiologic-postoperative intensive care unit and a general medical ward at a university hospital. PATIENTS: A total of 16 intensive care unit patients (group 1; age, 61.1 +/- 16 yrs; male/female ratio, 7/9; Acute Physiology and Chronic Health Evaluation II score, 20.9 +/- 7; mechanical ventilation, n = 15; vasopressors, n = 13) and 13 noncritically ill medical patients (group 2; age, 61.7 +/- 9 yrs; male/female ratio, 7/6) were studied. Body mass index (25.7 +/- 5 vs. 24 +/- 6 kg/m2, p = not significant) was comparable and serum creatinine levels (0.83 +/- 0.25 vs. 1.07 +/- 0.3 mg/dL, group 1 vs. 2) were within the normal range in both groups. Patients with impaired renal function, receiving hemofiltration, or requiring therapeutic anticoagulation were not eligible. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Anti-Xa activities were determined at 0, 1, 3, 6, and 12 hrs after a single daily subcutaneous dose of 40 mg enoxaparin on day 1 and at 3 hrs after 40 mg of enoxaparin on days 2-5. Mean anti-Xa levels at 0 to 12 hrs were consistently lower in group 1 compared with group 2 by analysis of variance (p =.001 between groups and over time), as was the area under the curve at 0 to 12 hrs (2.6 +/- 1 vs. 4.2 +/- 1.7 units x mL(-1) x hr(-1), group 1 vs. 2, p =.008). Significant differences in anti-Xa activity were also found on days 2-5 (p =.001). Peak anti-Xa activities at 3 hrs after administration were negatively correlated with the body mass index (r = -.41, p <.03). No correlation was found between the anti-Xa activity at 3 hrs and the dose of norepinephrine (r =.12, p =.7). CONCLUSION: Critically ill patients with normal renal function demonstrated significantly lower anti-Xa levels in response to a single daily dose of subcutaneous enoxaparin when compared with medical patients in the normal ward.     

Monitoring of subcutaneous dalteparin in patients with renal insufficiency under intensive care: an observational study

OBJECTIVE: The objective of this study was to investigate the pharmacodynamic parameters of dalteparin in patients with renal insufficiency under intensive care. MATERIALS AND METHODS: In this open, nonrandomized, nonblinded, prospective, single-dose observational study, 10 critically ill patients with renal insufficiency (mean creatinine clearance = 29.5 +/- 6.42 mL/min) were administered a single 5000-IU subcutaneous dose of dalteparin. RESULTS: Dalteparin blood levels were estimated indirectly over a 12-hour period by measuring anti-Xa activity and by performing a clotting assay known as the ATHU (AHEPA Thrombosis and Hemostasis Unit) test. Maximum anti-Xa activity (ie, 0.42 +/- 0.13 IU/mL) was achieved 4 hours after administration (in 8 of 10 patients). Adequate anticoagulant activity was maintained throughout the 12-hour dosage interval in all study patients. However, at time 0 hour of the study, 36 hours after the administration of a previous dose of dalteparin, considerable anti-Xa activity (ie, 0.39 +/- 0.11 IU/mL) was measured in 6 patients. A good correlation was found between anti-Xa activity and the results of the ATHU test. CONCLUSIONS: The presence of medium/severe edema and the concurrent administration of 1 to 3 inotropic drugs appear to contribute to a decrease in the rate of elimination of dalteparin, resulting in a greater-than-expected (as a result of decreased renal function) prolongation of its pharmacologic activity. We recommend that care be taken with repeated dosing of dalteparin in intensive care unit patients taking inotropic drugs until observed results can be confirmed.     

