Pharmacokinetics of cefpirome in critically ill patients with renal failure treated by continuous veno-venous hemofiltration

Objective: To study the cefpirome pharmacokinetics of patients with sepsis and multiple organ failure treated with CVVH. Design: Measurements of serum and ultrafiltrate (UF) concentrations and in vitro sensitivity testing of isolated micro-organisms. Setting: University hospital-based, single ICU. Patients: Six critically ill CVVH- dependent patients with sepsis and multiple organ dysfunction syndrome in need of antimicrobial therapy. Age range: 60–75 years; APACHE II score for severity of illness on admission: 19–30. One patient survived. Interventions: Cefpirome i. v. was started at 2 g in 30 min, then continued 1 g i. v. b. i. d. Measurements: The UF rate was 27 ± 7 ml/min on day 1 and 34 ± 2 ml/min on day 2. Serum and ultrafiltrate samples were measured by a validated high performance liquid chromatography assay. Volume of distribution: 23 · 5(SD ± 4 · 6) l. Total cefpirome clearance was 32 ± 6 · 3 ml/min; cefpirome CVVH clearance (Cl_CVVH): 17 ± 4.2 ml/min; mean serum half-life (t^1/2): 8.8 ± 2.3 h; mass transfer on day 1: 660 ± 123 mg/12 h (33 ± 6 % of administered dose)and day 2: 642 ± 66 mg/12 h (64 ± 7 %). Estimated sieving coefficient (Cl_CVVH/UF rate): 64 ± 11 %. In vitro sensitivity of isolated microbes was excellent except for two non-sensitive enterococci and Candida spp. Conclusions: The sieving coefficient (64 %) indicates that a substantial fraction of the drug is not filtered; clearance by pathways other than CVVH mounted to 50 % of the total clearance and increased on day 2, indicating that the dosing schedule used is appropriate for this setting. Cefpirome appeared to be safe in these patients and effective for most of the nosocomial microbial isolates. During more than 90 % of the time, serum levels were maintained above killing concentrations for susceptible micro-organisms. Received: 23 July 1999 Accepted: 19 October 1999     

Cytokine removal and cardiovascular hemodynamics in septic patients with continuous venovenous hemofiltration

Objectives: To determine whether continuous venovenous hemofiltration leads to extraction of tumor necrosis factor alpha (TNFα) and cytokines from the circulation of critically ill patients with sepsis and acute renal failure and to quantitate the clearance and the removal rate of these cytokines and their effect on serum cytokine concentrations. Design: Prospective, controlled study in patients with continuous venovenous hemofiltration (24 l/24 h) using a polysulphone membrane in patients with acute renal failure. Patients: 33 ventilated patients with acute renal failure of septic (n = 18) and cardiovascular origin (n = 15) were studied. Interventions: Hemodynamic monitoring and collection of blood and ultrafiltrate samples before and during the first 72 h of continuous hemofiltration. Measurements and main results: Cardiovascular hemodynamics (Swan-Ganz catheter), Acute Physiology and Chronic Health Evaluation II score, creatinine, electrolytes, and blood urea nitrogen were recorded daily. Cytokines (TNFα, TNFα-RII, interleukin (IL) 1β , IL1RA, IL2, IL2R, IL6, IL6R, IL8, IL10) were measured in prefilter blood and in ultrafiltrate immediately preceding and 12, 24, 48, and 72 h after initiating continuous venovenous hemofiltration (CVVH). Septic patients showed elevated cardiovascular values for cardiac output (7.2 ± 2.1 l/min), cardiac index (4.2 ± 1.3 l/min per m²), and stroke volume (67 ± 23 ml) and reduced values for systemic vascular resistance (540 ± 299 dyn · s · cm^{− 5}). All hemodynamic values normalized within the first 24 h after initiating CVVH treatment. TNFα was 1833 ± 1217 pg/ml in septic patients and 42.9 ± 6.3 pg/ml in nonseptic patients (p < 0.05) prior to CVVH. TNFα was detected in ultrafiltrate but did not decrease in blood during treatment with CVVH. There was no difference in IL 1β between septic (3.8 ± 1.9 pg/ml) and nonseptic patients (1.7 ± 0.5 pg/ml). No significant elimination of cytokines was achieved in the present study by CVVH treatment. Conclusions: These findings demonstrate that CVVH can remove TNFα and special cytokines from the circulation of critically ill patients. Cardiovascular hemodynamics seemed to improve in septic patients after induction of hemofiltration treatment, although there was no evidence that extracorporeal removal of cytokines achieved a reduction in blood levels. The study indicates that low volume continuous hemofiltration with polysulphone membranes in patients with acute renal failure is not able to induce significant removal of cytokines. Received: 12 February 1996 Accepted: 27 November 1996     

Pharmacokinetics of milrinone in patients with congestive heart failure during continuous venovenous hemofiltration

