Abstract: PURPOSE: The aim of this study is to evaluate the relationship between timing of renal replacement therapy (RRT) in severe acute kidney injury and clinical outcomes. METHODS: This was a prospective multicenter observational study conducted at 54 intensive care units (ICUs) in 23 countries enrolling 1238 patients. RESULTS: Timing of RRT was stratified into "early" and "late" by median urea and creatinine at the time RRT was started. Timing was also categorized temporally from ICU admission into early (<2 days), delayed (2-5 days), and late (>5 days). Renal replacement therapy timing by serum urea showed no significant difference in crude (63.4% for urea <or=24.2 mmol/L vs 61.4% for urea >24.2 mmol/L; odds ratio [OR], 0.92; 95% confidence interval [CI], 0.73-1.15; P = .48) or covariate-adjusted mortality (OR, 1.25; 95% CI, 0.91-1.70; P = .16). When stratified by creatinine, late RRT was associated with lower crude (53.4% for creatinine >309 micromol/L vs 71.4% for creatinine <or=309 micromol/L; OR, 0.46; 95% CI, 0.36-0.58; P < .0001) and covariate-adjusted mortality (OR, 0.51; 95% CI, 0.37-0.69; P < .001). However, for timing relative to ICU admission, late RRT was associated with greater crude (72.8% vs 62.3% vs 59%, P < .001) and covariate-adjusted mortality (OR, 1.95; 95% CI, 1.30-2.92; P = .001). Overall, late RRT was associated with a longer duration of RRT and stay in hospital and greater dialysis dependence. CONCLUSION: Timing of RRT, a potentially modifiable factor, might exert an important influence on patient survival. However, this largely depended on its definition. Late RRT (days from admission) was associated with a longer duration of RRT, longer hospital stay, and higher dialysis dependence.

Abstract: Hemorrhagic shock (HS) is an oxidative stress that causes intestinal tissue injury. Heme oxygenase 1 (HO-1) is induced by oxidative stress and is thought to play an important role in the protection of tissues from oxidative injury. We previously reported the ileum to be the most susceptible to HS-induced tissue injury site in the intestine because HO-1 induction is the lowest at this site. We also previously demonstrated that glutamine (GLN) significantly induced HO-1 in the lower intestinal tract. In the present study, we investigated whether GLN pretreatment improves HS-induced intestinal tissue injury in the ileum by HO-1 induction. Treatment of rats with GLN (0.75 g/kg, i.v.) markedly induced functional HO-1 protein in mucosal epithelial cells in the ileum. Glutamine treatment before HS (MAP of 30 mmHg for 60 min) significantly ameliorated HS-induced mucosal inflammation and apoptotic cell death in the ileum, as judged by significant decreases in gene expression of TNF-alpha, iNOS, intercellular adhesion molecule 1, and vascular cell adhesion molecule 1, myeloperoxidase activity, the number of infiltrated neutrophils, DNA fragmentation by in situ oligo ligation assay, and activated caspase-3 expression, and by increases in gene expression of IL-10 and Bcl-2. In contrast, treatment with tin mesoporphyrin, a specific inhibitor of HO activity, abolished the beneficial effect of GLN pretreatment. These findings indicate that GLN pretreatment significantly ameliorated tissue injury in the ileum after HS by inducing HO-1. Glutamine treatment may thus protect mucosal cells from HS-induced oxidative damage via the anti-inflammatory and antiapoptotic properties of HO-1.

Abstract: Hemorrhagic shock causes oxidative stress that leads to tissue injuries in various organs including the lung, liver, kidney and intestine. Excess amounts of free heme released from destabilized hemoproteins under oxidative conditions might constitute a major threat because it can catalyze the formation of reactive oxygen species. Cells counteract this by rapidly inducing the rate-limiting enzyme in heme breakdown, heme oxygenase-1 (HO-1), which is a low-molecular-weight stress protein. The enzymatic HO-1 reaction removes heme. As such, endogenous HO-1 induction by hemorrhagic shock protects tissues from further degeneration by oxidant stimuli. In addition, prior pharmacological induction of HO-1 ameliorates oxidative tissue injuries induced by hemorrhagic shock. In contrast, the deletion of HO-1 expression, or the chemical inhibition of increased HO activity ablated the beneficial effect of HO-1 induction, and exacerbates tissue damage. Thus, HO-1 constitutes an essential cytoprotective component in hemorrhagic shock-induced oxidative tissue injures. This article reviews recent advances in understanding of the essential role of HO-1 in experimental models of hemorrhagic shock-induced oxidative tissue injuries with emphasis on the role of its induction in tissue defense.