The impact of lactate-buffered high-volume hemofiltration on acid-base balance

OBJECTIVE: To evaluate the effect of high-volume hemofiltration (HVHF) with lactate-buffered replacement fluids on acid-base balance. DESIGN: Randomized crossover study. SETTING: Intensive Care Unit of Tertiary Medical Center PARTICIPANTS: Ten patients with septic shock and acute renal failure. INTERVENTIONS: Random allocation to 8 h of isovolemic high-volume hemofiltration (ultrafiltration rate: 6 l/h) or 8 h of isovolemic continuous venovenous hemofiltration (ultrafiltration rate: 1 l/h) with lactate-buffered replacement fluid with subsequent crossover. MEASUREMENTS AND RESULTS: We measured blood gases, electrolytes, albumin, and lactate concentrations and completed quantitative biophysical analysis of acid-base balance changes. Before high-volume hemofiltration, patients had a slight metabolic alkalosis [pH: 7.42; base excess (BE) 2.4 mEq/l] despite hyperlactatemia (lactate: 2.51 mmol/l). After 2 h of high-volume hemofiltration, the mean lactate concentration increased to 7.30 mmol/l ( p=0.0001). However, a decrease in chloride, strong ion difference effective, and strong ion gap (SIG) compensated for the effect of iatrogenic hyperlactatemia so that the pH only decreased to 7.39 ( p=0.05) and the BE to -0.15 ( p=0.001). After 6 h, despite persistent hyperlactatemia (7 mmol/l), the pH had returned to 7.42 and the BE to 2.45 mEq/l. These changes remained essentially stable at 8 h. Similar but less intense changes occurred during continuous venovenous hemofiltration. CONCLUSIONS: HVHF with lactate-buffered replacement fluids induces iatrogenic hyperlactatemia. However, such hyperlactatemia only has a mild and transient acidifying effect. A decrease in chloride and strong ion difference effective and the removal of unmeasured anions all rapidly compensate for this effect.     

持续高流量血液滤过对重症急性胰腺炎猪炎症反应的影响

目的探讨高流量持续血液滤过对重症急性胰腺炎(SAP)时炎症反应的影响。方法采用胰管内高压力注射牛磺胆酸钠和胰蛋白酶的方法诱导猪SAP模型。将SAP模型动物随机分为3组,每组8只:对照组只行常规支持治疗;低流量持续性静静脉血液滤过(CVVH)组除常规支持治疗外,模型诱导成功后立即行低流量(20 m l.kg-1.h-1)CVVH;高流量CVVH组模型诱导成功后立即行高流量(100 m l.k-g 1.-h 1)CVVH以及常规支持治疗。于SAP诱导前和诱导成功后6、12、24和36 h间断测定血浆肿瘤坏死因子α(TNFα)、白细胞介素6(IL 6)和IL 10含量,于SAP诱导后6、12和24 h测定外周血中单核细胞核转录因子κB(NFκB)活性。结果对照组平均生存时间为41 h,低流量CVVH组平均生存时间为50 h,高流量CVVH组平均生存时间为65 h。早期行CVVH治疗动物生存时间均显著高于对照组(P<0.05和P<0.01),高流量CVVH组的生存时间明显高于低流量CVVH组(P<0.05)。CVVH治疗后TNFα、IL 6和IL 10均较对照组显著降低,高流量CVVH组的TNFα、IL 6和IL 10含量均显著低于低流量CVVH组。两个CVVH组动物的外周血单核细胞NFκB活性在6、12和24 h均显著低于对照组,高流量CVVH组更低。结论早期CVVH能改善SAP猪过度的炎症反应,明显延长生存时间,改善预后,而且高流量CVVH的效果明显优于低流量CVVH。     

Continuous venovenous hemofiltration improves intensive care unit, but not hospital survival rate, in nonoliguric septic patients