Objective: To evaluate the pharmocokinetics of intravenous milrinone in patients with severe congestive heart failure during continuous venovenous hemofiltration (CVVH). Design: Prospective study of patients with congestive heart failure admitted to the intensive care unit (ICU). Setting: ICU between September 1997 and August 1999. Patients and methods: Six patients with severe congestive heart failure during CVVH: all patients received a continuous infusion of milrinone of 0.25 μg · kg^{− 1}· min^{− 1}. The hemodynamics and plasma concentration of milrinone were measured before and after the infusion. Pharmacokinetics were analyzed with one-compartment model featuring constant rate infusion. Results: The steady-state concentration (Css) was 845 ± 135 (mean ± SD) ng/ml, and the half-life time (t_1/2) was 20.1 ± 3.3 h. Cardiac index and stroke volume index after the infusion of milrinone increased significantly compared with pre-infusion levels. Other hemodynamic parameters did not change significantly. All patients died within 1 month after the injection of milrinone because of severe forms of arrhythmia, such as ventricular tachycardia and ventricular fibrillation. Conclusions: We found that the mean Css and the mean t_1/2 of milrinone in subjects during CVVH were much higher and longer than those previously reported for subjects with normal renal function. It is therefore essential to adjust the dose or modify the dosing interval of milrinone during renal replacement therapy for patients with severe congestive heart failure. However, further studies are needed to determine the details of pharmacokinetics of milrinone and therapeutic procedures for patients with severe heart failure during CVVH. Received: 1 December 1999 Final revision received: 9 March 2000 Accepted: 11 April 2000     

Enhanced fluid management with continuous venovenous hemofiltration in pediatric respiratory failure patients receiving extracorporeal membrane oxygenation support

Background/purpose  Children receiving extracorporeal membrane oxygenation (ECMO) for respiratory failure can have significant fluid overload and renal insufficiency. Addition of inline continuous venovenous hemofiltration (CVVH) could provide additional benefits in fluid management compared to use of standard medical therapies with ECMO. Methods  Patients with pediatric respiratory failure receiving ECMO with CVVH were case-matched to similar patients receiving ECMO without CVVH to compare fluid balance, medication use, and clinical outcomes. Results  Twenty-six of eighty-six patients with pediatric respiratory failure on ECMO (30%) received CVVH for >24 h (median 7.5 days on CVVH). Survival was not significantly different between patients receiving CVVH and those who did not receive CVVH (P = 0.51). For ECMO survivors receiving CVVH, overall fluid balance was less than that in non-CVVH survivors (median 25.1 ml kg⁻¹ day⁻¹; range −40.2 to 71.2 vs. 40.2, 1.1 to 134.9; P = 0.028). Time to desired caloric intake was faster in patients receiving CVVH (1 day, 1–5) than in patients who did not receive CVVH (5 days; 1–11; P < 0.001). Patients receiving CVVH–ECMO also received less furosemide (0.67 vs. 2.11 mg kg⁻¹ day⁻¹; P = 0.009). Conclusions  Use of CVVH in ECMO was associated with improved fluid balance and caloric intake and less diuretics than in case-matched ECMO controls.     

Ibuprofen does not impair renal function in patients undergoing infrarenal aortic surgery with epidural anaesthesia

Objective: To investigate the effect of preoperative ibuprofen administration on renal function during and after infrarenal aortic surgery under thoracolumbar epidural anaesthesia (EPA). Design: A prospective randomised, double-blinded clinical study. Setting: Operation room and intensive care unit in a university hospital. Patients: Twenty-six consecutive patients scheduled for elective infrarenal aortic surgery. Interventions: The patients were prospectively randomised to receive 400 mg ibuprofen intravenously (i. v.) or a placebo aliquot before surgery. Measurements and results: We assessed renal function by calculating creatinine clearance, and fractional sodium excretion before surgery (baseline), 1 h after cross-clamping (intraoperative), 6 h after cross-clamping (postoperative) and 24 h after cross-clamping (on the 1 st postoperative day). At each point in time, we additionally registered haemodynamics and determined the plasma concentration of 6-keto-PGF₁α (stable metabolite of prostacyclin, PGI₂), bicyclic PGE₂ (stable metabolite of PGE₁ E₂), active renin, aldosterone and vasopressin by radioimmunoassays. Throughout the observation period the renal function parameters mostly remained within the normal range without a significant difference between ibuprofen- and placebo-treated patients (creatinine clearance: baseline 41 ± 3 vs 38 ± 6, intraoperative 57 ± 8 vs 64 ± 11, postoperative 64 ± 9 vs 56 ± 9, first postoperative day 43 ± 5 vs 47 ± 6 ml · min · m^{− 2}, means ± SEM). The plasma levels of 6-keto-PGF₁α (68 ± 8 vs 380 ± 71^* ng · l^{− 1}), bicyclic PGE₂ (57 ± 5 vs 88 ± 9^* ng · l^{− 1}) and vasopressin (14 ± 7 vs 45 ± 10^* ng · l^{− 1}, p < 0.0125), however, were significantly higher during the intraoperative period in the placebo-treated patients. Conclusion: The inhibition of endogenous prostaglandin release by ibuprofen does not substantially impair renal function during infrarenal aortic surgery under EPA. Received: 24 June 1997 Accepted: 26 January 1998     

The use of different buffers during continuous hemofiltration in critically ill patients with acute renal failure