Abstract: Validation of a scoring algorithm for non-overt disseminated intravascular coagulation (DIC) proposed by the International Society on Thrombosis and Haemostasis (ISTH) is still incomplete. It was the objective of this study to assess the impact of including AT to non-overt DIC scoring on the predictability for intensive care unit (ICU) death and the later development of overt-DIC defined by the Japanese Ministry of Health and Welfare (JMHW) or the ISTH. We performed a retrospective observational study conducted in 364 patients in critical care. Coagulation parameters obtained daily for DIC screening were utilised for scoring. There were 194 and 196 patients scored as positive non-overt DIC with and without AT, respectively; diagnostic agreement between the two was 78%. As compared with patients without non-overt DIC, these non-overt DIC patients had significantly higher mortality. In 37 ICU non-survivors, positive non-overt DIC scoring with AT preceded ICU death by a median of 6.8 days, which was significantly earlier as compared with a median of 5.4 days for non-overt DIC without AT (p = 0.022). In patients who developed overt-DIC after admission, the time period from positive non-overt DIC to positive overt-DIC was significantly longer when AT was utilised (overt-DIC ISTH; 1.3 days vs. 0.1 days, p = 0.004, overt-DIC JMHW; 2.5 days vs. 2.0 days, p = 0.04, with AT vs. without AT, respectively). Non-overt DIC scoring predicted a high risk of death in critically ill patients. When information on AT levels was included, non-overt DIC scoring was found to predict development of overt-DIC significantly earlier than non-overt DIC scoring without AT.

Abstract: Impaired deformability might contribute to the accumulation of activated leukocytes within pulmonary microcapillaries, leading to acute lung injury. The purpose of our study was to investigate changes in leukocyte deformability during periods of inflammation after esophagectomy. The study group comprised 20 patients who underwent esophagectomy. Changes in leukocyte deformability were investigated by examining filtration through a silicon microchannel, which simulated human pulmonary microcapillaries. Changes in the neutrophil cytoskeleton were investigated by measuring neutrophil F-actin assembly. The severity of patient clinical outcome was evaluated by the lung injury score. Leukocyte filtration through the microchannel was significantly weaker in esophagectomy patients than in healthy subjects (p<0.01). After esophagectomy, filtration was further impaired compared with preoperative values (p<0.05). The neutrophil F-actin content was higher in patients than in controls (p<0.01), and increased after esophagectomy compared with preoperative values (p<0.01). We concluded that circulating leukocytes showed reduced deformability and appeared to be sequestered within microcapillaries after esophagectomy. Changes in neutrophil cytoskeleton were considered to be responsible for the reduced deformability. Leukocyte accumulation within pulmonary microcapillaries might be related to the pathogenesis of lung injury after esophagectomy.

Abstract: BACKGROUND: The RIFLE classification scheme for acute kidney injury (AKI) is based on relative changes in serum creatinine (SCr) and on urine output. The SCr criteria, therefore, require a pre-morbid baseline value. When unknown, current recommendations are to estimate a baseline SCr by the MDRD equation. However, the MDRD approach assumes a glomerular filtration rate of approximately 75 mL/min/1.73 m(2). This method has not been validated. METHODS: Data from the Beginning and Ending Supportive Therapy for the Kidney (BEST Kidney) study, a prospective observational study from 54 ICUs in 23 countries of critically ill patients with severe AKI, were analysed. The RIFLE class was determined by using observed (o) pre-morbid and estimated (e) baseline SCr values. Agreement was evaluated by correlation coefficients and Bland-Altman plots. Sensitivity analysis by chronic kidney disease (CKD) status was performed. RESULTS: Seventy-six percent of patients (n = 1327) had a pre-morbid baseline SCr, and 1314 had complete data for evaluation. Forty-six percent had CKD. The median (IQR) values were 97 mumol/L (79-150) for oSCr and 88 mumol/L (71-97) for eSCr. The oSCr and eSCr determined at ICU admission and at study enrolment showed only a modest correlation (r = 0.49, r = 0.39). At ICU admission and study enrolment, eSCr misclassified 18.8% and 11.7% of patients as having AKI compared with oSCr. Exclusion of CKD patients improved the correlation between oSCr and eSCr at ICU admission and study enrolment (r = 0.90, r = 0.84) resulting in 6.6% and 4.0% being misclassified, respectively. CONCLUSIONS: While limited, estimating baseline SCr by the MDRD equation when pre-morbid SCr is unavailable would appear to perform reasonably well for determining the RIFLE categories only if and when pre-morbid GFR was near normal. However, in patients with suspected CKD, the use of MDRD to estimate baseline SCr overestimates the incidence of AKI and should not likely be used. Improved methods to estimate baseline SCr are needed.