PURPOSE: The purpose of this study was to assess the effect of the early institution of continuous veno-venous hemofiltration on survival rates of nonoliguric, septic patients. MATERIALS AND METHODS: A retrospective study of 48 nonoliguric septic patients with PaO(2)/FIO(2) < or = 250, who were admitted to the General Intensive Care of the Soroka Medical Center. Twenty-six patients were treated with continuous venovenous hemofiltration (CVVH group) and 22 were treated by conventional therapy. The end point of treatment was weaning from mechanical ventilation, adequate oxygenation, and the need for minimal cardiocirculatory support. RESULTS: The study groups were similar in terms of age, gender, percentage of surgical or nonsurgical patients, APACHE II scores, and the Therapeutic Intervention Scoring System (TISS). Baseline serum urea and creatinine levels were similar in the groups, but the PAO(2)/FIO(2) ratio was significantly lower in the CVVH group (150.6 +/- 86 vs. 214.2 +/- 8.9). Twenty of the CVVH patients and 10 of the patients receiving conventional therapy were discharged from the intensive care unit (P =.03), but the hospital discharge rate was only slightly higher in the CVVH group (12 of 26) compared with the conventional therapy group (7 of 22) (P =.145). CONCLUSIONS: In this retrospective uncontrolled study, the mortality rate was considerably lower in nonoliguric septic patients who received continuous venovenous hemofiltration early in the course of the disease. The improved survival rate may be due to the ability of CVVH to eliminate mediators involved in the septic process, thus averting the multiple system organ failure consequent to septic insult.     

Hemostasis during low molecular weight heparin anticoagulation for continuous venovenous hemofiltration: a randomized cross-over trial comparing two hemofiltration rates

Introduction  

Renal insufficiency increases the half-life of low molecular weight heparins (LMWHs). Whether continuous venovenous hemofiltration (CVVH) removes LMWHs is unsettled. We studied hemostasis during nadroparin anticoagulation for CVVH, and explored the implication of the endogenous thrombin potential (ETP).     

心脏瓣膜置换后的连续性静脉-静脉血液滤过

背景：心脏瓣膜置换后可发生机体免疫功能异常,但是关于连续性静脉-静脉血液滤过对心脏瓣膜置换后患者机体免疫功能影响的研究较少见报道。目的：观察连续性静脉-静脉血液滤过对心脏瓣膜置换后多脏器功能障碍综合征患者细胞免疫功能的影响。方法：2008年8月至2009年7月期间,收集解放军第四军医大学西京医院心脏手术后并发多脏器功能障碍综合征的患者31例,行连续性静脉-静脉血液滤过治疗,17例存活（存活组）,14例死亡（死亡组）。另选取16例健康献血者作为对照组。结果与结论：存活组患者确诊急性肾衰竭后至开始连续性静脉-静脉血液滤过的时间明显短于死亡组（P ＜0.05）。在连续性静脉-静脉血液滤过治疗前,存活组和死亡组的CD4＋/CD8＋比值和Th1/Th2比值均低于健康对照组（P＜0.05）,淋巴细胞凋亡率和淋巴细胞Fas/FasL抗原表达均高于健康对照组（P＜0.05）,提示存在免疫抑制状态和Th1/Th2失衡。连续性静脉-静脉血液滤过治疗过程中,存活组患者24 h后CD4＋/CD8＋比值和Th1/Th2比值增加（P＜0.05）,淋巴细胞凋亡率和和淋巴细胞Fas/FasL抗原表达降低（P＜0.05）,而死亡组患者CD4＋/CD8＋比值、Th1/Th2比值、淋巴细胞凋亡率和和淋巴细胞Fas/FasL抗原表达与存活组有相似的变化趋势,但是较存活组出现更晚。说明连续性静脉-静脉血液滤过有助于改善心脏术后多脏器功能障碍综合征伴急性肾衰竭患者机体的细胞免疫功能,维持T淋巴细胞亚群间和Th1/Th2的平衡,下调淋巴细胞膜表面的Fas/FasL表达,减少淋巴细胞凋亡,早期行连续性静脉-静脉血液滤过可以改善患者的预后。     

Pharmacokinetics and dosing regimen of meropenem in critically ill patients receiving continuous venovenous hemofiltration