Objective: To determine the impact of different hemofiltration (HF) replacement fluids on the acid-base status and cardiovascular hemodynamics in patients with acute renal failure (ARF) and continuous veno-venous hemofiltration (CVVH).¶Design: Prospective, cohort study.¶Setting: Intensive Care Unit of the Heinrich Heine University Hospital, Düsseldorf, Germany.¶Subject and methods: One hundred and thirty-two critically ill patients with acute renal failure and continuous veno-venous HF were studied. Fifty-two patients were subjected to lactate-based (group 1), and 32 to acetate-based hemofiltration (group 2)while 48 (group 3) were treated with bicarbonate-based buffer hemofiltration fluid. Fifty-seven had a septic, and 75 a cardiovascular, origin of the ARF. Creatinine, blood urea nitrogen (BUN), serum bicarbonate, arterial pH, lactate and Apache II scores were noted daily.¶Main results: The mean CVVH duration was 9.8 ± 8.1 days, mortality was 65 %. No difference was present between the groups under investigation with regard to the main clinical parameters. Lactate- and bicarbonate-based hemofiltration led to significantly higher serum bicarbonate and arterial pH values as compared to the acetate-based hemofiltration. Serum bicarbonate values at 48 h after the initiation of CVVH treatment were 25.7 ± 3.8 mmol/l (p < 0.001) in group 1, 20.6 ± 3.1 mmol/l in group 2 and 23.3 ± 3.9 mmol/l (p < 0.001) in group 3. While a lack of increase in serum bicarbonate and arterial pH was correlated to poor prognosis in lactate- and bicarbonate-based hemofiltration, no such observation was made in acetate-based hemofiltration. Cardiovascular hemodynamics were superior in patients treated with lactate- and bicarbonate-based buffer solution as compared to those treated with acetate-based buffer solution.¶Conclusions: The degree of correction of acidosis during hemofiltration was determined by patient outcome in patients treated with lactate- and bicarbonate-based buffer solutions, but not in patients receiving acetate-buffered solution. Bicarbonate and lactate-based buffer solutions were found to be superior to acetate-based replacement fluid.     

Pharmacokinetics of single‐dose rosiglitazone in chronic ambulatory peritoneal dialysis patients

Background: End‐stage renal disease (ESRD) is associated with marked alterations in the pharmacokinetics of many drugs, not only from reduction in renal clearance but also from changes in metabolic activity, bioavailability, volume of distribution and plasma protein binding. Objective: To study the pharmacokinetics of a single 8‐mg oral dose of rosiglitazone in patients with ESRD and requiring long‐term chronic ambulatory peritoneal dialysis (CAPD). Method: The medication was administered just before the first exchange of peritoneal dialysis fluid on the day that blood and peritoneal dialysate collection was performed. Results: In our CAPD patients the mean (±SD) T_max and T_1/2 of rosiglitazone were 1·20 ± 0·26 and 21·38 ± 21·96 h respectively. These values were different to those reported for healthy volunteers reported in previous studies. The mean area under the concentration–time curve (AUC_(0–∞)) and an average maximum observed plasma concentration (C_max) of rosiglitazone in our CAPD patients were 4203·56 ± 2916·97 ng h/mL and 409·67 ± 148·89 ng/mL respectively. These appear no different from those reported in healthy volunteers . Conclusion: The apparently significant difference in T_1/2 of rosiglitazone in CAPD patients compared with healthy volunteers suggest that dose adjustment may be necessary in order to avoid toxicity.     

Sympathetic nervous activity, renin-angiotensin system and renal excretion of prostaglandin E2 in cirrhosis. Relationship to functional renal failure and sodium and water excretion

Abstract. To investigate if functional renal failure in cirrhosis could be related to disturbances of vasoactive systems, plasma renin activity, plasma catecholamines and urinary prostaglandin E₂ (PGE₂) were determined in twenty-two normal subjects and sixty-five cirrhotics. Furthermore, in thirty-three of these subjects, the effect of lysine-acetylsalicylate (450 mg i.v.) on renal function was studied. Patients with ascites without renal failure showed higher renin, noradrenalin and urinary PGE² than normal subjects (5.9±0.8 v. 1.1±0.1 ng ml^-1 h^-1, P < 0.001; 512 ± 39 v. 224±17 pg/ml, P < 0.001; and 603 ± 71 v. 377±36 ng/day, P < 005, respectively). Patients with functional renal failure showed higher (P < 0001) renin (13.5±1.9) and noradrenalin (1114±134) and lower (P < 005) urinary PGE₂ (199 ± 36) than normal subjects and cirrhotics without renal failure. On the whole, patients glomerular filtration rate correlated (P < 0001) with urinary PGE₂ (r= 0.55), renin (r=-0.52) and noradrenalin (r=-0.52). Lysine-acetylsalicylate did not alter renal function in normal subjects and cirrhotics without ascites. However, it reduced water diuresis (8.8 ± 0.9–2.7 ± 0.5 ml/min) and sodium excretion (from 57.1 ± 13.9 to 3.9 ± 11 μmol/min) in all the nineteen cirrhotics with ascites studied and the glomerular filtration rate (95.4 ± 11.8–46.7 ± 9.5 ml/min) in eleven of these patients. Urinary PGE₂ decreased in all patients (3.13 ± 0.65–0.54 ± 0.11 ng/min). The study suggests that: (a) functional renal failure in cirrhosis with ascites may be a consequence of an imbalance between vasoactive systems, (b) renal prostaglandins are involved in the tubular handling of sodium and water in these patients.     