Abstract: Central pontine myelinolysis (CPM) is the most serious central nervous system complication that could be seen after liver transplantation and represents an important source of mortality early after liver transplantation. CPM following liver transplantation was reported more and more in literatures, but the true incidence of CPM after living related liver transplantation (LDLT) remains unknown. However, with the introduction of magnetic resonance imaging (MRI), early recognition has become possible. In this report, we present a case of rapid resolution of CPM followed by MRI examinations.

Abstract: Treatment of rats with monocrotaline (MCT), a pyrrolizidine alkaloid plant toxin, is known to cause pulmonary hypertension (PH), and it has been used as a useful experimental model of PH. Recent findings suggested that pulmonary inflammation may play a significant role in the pathogenesis of MCT-induced PH. We also demonstrated that, following MCT administration to rats, there was a significant and sustained increase in the pulmonary expression of heme oxygenase-1 (HO-1), which is known to be induced by various oxidative stresses, including inflammation and free heme, and is thought to be essential in the protection against oxidative tissue injuries. In this study, we administered hemin (ferriprotoporphyrin chloride, 30 micromol/kg b.w., subcutaneously), a potent inducer of HO-1, every 3 days to rats following subcutaneous administration of MCT (60 mg/kg) and examined its effect on MCT-induced PH and pulmonary inflammation. MCT administration caused pulmonary arterial wall thickening with marked elevation of right ventricular pressure, in association with prominent pulmonary inflammation as revealed by the increase in gene expression of tumor necrosis factor-alpha and the number of infiltrated neutrophils in the lung. In contrast, hemin treatment of MCT-administered animals, which led to a further increase in pulmonary HO-1 mRNA expression, significantly ameliorated MCT-induced PH as well as tissue inflammation. These findings suggest that hemin treatment ameliorates MCT-induced PH possibly mediated through induction of pulmonary HO-1 which leads to the attenuation of pulmonary inflammation.

Abstract: BACKGROUND: Severe hepatic failure (SHF) commonly leads to major changes in acidbase balance status. However, the direct effects of liver failure per se on acid base balance are poorly understood because this condition is usually associated with acute renal failure (ARF). AIM: To assess the effect of SHF on acid-base balance. DESIGN: Retrospective laboratory investigation. SUBJECTS: Thirty-seven critically ill patients with SHF complicated by ARF, and 42 patients with severe ARF without liver failure prior to renal replacement therapy. INTERVENTION: Retrieval of clinical and laboratory data from prospective unit and laboratory databases. METHODS: Quantitative acid-base assessment using Stewart-Figge methodology. Comparison of findings between the two groups. Comparison of demographic and clinical features. RESULTS: Patients with combined SHF and ARF were younger and had significantly higher mean bilirubin, ALT and INR levels (p<0.0001). Their mean lactate concentration was higher (6.4 vs. 2.1 mmol/L; p<0.0001) leading to a greater anion gap (25.8 vs. 16.1 mmol/L; p<0.0001). The ionized calcium concentration (1.00 vs. 1.15 mmol/L; p<0.0001) was lower but the strong ion difference apparent (SIDa) was greater (42.0 vs. 38.0 mEq/L; p<0.005) due to hypochloremia. The albumin concentration was low but higher than in control patients (28 vs. 24 g/L; p<0.01) and the calculated strong ion gap (SIG) was greater (12.6 vs. 9.3 mEq/L; p<0.01). The base excess was similar to controls and the pH was preserved in the near normal range by marked hypocapnea. CONCLUSIONS: Combined SHF and ARF is a syndrome with unique acid-base changes due mostly to lactic metabolic acidosis and, in smaller part, to the accumulation of unmeasured anions. This acidosis, like that of ARF, is attenuated by hypoalbuminemia, by a unique preservation of the SIDa due to hypochloremia, and by marked hypocapnea.