OBJECTIVE: To study the pharmacokinetics of meropenem in critically ill patients with acute renal failure receiving continuous venovenous hemofiltration (CWHF). DESIGN: Prospective, open-labeled study. SETTING: Medical intensive care unit of the University Medical Center Utrecht. PATIENTS: Five critically ill patients receiving CWHF for acute renal failure treated with meropenem for documented or suspected bacterial infection. INTERVENTION: All patients received meropenem (500 mg) administered intravenously every 12 hrs. Plasma samples and ultrafiltrate aliquots were collected during one dosing interval. MEASUREMENTS AND RESULTS: Mean age and body weight of the patients studied were 46.6 yrs (range, 28-61 yrs) and 85.8 kg (range, 70-100 kg), respectively. The following pharmacokinetic variables for meropenem were obtained: mean peak plasma concentration was 24.5 +/- 7.2 mg/L, mean trough plasma concentration was 3.0 +/- 0.9 mg/L, mean terminal elimination half-life was 6.37 +/- 1.96 hrs, mean total plasma clearance was 4.57 +/- 0.89 L/hr, mean CWHF clearance was 1.03 +/- 0.42 L/hr, mean nonrenal clearance was 3.54 +/- 1.06 L/hr, and mean volume of distribution was 0.37 +/- 0.15 L/kg. CONCLUSION: In critically ill patients with acute renal failure, nonrenal clearance became the main elimination route. CWHF substantially contributed to the clearance of meropenem (23% of mean total plasma clearance). We recommend meropenem to be dosed at 500 mg intravenously every 12 hrs in patients receiving CWHF, according to our operational characteristics. This dosing regimen resulted in adequate trough plasma levels for susceptible microorganisms.     

Hemoadsorption removes tumor necrosis factor, interleukin-6, and interleukin-10, reduces nuclear factor-kappaB DNA binding, and improves short-term survival in lethal endotoxemia

OBJECTIVES: Previous studies have shown that inflammatory mediators can be removed from the circulation with hemofiltration and that adsorption plays an important role. Because adsorptive capacity of hollow-fiber dialyzers is limited, we sought to determine whether hemoadsorption using high surface area beads would result in greater mediator removal and improved survival in experimental sepsis. DESIGN: Randomized controlled laboratory experiment. SETTING: University laboratory. SUBJECTS: Sixty-six adult Sprague-Dawley rats. INTERVENTIONS: We conducted two ex vivo and two in vivo experiments. For in vivo experiments, we administered Escherichia coli endotoxin (20 mg/kg) by intravenous infusion and then randomized each animal to receive either hemoadsorption or a sham circuit for 4 hrs. Hemoadsorption was performed for 4 hrs using an arterial-venous circuit and a CytoSorb cartridge containing 10 g of polystyrene divinyl benzene copolymer beads with a biocompatible polyvinylpyrrolidone coating. Survival time was measured to a maximum of 12 hrs. In a separate set of experiments, we studied 12 animals using the same protocol except that we killed all animals at 4 hrs and removed standardized sections of liver for analysis of nuclear factor-kappaB DNA binding. MEASUREMENTS AND MAIN RESULTS: Mean survival time among hemoadsorption-treated animals was 629+/-114 vs. 518+/-120 mins for sham-treated animals (p <.01). Overall survival (defined at 12 hrs) was also significantly better in the hemoadsorption group, seven of 20 vs. one of 20 (p <.05). Plasma interleukin-6 and interleukin-10 concentrations and liver nuclear factor-kappaB DNA binding were significantly reduced by hemoadsorption. Ex vivo experiments showed no endotoxin adsorption but strengthened our in vivo observations by showing rapid adsorption of tumor necrosis factor, interleukin-6, and interleukin-10. CONCLUSIONS: Hemoadsorption was associated with reduced inflammation and improved survival in this murine model of septic shock.     

Attenuation of sepsis-related immunoparalysis by continuous veno-venous hemofiltration in experimental porcine pancreatitis.