Myoglobin clearance and removal during continuous venovenous hemofiltration

Myoglobin has a relatively high molecular weight of 17,000 Da and is poorly cleared by dialysis (diffusion). However, elimination of myoglobin might be enhanced by an epuration modality based on convection for solute clearances. We present a single case of myoglobin-induced renal failure (peak creatine kinase level: 313,500 IU/l) treated by continuous venovenous hemofiltration (CVVH). Our purpose was to evaluate the efficiency of such a modality using an ultrafiltration rate of 2 to 3 l/h for myoglobin removal and clearance. The hemofilter was a 0.9 m² polyacrylonitrile (AN69) membrane Multiflow-100 (Hospal-Gambro, St-Leonard, Canada) and the blood flow rate was maintained at 150 ml/min by an AK-10 pump (Hospal-Gambro, St-Leonard, Canada). The ultrafiltration bag was placed 60 cm below the hemofilter and was free of pump control or suction device. Serum myoglobin concentration was 92,000 μg/l at CVVH initiation and dropped to 28,600 μg/l after 18 h of the continuous modality. The mean sieving coefficient for myoglobin was 0.6 during the first 9 h of therapy and this decreased to 0.4 during the following 7 h. Mean clearance of myoglobin was 22 ml/min, decreasing to 14 ml/min during corresponding periods, while the mean ultrafiltration rates were relatively stable at 2,153 ± 148 ml/h and 2,074 ± 85 ml/h, respectively. In contrast to myoglobin, the sieving coefficeint for urea, creatinine, and phosphorus remained stable at 1.0 during the first 16 h of CVVH. More than 700 mg of myoglobin were removed by CVVH during the entire treatment.¶In conclusion, considerable amounts of myoglobin can be removed by an extracorporeal modality allowing important convective fluxes and middle molecule clearances, such as CVVH at a rate of 2 to 3 l/h using an AN69 hemofilter. If myoglobin clearance had been maintained at 22 ml/min, 32 l of serum would have been cleared per day. However, the sieving coefficient of myoglobin decreased over time, probably as a consequence of protein coating and/or blood clotting of the hemofilter. Whereas myoglobin can be removed by CVVH, it remains unknown at this point if such a modality, applied early, can alter or shorten the course of myoglobinuric acute renal failure.     

Pharmacokinetics of Azlocillin in Subjects with Normal and Impaired Renal Function

The pharmacokinetics of azlocillin were investigated in five healthy subjects and in 16 subjects with chronic renal failure. After intravenous bolus injection of a single dose of 30 mg/kg in normal subjects, pharmacokinetic data were calculated, using a two-compartment open body model. The mean distribution serum half-life (T_1/2α) was 0.11 h, and the mean elimination serum half-life (T_1/2β) was 0.89 h. The volume of the central compartment (V_C) was 7.36 liters/1.73 m², and the apparent volume of distribution (V_dss) was 14.15 liters/1.73 m², i.e., 21.9% of body weight. The T_1/2β after a 30-min intravenous infusion of 80 mg/kg to the same healthy subjects was 1.11 h. Serum clearances (C_S) for the 30- and 80-mg/kg doses were 215.0 and 152.9 ml/min per 1.73 m². The mean renal clearances (C_R) were 145.2 and 94.1 ml/min per 1.73 m² for the respective doses. Between 61.8 and 69.6% of the injected dose was recovered in urine during the first 24 h. The elimination half-life in subjects with chronic renal impairment increased with the degree of renal insufficiency. After a 30-min intravenous infusion of 80 mg/kg the T_1/2β values were 2.03, 4.01, and 5.66 h with creatinine clearances (C_cr) within 30 to 50, 10 to 30, and <10 ml/min per 1.73 m², respectively. Urinary elimination was inversely related to the degree of renal impairment. In four patients out of and on a 6-h hemodialysis session mean elimination half-life values were 6.53 and 2.81 h, respectively. The fraction of drug removed by dialysis was 45.8%. The linear relationships between the elimination of half-life (T_1/2β) and serum creatinine and the elimination rate constant (β) and creatinine clearance (C_cr) provided a basis for adjustment of dosage in renal failure.     