Abstract: Exhaled carbon monoxide concentration (ExCO-C) has been reported to increase in oxidative tissue injuries such as systemic inflammation, and is thought to reflect increased heme breakdown in the affected organ. As a transplanted liver undergoes ischemia-reperfusion, we hypothesized that ExCO-C might also increase following liver transplantation and might serve as a measure of the severity of the graft tissue injury. We prospectively studied 67 living donor liver transplantation (LDLT) patients in a consecutive fashion. During anesthesia, ExCO-C was determined at 6 time points, ranging from anesthesia induction, to admission to the intensive care unit. We also measured two markers of endothelial cellular injury, i.e., serum soluble thrombomodulin (sTM) and intercellular adhesion molecule (ICAM)-1. At 5 min after reperfusion of the grafted liver, ExCO-C markedly increased from 5.69+/-2.34 ppm at baseline, to 9.79+/-4.72 ppm (p<0.0001). There was an excellent correlation among an increase in CO concentration, arterial carboxyhemoglobin levels at the time of reperfusion (r(2)=0.19, p=0.0003), and postoperative total bilirubin levels (day 1, 2, and 3; r(2)=0.102, 0.109 and 0.100; p=0.008, 0.007 and 0.010, respectively). Serum sTM and ICAM-1 levels were also significantly increased after reperfusion (sTM: 3.3+/-0.8 to 5.1+/-1.7 FU/ml, p=0.0001; ICAM-1: 271.9+/-86.3 to 515.0+/-157.8 FU/ml, p=0.0001). ExCO-C had a positive relationship with sTM (r(2)=0.16, p=0.035) and ICAM-1 (r(2)=0.12, p=0.08). There was however, no correlation of ExCO-C with serum AST/ALT levels or clinical outcomes. This study demonstrated that ExCO-C significantly increased after reperfusion during LDLT. The increased ExCO-C may likely reflect increased heme breakdown and endothelial cell injury in the grafted liver.

Abstract: Heme oxygenase (HO) 1 is inducible by a variety of oxidative stress and is thought to play an important role in the protection of tissues from oxidative injuries. Because hemorrhagic shock (HS) is an oxidative stress that results in tissue injury, we examined in this study the role of HO-1 induction in intestinal tissue injuries in a rat model of HS. The levels of HO-1 were significantly increased after HS both at transcriptional and protein levels in mucosal epithelial cells in the duodenum, jejunum, and colon, whereas their expression in the ileum was hardly detectable and not increased at all by the treatment. In contrast, HS-induced mucosal inflammation and apoptotic cell death in the duodenum, jejunum, and colon were far less than those observed in ileum as judged by the levels of expression of TNF-alpha, iNOS, activated caspase 3, and Bcl-2. Of note, inhibition of HO activity by tin-mesoporphyrin resulted in an aggravation of HS-induced tissue inflammation and apoptotic cell death. These findings indicate that HO-1 expression in the intestine is regulated in a highly site-specific manner after HS, and that HO-1 induction plays a fundamental role in protecting mucosal cells of the intestine from oxidative damages induced by HS.

Abstract: OBJECTIVE: To study the nature of the association between glycemia and ICU mortality in pediatric cardiac surgery patients treated with peritoneal dialysis (PD). MATERIALS AND METHODS: Retrospective observational study in the ICU of a tertiary hospital involving forty pediatric cardiac surgery patients treated with PD. We selected patients requiring PD, extracted glucose measurements and nutritional intake data during ICU stay and calculated mean and maximum blood glucose values i) during ICU stay; ii) during dependence on PD; and iii) during independence from PD. We statistically assessed the relationship between glycemia-related variables and ICU mortality. MEASUREMENTS AND RESULTS: Twenty-two patients treated with PD died (mortality 55%). In the PD cohort, 9725 blood glucose measurements were performed (every 3.3 hours on average). The mean glycemia during dependence on PD was significantly higher in non-survivors than survivors (p<0.0001), but not during independence from PD (p=0.49). The area under the receiver operator characteristic curve for the mean glycemia during dependence on PD was significantly greater than that obtained during independence from PD. Even after adjustment for severity of illness using multivariate logistic analysis, the mean glycemia and calorie intake during PD were significant and independent predictors of ICU mortality. CONCLUSIONS: A higher mean blood glucose concentration during PD, but not during PD-free periods was associated with greater ICU mortality. Mean glycemia and calorie intake during PD were significant and independent predictors of ICU mortality.