OBJECTIVES: In light of evidence suggesting that hemofiltration favorably influences septic diseases by removing sepsis mediators, the impact of different modalities of continuous veno-venous hemofiltration (CVVH) on outcome and immunologic derangements in porcine pancreatogenic sepsis was evaluated. DESIGN: Randomized, controlled intervention trial. SUBJECTS: Forty-eight minipigs of either sex. INTERVENTIONS: Pancreatitis was induced by intraductal injection of sodium taurocholate (4%, 1 mL/kg body weight [BW]) and enterokinase (2 U/kg BW). Animals were allocated either to untreated controls-group 1-or to one of three treatment groups-group 2: low-volume CVVH (20 mL/kg BW), no change of hemofilters; group 3: low-volume CVVH, filters changed every 12 hrs; and group 4: high-volume CVVH (100 mL/kg BW), filters changed every 12 hrs. Survival represented the major parameter of the study. Serum cytokine levels, sepsis-related down-regulation of major histocompatibility complex II and CD14 expression on leukocytes, bacterial translocation, and endotoxemia were further parameters evaluated in the study. MEASUREMENTS AND MAIN RESULTS: High-volume CVVH combined with periodic filter change was significantly superior compared with less intensive treatment modalities (low-volume CVVH, no filter change) in sepsis protection. Long-term survival (>60 hrs) was found in 67% of group 4 and 33% of group 3 animals (p <.05), whereas in controls and group 2 no animal survived. CVVH ameliorated the initial serum tumor necrosis factor-alpha response and prevented sepsis-induced in vitro endotoxin hyporesponsiveness. Down-regulation of major histocompatibility complex II and CD14 expression on monocytes was significantly improved by CVVH. Improved oxidative burst and phagocytosis capacity in polymorphonuclear leukocytes suggested that leukocyte function was stabilized by CVVH. Also, CVVH significantly reduced bacterial translocation and endotoxemia. CONCLUSIONS: Hemofiltration reversed sepsis-induced immunoparalysis in a porcine model of bile acid-induced pancreatitis. Implications for human pancreatitis must be validated in prospective, clinical protocols.     

Intravenous omeprazole in critically ill patients: a randomized, crossover study comparing 40 with 80 mg plus 8 mg/hour on intragastric pH

OBJECTIVE: To compare intravenous omeprazole 40-mg single dose with 8 mg/hr after an 80-mg bolus injection on 24-hr intragastric pH in intensive care unit (ICU) ventilated patients. DESIGN: Prospective, randomized crossover study. SETTING: A 42-bed medicosurgical ICU in a university hospital PATIENTS: Medicosurgical ventilated patients at risk of gastrointestinal bleeding. INTERVENTIONS: After baseline determination of intragastric pH, patients were randomly allocated to have a 40-mg iv omeprazole bolus injection (arm I) or 80 mg bolus, followed by 8 mg/hr continuous infusion for 24 hrs (arm II). After a 24-hr washout period, the opposite regimen was given in a crossover design. Intragastric pH was determined at regular intervals during the treatment period. RESULTS: In ten patients completing the protocol, the intragastric pH was similar for the two regimens for the first 12 hrs. The area under the pH curve was 5.51 +/- 0.48 for arm I compared with 6.02 +/- 0.33 for arm II (NS). Time to reach a pH of 4 or 6 was not significantly different for the two regimens. Time spent with a pH greater than 4 and 6 for the first 12 hrs was 10.11 +/- 1.14 and 8.31 +/- 1.16 hrs vs. 10.11 +/- 0.75 and 7.43 +/- 1.19 hrs for arm I and arm II, respectively (NS). When the first 24 hrs are considered, the area under the pH curve was 5.17 +/- 0.49 for arm I vs. 6.36 +/- 0.25 for arm II (p <.05). Time spent with a pH greater than 4 and 6 was 17.2 +/- 2.4 hrs and 12.63 +/- 2.22 vs. 23 +/- 0.41 and 19.48 +/- 1.63 in arm I and arm II, respectively (p <.05 and.01). An intragastric pH above 6 for all determinations was only observed in arm II. CONCLUSIONS: In critically ill patients, intravenous omeprazole 40 mg single dose is as effective as 8 mg/hr after an 80-mg bolus injection on mean intragastric pH, time spent with a pH greater than 4 and 6, but only for the first 12 hrs. If an intragastric pH greater than 6 has to be maintained for 24 hrs in all patients, an 80-mg bolus followed by 8 mg/hr iv omeprazole is to be given. Our data suggest that in several critically ill patients, a single 40-mg iv omeprazole bolus injection may be able to achieve stress ulcer prophylaxis and that 40 mg twice daily should be compared with 8 mg/hr after an 80-mg bolus injection in bleeding ulcers.     