Comparison of systemic and regional effects of dobutamine and dopexamine in norepinephrine-treated septic shock

Objectives: To compare the effects of dobutamine and dopexamine on systemic hemodynamics, lactate metabolism, renal function and the intramucosal-arterial PCO₂ gap in norepinephrine-treated septic shock. Design: A prospective, interventional, randomized clinical trial. Setting: Adult medical/surgical intensive care unit in a university hospital. Patients: After volume resuscitation, 24 patients were treated with norepinephrine alone titrated to obtain a mean arterial pressure of 75 mmHg and a cardiac index greater than 3.5 l/min^-1· m^-2. Interventions: Patients were randomized to receive an infusion of dobutamine (n = 12) (5 μg/kg per min) or dopexamine (n = 12) (1 μg/kg per min). Measurements and main results: Baseline measurements included: hemodynamic parameters, renal parameters (diuresis, creatinine clearance and urinary sodium excretion), gastric mucosal-arterial PCO₂ gap, arterial and mixed venous gases and arterial lactate and pyruvate levels. These measurements were repeated after 1 (H₁), 4 (H₄) and 24 (H₂₄) h. No difference was found between dobutamine and dopexamine among H₀ and H₁, H₄ and H₂₄ values for hemodynamics. Dobutamine and dopexamine at low doses had no significant effect on mean arterial pressure, heart rate, cardiac index, oxygen delivery, oxygen consumption and pulmonary artery occlusion pressure. No patients developed arrhythmia or electrocardiographic signs of myocardial ischemia. After 4 and 24 h lactate concentration decreased in the dobutamine group from 2.4 ± 1 mmol/l to 1.7 ± 0.7 mmol/l and 1.5 ± 0.4 mmol/l, respectively, while it increased in the dopexamine group from 2.3 ± 1 mmol/l to 2.7 ± 1 mmol/l after 4 h and returned to baseline values after 24 h (2.2 ± 0.6). After 24 h the lactate/pyruvate ratio decreased in the dobutamine group from 15 ± 5 to 12 ± 3 (p < 0.05) while it was unchanged in the dopexamine group (from 16 ± 6 to 17 ± 4). Arterial pH increased in the dobutamine group from 7.35 ± 0.05 to 7.38 ± 0.07 (p < 0.05) while it was unchanged in the dopexamine group (from 7.34 ± 0.01 to 7.35 ± 0.10). The PCO₂ gap decreased after 1 and 4 h in both the dobutamine and dopexamine groups (p < 0.05 with respect to baseline). When looking at individual responses, however, patients from both groups exhibited an increased gastric PCO₂ gap. No difference was found between dobutamine and dopexamine for renal parameters. Conclusions: In norepinephrine-treated septic shock, low doses of neither dobutamine nor dopexamine caused significant effects on systemic hemodynamics and renal function and both dobutamine and dopexamine inconsistently improved the PCO₂ gap. The present results support the need for individual measurement of the effects of catecholamine on the PCO₂ gap. Received: 26 October 1998 Final revision received: 11 April 1999 Accepted: 8 June 1999     

Five years experience with continuous extracorporeal renal support in paediatric intensive care

Continuous arterio-venous haemofiltration (CAVH) and continuous veno-venous haemofiltration (CVVH) were used as renal support in 52 critically ill infants and children with acute renal failure. The majority of the patients were on mechanical ventilation (90%) and needed vasopressor support (85%). Uraemia was satisfactorily controlled with both treatment modes. Post-treatment serum urea levels were not different between survivors (94±8.8 mg/dl) and non-survivors (99.5±8.8 mg/dl). There were significant differences between survivors and non-survivors in the mean arterial pressure (64.7±3.8 vs 48.0±2.2 mmHg,p<0.001), the number of organ system failures (2.9±0.16 vs 3.8±0.21,p<0.025), and the severity of illness assessed by the acute physiologic score for children (APSC 19.4±1.9 vs 26.3±1.9,p<0.01). The overall mortality was 48%. The mortality in the CVVH group (65%) was higher than in the CAVH group (40%). Death was significantly related to sepsis (p<0.005) and multiple system organ failure (p<0.005). A major complication during CAVH was one femoral artery thrombosis after 12 days of treatment. Technical problems were only observed during CVVH. CAVH and CVVH are safe and effective methods of continuous renal support for critically ill paediatric patients with multiple system organ failure. CAVH is simpler, needs no specially trained staff and seems to the ideal renal replacement system for critically ill infants.     

The effects of pentoxifylline on circulating adhesion molecules in critically ill patients with acute renal failure treated by continuous veno-venous hemofiltration