Abstract:

Abstract: BACKGROUND: We tested the hypothesis that the difference between indirect and direct sodium assays would be related to the plasma albumin concentration. Further, we proposed that differences between indirect and direct chloride assays might be explained by interference from other plasma constituents, particularly bicarbonate, and possibly albumin. METHODS: We studied 300 critically ill patients at the time of admission to the intensive care unit (ICU) and compared each patient's plasma sodium and chloride measurements from a central laboratory assay (indirect electrode) and an ICU blood gas machine assay (direct electrode). RESULTS: The central laboratory sodium measurement was, on average, 2.1 mmol/L more than the ICU assay, limits of agreement 1.8-2.4 mmol/L greater, P < 0.001. The central laboratory chloride measurement was, on average, 1 mmol/L less than the ICU assay (limits of agreement 1.3-0.7 mmol/L less, P < 0.001). All correlations between the assay differences and plasma constituents were weak except for a moderately strong correlation between differences in sodium measurements and albumin. The difference in plasma sodium concentration between the assays (central laboratory - ICU) increased as the plasma concentration albumin decreased (difference = 6.2-0.16 albumin (g/L); P < 0.001, r = -0.46, r(2) = 0.22). CONCLUSIONS: The central laboratory and ICUs assays are analytically, statistically, and clinically different for both sodium and chloride. Unless taken into account, the differences could be large enough in hypoalbuminemic populations (such as critically ill patients) to affect clinical diagnosis and decision making.

Abstract: Sepsis is the most common cause of acute kidney injury (AKI) in critical illness, but there is limited information on septic AKI. A prospective, observational study of critically ill patients with septic and nonseptic AKI was performed from September 2000 to December 2001 at 54 hospitals in 23 countries. A total of 1753 patients were enrolled. Sepsis was considered the cause in 833 (47.5%); the predominant sources of sepsis were chest and abdominal (54.3%). Septic AKI was associated with greater aberrations in hemodynamics and laboratory parameters, greater severity of illness, and higher need for mechanical ventilation and vasoactive therapy. There was no difference in enrollment kidney function or in the proportion who received renal replacement therapy (RRT; 72 versus 71%; P = 0.83). Oliguria was more common in septic AKI (67 versus 57%; P < 0.001). Septic AKI had a higher in-hospital case-fatality rate compared with nonseptic AKI (70.2 versus 51.8%; P < 0.001). After adjustment for covariates, septic AKI remained associated with higher odds for death (1.48; 95% confidence interval 1.17 to 1.89; P = 0.001). Median (IQR) duration of hospital stay for survivors (37 [19 to 59] versus 21 [12 to 42] d; P < 0.0001) was longer for septic AKI. There was a trend to lower serum creatinine (106 [73 to 158] versus 121 [88 to 184] mumol/L; P = 0.01) and RRT dependence (9 versus 14%; P = 0.052) at hospital discharge for septic AKI. Patients with septic AKI were sicker and had a higher burden of illness and greater abnormalities in acute physiology. Patients with septic AKI had an increased risk for death and longer duration of hospitalization yet showed trends toward greater renal recovery and independence from RRT.

Abstract:

Abstract: BACKGROUND: Intraluminal contamination of catheter hubs has been recognized as the most frequent cause of catheter-related blood stream infections. We have investigated the efficacy of a new hub device, Planecta SC(R) (PNSC), in preventing endoluminal catheter contamination, compared to a conventional three-way stopcock. MATERIAL/METHODS: Adults patients requiring an intravascular catheter placement for at least 48 hours in intensive care units were randomly assigned to receive either the infusion device with the newly designed hub, PNSC (P group, n=89), or with a conventional three-way stopcock (C group, n=73). To evaluate intraluminal contamination, we examined the bacteria isolated in the inline bacterial filters which were attached to downstream of the injection ports. In addition to the clinical study, we conducted a bench study to investigate if use of protection caps or strict disinfection technique prevented intraluminal contamination with this new needleless connector. RESULTS: The incidence of bacterial contamination was not significantly different between the groups (P group 9/89 (10.1%) vs. C group 6/73 (8.2%), P=0.79). There was no correlation between the numbers of injections, duration of the use of the device or the microbial contamination rate. In the bench study, protection caps and disinfection technique significantly decreased microbial transfer from the hub to the fluid space. CONCLUSIONS: We concluded that the use of the new hub device did not reduce endoluminal bacterial contamination rate in comparison with that of a three way stopcock. Intraluminal bacterial contamination may be reduced by either strict disinfection technique or when a protection cap is use.