Dalteparin thromboprophylaxis for critically ill medical-surgical patients with renal insufficiency

PURPOSE: Thromboprophylaxis with low-molecular-weight heparin (LMWH) may be more effective than unfractionated heparin but also more likely to bioaccumulate and potentially cause bleeding in patients with renal insufficiency. The objectives of this study were to assess, among medical-surgical patients in the intensive care unit receiving dalteparin 5,000 IU daily for thromboprophylaxis, (1) the relationship between renal dysfunction and LMWH bioaccumulation as measured by trough anti-Xa levels, (2) the relationship between renal dysfunction and risk of bleeding as measured by a surrogate marker (peak anti-Xa levels), and (3) the relationship between anti-Xa levels, bleeding events, and thrombotic events. MATERIALS AND METHODS: In this prospective single-center cohort study, we enrolled patients 18 years or older, expected to stay 72 hours or longer, and with a creatinine clearance 30 mL/min or higher at intensive care unit admission. We administered 5,000 IU dalteparin subcutaneously each day. The main phase 1 objective was to detect bioaccumulation of dalteparin by measuring trough anti-Xa levels (22-23 hours post dalteparin). The main phase 2 objective was to examine the relationship between renal dysfunction and peak anti-Xa levels (4 hours post dalteparin). We recorded creatinine clearance daily and bleeding and thrombotic events, blinded to anti-Xa levels. RESULTS: We enrolled 19 patients aged 62.7 (13.2) years with an APACHE II score of 23.5 (9.4). We measured trough anti-Xa levels on 185 occasions in 19 patients; we measured peak anti-Xa levels on 113 occasions in 11 patients. We identified no bioaccumulation of LMWH in this study, as detected by trough anti-Xa levels. Most peak anti-Xa levels were in the conventional prophylactic range. CONCLUSIONS: When administered in prophylactic doses to critically ill patients with a wide range of calculated creatinine clearances, we found no evidence of bioaccumulation of dalteparin. If dalteparin does not bioaccumulate, it may be an attractive alternative agent for thromboprophylaxis.     

Pharmacokinetics of Catecholamines During Hemofiltration in Pediatric Patients

BACKGROUND: Continuous hemofiltration is used in pediatric patients with acute renal failure. Many of these patients are treated with catecholamines for hemodynamic instability. The authors studied the pharmacokinetics of dopamine and dobutamine on patients undergoing continuous venovenous hemofiltration. METHODS AND RESULTS: Three critically ill pediatric patients with acute renal failure and cardiovascular instability treated with hemofiltration and intravenous infusion of dopamine and/or dobutamine were entered into the study. Blood samples were drawn at steady-state levels from the arterial port (inflow) of the hemofilter, from the venous port (outflow) of the hemofilter, and from the ultrafilter. Sixteen (n = 16) pharmacokinetic measurements were made, six (n = 6) for dopamine and 10 (n = 10) for dobutamine. The clearance of dopamine by the hemofilter was 0.078 +/- 0.011 mL/kg/min, and for dobutamine it was 0.036 +/- 0.008 mL/kg/min. On the average, 0.56% of the dopamine dose and 0.13% of the dobutamine dose was removed by the hemofilter. CONCLUSIONS: The pharmacokinetics of dopamine and dobutamine at the dosage range of 5-25 μg/kg/min are not altered by continuous hemofiltration. Relative to total plasma clearance, negligible amounts of the drug were removed. The dosage of these catecholamines need not be adjusted during continuous hemofiltration.