Objective Circulating adhesion molecules appear to be excellent markers of endothelial activation in critically ill patients. Pentoxifylline (PTX) may limit sequelae of inflammation and subsequent endothelial activation by various mechanisms. The influence of PTX on the plasma levels of soluble adhesion molecules in critically ill patients undergoing continuous veno-venous hemofiltration (CVVH) was studied.Design Prospective, randomized, blinded study.Setting Clinical investigation in the surgical intensive care unit of a university hospital.Patients and participants Fourteen consecutive patients suffering from acute renal failure (ARF) with postoperative complications who received continuous pentoxifylline (CVVH-PTX) i.v. were compared with 14 patients with ARF who did not receive PTX (CVVH control group).Interventions Pump-driven CVVH was carried out with a blood flow ranging from 120 to 150 ml/min. All patients received fentanyl and midazolam continuously and were on mechanical ventilation. PTX (300 mg) was given as a loading dose, followed by continuous infusion of 1.2 mg/kg per h for the next 5 days.Measurements and results From arterial blood samples, plasma levels of soluble adhesion molecules (endothelial leukocyte adhesion molecules [sELAM-1], and intercellular adhesion molecule-1 [sICAM-1], vascular cell adhesion molecule-1 [sVCAM-1], and P-selectin granule membrane protein [sGMP-140] were measured using enzyme-linked immuno-sorbent assays (ELISA). Measurements were carried out before the start of CVVH to establish baseline values and continued during the next 5 days.Main results Eleven of the CVVH-PTX patients and 8 of the CVVH control patients survived during the investigation period. In the CVVH-PTX patients 2.4±0.3 g/day of PTX was given. At baseline, plasma levels of sELAM-1, sICAM-1, and sVCAM-1 were markedly higher than normal in both groups. In the CVVH control patients, all measured soluble adhesion molecules increased further during the study period (sELAM-1 from 90±22 to 134±30 ng/ml; sICAM-1 from 958±173 to 1460±209 ng/ml; sVCAM-1 from 1100±188 to 1804 ng/ml; sGM-140 from 499±102 to 688±121 ng/ml) (p<0.05), whereas in the PTX-treated CVVH patients, plasma levels of all soluble adhesion molecules remained almost unchanged. The PaO₂/FIO₂ increased in the PTX-treated patients (from 209±67 to 282±58 mmHg) and remained almost unchanged in the CVVH control patients.Conclusion Leukocyte/endothelial interactions play an important role in the inflammatory process. Circulating adhesion molecules may serve as markers of the extent of inflammation. Continuous i.v. administration of PTX was successful in blunting the increase of soluble adhesion molecules in critically ill patients undergoing CVVH. Whether these effects result from improved circulation at the microcirculatory level or from (direct or indirect) beneficial effects on endothelial cells warrants further controlled studies.     

大剂量呋塞米联合氨茶碱对老年危重症合并急性肾衰竭的影响

目的：探讨大剂量呋塞米联合氨茶碱微泵连续输注方法,对部分伴发急性肾功能衰竭的可暂缓连续性静脉静脉血液滤过（CVVH）老年危重病患者是否有效。方法选择符合急性肾衰竭的可暂缓CVVH老年危重患者58例,按照入住先后分为治疗组和对照组：治疗组予大剂量呋塞米针200～800 mg/d和氨茶碱0.25 g加入0.9％氯化钠注射液稀释成50 ml,对照组予呋塞米针200～800 mg/d 加入0.9％氯化钠注射液50 ml,均采用微泵静脉内注射,0～4 ml/h静脉维持。记录两组患者治疗前及治疗后第1天、第7天的24 h 尿量,治疗后第1天、第7天的24 h呋塞米用量,治疗前后血肌酐值,治疗后第7天心率及治疗过程中需要进行CVVH的患者比例和28 d 病死率。结果治疗组治疗后第1天和第7天的24 h 尿量明显高于对照组,差异均有统计学意义（t分别=-8.22、-3.30,P均＜0.05）,治疗组治疗过程中需要进行CVVH的患者比例明显低于对照组,差异有统计学意义（χ2=5.51,P＜0.05）。两组治疗后第1天和第7天的24 h呋塞米用量、治疗前及治疗后第7天血肌酐值、治疗后第7天的心率和28 d 病死率比较,差异均无统计学意义（t分别=-0.64、-1.42、0.71、2.79、-2.03,χ2=0.30, P均＞0.05）。结论大剂量呋塞米联合氨茶碱微泵连续输注,能明显增加伴发急性肾衰竭的老年危重病患者的尿量,减少CVVH治疗。     

Continuous venovenous hemofiltration in severely burned patients with acute kidney injury: a cohort study

Introduction

Acute kidney injury (AKI) is a common and devastating complication in critically ill burn patients with mortality reported to be between 80 and 100%. We aimed to determine the effect on mortality of early application of continuous venovenous hemofiltration (CVVH) in severely burned patients with AKI admitted to our burn intensive care unit (BICU).

Methods

We performed a retrospective cohort study comparing a population of patients managed with early and aggressive CVVH compared with historical controls managed conservatively before the availability of CVVH. Patients with total body surface area (TBSA) burns of more than 40% and AKI were treated with early CVVH and their outcomes compared with a group of historical controls.

Results

Overall, the 28-day mortality was significantly lower in the CVVH arm (n = 29) compared with controls (n = 28) (38% vs. 71%, P = 0.011) as was the in-hospital mortality (62% vs. 86%, P = 0.04). In a subgroup of patients in shock, a dramatic reduction in the pressor requirement was seen after 24 and 48 hours of treatment. Compared with controls (n = 19), significantly fewer patients in the CVVH group (n = 21) required vasopressors at 24 hours (100% vs 43%, P < 0.0001) and at 48 hours (94% vs 24%, P < 0.0001). In those with acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), there was a significant increase from baseline in the partial pressure of arterial oxygen (PaO₂) to fraction of inspired oxygen (FiO₂) ratio at 24 hours in the CVVH group (n = 16, 174 ± 78 to 327 ± 122, P = 0.003) but not the control group (n = 20, 186 ± 64 to 207 ± 131, P = 0.98).

Conclusions

The application of CVVH in adult patients with severe burns and AKI was associated with a decrease in 28-day and hospital mortality when compared with a historical control group, which largely did not receive any form of renal replacement. Clinical improvements were realized in the subgroups of patients with shock and ALI/ARDS. A randomized controlled trial comparing early CVVH to standard care in this high-risk population is planned.     

Blood hemoperfusion with resin adsorption combined continuous veno-venous hemofiltration for patients with multiple organ dysfunction syndrome

BACKGROUND:

Blood hemoperfusion with resin adsorption can clean larger molecules that exceed the molecular weight cutoff of combined continuous veno-venous hemofiltration (CVVH). Hence blood hemoperfusion with resin adsorption combined CVVH (HP+CVVH) has higher ability of mediator clearance, and can improve clinical outcomes in theory. This study aimed to investigate the effect of blood hemoperfusion with resin adsorption combined continuous veno-venous hemofiltration (HP+CVVH) on plasm cytokines like TNF-α, IL-1β, IL-6, cellular immunity and prognosis in patients with multiple organ dysfunction syndrome (MODS).

METHODS:

This was a prospective, randomized clinical trial. A total of 30 patients who had been diagnosed with MODS were enrolled in this study. Patients were randomly allocated to routine treatment+HP+CVVH group (treatment group) and routine treatment+only CVVH group (control group). In the treatment group, patients received blood hemoperfusion with resin adsorption for 2 hours, and then received CVVH for 10 hours every day. In the control group, patients received CVVH for 12 hours only every day. The patients in the two groups received blood purification therapy for three days. The plasma of patients in the treatment group was obtained at 0, 2, 12, 24, 26, 36, 48, 50, 60 hours, 5th day, 7th day and 10th day, respectively. The plasma of patients in the control group was obtained at 0, 12, 24, 36, 48, 60 hours, 5th day, 7th day and 10th day, respectively. APACHE II score, T-lymphocytes subpopulations, blood lactate acid concentration, heart rate, breathing rate, and oxygenation index were observed.

RESULTS:

Plasma cytokines like TNF-α, IL-1β, IL-6 decreased markedly after HP (P<0.01); T-lymphocytes subpopulations CD3+, CD4+, CD8+, CD4+/CD8+ increased after HP+CVVH or only CVVH. The plasma concentrations of TNF-α, IL-1β and IL-6 in the two groups were not markedly different at 12, 36, and 50 hours. But on the 5th day, the plasma concentrations of TNF-α, IL-1β and IL-6 in the treatment group were lower than those in the control group (P<0.05). On the 28th day, 5 patients died in the treatment group, and 6 patients in the control group.

CONCLUSIONS:

Both HP+CVVH and CVVH can clean plasma cytokines like TNF-α, IL-1β, and IL-6, and improve cellular immunity and clinical symptoms and signs of patients. Compared with only CVVH, the plasma concentrations of TNF-α, IL-1β and IL-6 were lower on the 5th day, and patients have an increased survival rate on the 28 day in the HP+CVVH group.KEY WORDS: Hemoperfusion with resin adsorption, Continuous veno-venous hemofiltration, Multiple organ dysfunction syndrome, Cytokines     

Endogenous α2-antiplasmin does not enhance glomerular fibrin deposition or injury in glomerulonephritis

Summary. Background: Fibrin deposition is an important mechanism of glomerular injury in crescentic glomerulonephritis (GN), a severe form of immune renal injury. Both coagulation and fibrinolysis (via the plasminogen–plasmin system) are important in net glomerular fibrin accumulation in GN. α₂‐Antiplasmin (α₂‐AP) is the major circulating inhibitor of plasmin and is expressed in the renal tubulointerstitium. Objective: To determine whether endogenous α₂‐AP contributes to glomerular fibrin accumulation in GN. Methods: Crescentic autologous phase antiglomerular basement membrane GN was induced in mice with intact and deficient endogenous α₂‐AP (α₂‐AP^+/+ and α₂‐AP^?/? mice). Results: In mice with crescentic GN, α₂‐AP was detected in the tubulointerstitium and in segmental deposits within some glomeruli. α₂‐AP^+/+ mice developed crescentic GN (38 ± 9% glomeruli affected) with glomerular fibrin deposition and renal impairment (serum creatinine 30 ± 1 µmol L^?1, normal without GN 11 ± 1 µmol L^?1). Genetic deficiency of α₂‐AP did not result in attenuated glomerular fibrin deposition, crescent formation (39 ± 8% glomeruli affected), glomerular leukocyte infiltration or renal impairment (serum creatinine 33 ± 7 µmol L^?1). α₂‐AP was unmeasurable in kidneys from α₂‐AP^?/? mice, which did not develop compensatory changes in plasminogen, tissue type plasminogen activator (tPA), urokinase type PA (uPA) or plasminogen activator inhibitor‐1 proteins, or changes in tPA or uPA activity. α₂‐AP^?/? mice did have enhanced total renal fibrinolytic capacity as assessed by in situ fibrin overlay (α₂‐AP^+/+ 0.19 ± 0.01, α₂‐AP^?/? 0.36 ± 0.03 lyzed area/total area). Conclusions: α₂‐AP is not important to net glomerular fibrin deposition, crescent formation or renal impairment in crescentic GN.     

Population pharmacokinetics of high‐dose methotrexate in Japanese adult patients with malignancies: a concurrent analysis of the serum and urine concentration data

Objective: This study aimed to develop a population pharmacokinetic model for high‐dose methotrexate (MTX), specifically focusing on the drug urinary excretion process. Methods and results: Three hundred and forty‐eight serum samples and 416 urine samples from 51 Japanese adult patients with malignancies were concurrently fitted into a multi‐compartment model using the nonmem program. In the final model, creatinine clearance (CCR, mL/min) and the MTX dose (DOSE10G; 0 when <10 g, 1 when ≥10 g) were the most significant factors that affected the renal clearance (CL_r) and non‐renal clearance (CL_nr), respectively: CL_r(L/h) = 5·57 × (CCR/80·0)^0·112, V₁(L) = 26·9, Q(L/h) = 0·0778, V₂(L) = 2·27, CL_nr(L/h) = 0·567 × 3·39^DOSE10G, where V₁ and V₂ are the volumes of distribution of the central and peripheral compartments, respectively, and Q is the inter‐compartmental (central–peripheral) clearance. For another nine patients, the model enabled a satisfactory Bayesian estimation using two time‐point serum concentrations. Conclusion: The newly developed population pharmacokinetic model should improve the quality of serum concentration monitoring of high‐dose MTX to predict and control toxic events.     

Levetiracetam pharmacokinetics in critically ill patients undergoing renal replacement therapy

PurposeTo determine clearance of levetiracetam in patients requiring continuous renal replacement therapy (CRRT) or sustained low efficiency dialysis (SLED).Materials and methodsAdult patients with acute kidney injury or end stage renal disease requiring either CRRT or SLED and levetiracetam were eligible for inclusion. Simultaneous arterial, venous, and effluent samples for analysis of levetiracetam concentrations were collected every two hours for up to 6–8 h. Levetiracetam clearance (CL) and half-life (t_1/2) were calculated for each modality.ResultsEight CRRT patients and 4 SLED patients completed the study: 67% male, mean age 50 ± 13 years, and 83% had AKI. Seven CRRT patients received continuous venovenous hemodiafiltration (CVVHDF) [median pre-replacement rate 700 mL/h (range 500–1000), post-replacement rate 500 mL/h (range 200–1000), effluent rate 2500 mL/h (range 1700–3650) and delivered CRRT dose 27 mL/kg/h (range 19–54)] and one patient received CVV hemofiltration (CVVH). The mm mean levetiracetam CL during CVVHDF was 31.2 ± 8.5 mL/min, and the and the mean t_1/2 was 10.4 ± 2.2 h. For the patient requiring CVVH, clearance and t_1/2 were 22.5 mL/min and 9.5 h, respectively. Mean levetiracetam CL during SLED performed at a blood flow rate of 250 mL/min and a dialysate flow rate of 100 mL/min was 74.0 ± 25.3 mL/min and t_1/2 was 4.8 ± 2.3 h.ConclusionsLevetiracetam clearance was substantial with both modalities under the operating conditions reported. There is the potential for subtherapeutic concentrations with current recommended dosing strategies that account only for kidney function and not these extracorporeal routes of elimination.     

Cardiac sympathetic activity is associated with inflammation and neurohumoral activation in patients with idiopathic dilated cardiomyopathy

Background: Idiopathic dilated cardiomyopathy (IDC) is characterized by sympathetic nervous overactivity, inflammation and neurohumoral activation; however, their interrelationships are poorly understood. Methods and results: We studied 99 patients with IDC (age 54 ± 1 years, left ventricular ejection fraction (EF) 40 ± 1%, maximum oxygen uptake (VO₂max) 20 ± 1 ml kg^?1 min^?2, mean ± SEM) by using ¹²³I‐metaiodobenzylguanidine (MIBG) imaging. MIBG washout and MIBG heart/mediastinum (H/M)‐ratio at 4 h postinjection were calculated. In addition, the plasma levels of interleukin (IL)‐6 and N‐terminal B‐type natriuretic peptide (NT‐proBNP) were measured. MIBG washout and MIBG H/M ratio had a significant correlation with IL‐6 (r = 0·42, P<0·001 and r = ?0·31, P<0·01) and NT‐proBNP (r = 0·48, P<0·001 and r = ?0·40, P<0·001). During a median follow‐up of 4·1 years, 20 patients (20%) had an adverse cardiac event (death, heart transplantation or application of biventricular pacemaker or implantable cardioverter–defibrillator). In these patients, MIBG washout was higher (53 ± 4 versus 40 ± 2%, P = 0·01) and H/M ratio lower (1·38 ± 0·04 versus 1·51 ± 0·02, P = 0·01) than in patients without an event. Conclusions: In dilated cardiomyopathy, myocardial sympathetic innervation and activity are related to inflammation and neurohumoral activation. These relationships are at least partly independent of left ventricular function and exercise capacity.