Abstract:

Abstract: Free heme contributes as a major threat to the oxidative tissue injuries because it catalyzes the formation of reactive oxygen species. When free heme concentration is increased, it results in the induction of heme oxygenase-1 (HO-1), which then breaks free heme down. As such, HO-1 plays a pivotal role in the protection of tissues from oxidative injuries.

Abstract: OBJECTIVE: Little information is available regarding current practice in continuous renal replacement therapy (CRRT) for the treatment of acute renal failure (ARF) and the possible clinical effect of practice variation. DESIGN: Prospective observational study. SETTING: A total of 54 intensive care units (ICUs) in 23 countries. PATIENTS AND PARTICIPANTS: A cohort of 1006 ICU patients treated with CRRT for ARF. INTERVENTIONS: Collection of demographic, clinical and outcome data. MEASUREMENTS AND RESULTS: All patients except one were treated with venovenous circuits, most commonly as venovenous hemofiltration (52.8%). Approximately one-third received CRRT without anticoagulation (33.1%). Among patients who received anticoagulation, unfractionated heparin (UFH) was the most common choice (42.9%), followed by sodium citrate (9.9%), nafamostat mesilate (6.1%), and low-molecular-weight heparin (LMWH; 4.4%). Hypotension related to CRRT occurred in 19% of patients and arrhythmias in 4.3%. Bleeding complications occurred in 3.3% of patients. Treatment with LMWH was associated with a higher incidence of bleeding complications (11.4%) compared to UFH (2.3%, p = 0.0083) and citrate (2.0%, p = 0.029). The median dose of CRRT was 20.4 ml/kg/h. Only 11.7% of patients received a dose of > 35 ml/kg/h. Most (85.5%) survivors recovered to dialysis independence at hospital discharge. Hospital mortality was 63.8%. Multivariable analysis showed that no CRRT-related variables (mode, filter material, drug for anticoagulation, and prescribed dose) predicted hospital mortality. CONCLUSIONS: This study supports the notion that, worldwide, CRRT practice is quite variable and not aligned with best evidence.

Abstract: BACKGROUND: During perioperative management of patients with gastrointestinal cancer complicated by diabetes mellitus, adequate alimentation is required, but we often face difficulties associated with hyperglycemia and other accompanying complications. Recently, we investigated the effects of a novel palatinose based enteral formula (MHN-01) in suppressing post-prandial hyperglycemia and improving lipid metabolism in experimental animals and perioperative management of patients with esophageal cancer complicated by diabetes mellitus. MATERIALS AND METHODS: We gave normal rats and rats with type 2 diabetes mellitus a single oral dose of fluid diet, and analyzed comparatively the time course of blood glucose level in each group until 3 h after the dose. In both the normal rat group and the type 2 diabetes group, peak blood glucose level after the MHN-01 dose was significantly lower than after a dose of ordinary fluid diet and was comparable to the peak level after a dose of a fluid diet rich in MUFA (monounsaturated fatty acid). We allowed normal mice free access to fluid diet for 43 days, and measured their body fat levels. Fat accumulation was significantly lower in mice given MHN-01 than in mice given ordinary fluid diet. We also analyzed the respiratory quotient and resting energy expenditure of normal Sprague-Dawley rats fed by MHN-01 or an ordinary fluid diet. The respiratory quotient of the MHN-01 group was significantly lower than the ordinary fluid group, although the resting energy expenditure of both groups was almost the same level. The effect of MHN-01 was estimated to be based on improvement of lipid metabolism. RESULTS: Between 2003 and 2005, among 164 patients who underwent radical thoracic esophagectomy and/or reconstruction for esophageal carcinoma at Okayama University Hospital, nine patients (5.5%) were diagnosed with diabetes mellitus in pre-operative screening and were treated with MHN-01. Clinical courses of two cases with severe status of diabetes mellitus were presented as successful case reports of MHN-01. CONCLUSION: MHN-01 was very useful in perioperative management of patients complicated by diabetes mellitus, unable to ingest food p.o. such as esophageal cancer or other diseases.

Abstract: Using a large, international cohort, we sought to determine the effect of initial technique of renal replacement therapy (RRT) on the outcome of acute renal failure (ARF) in the intensive care unit (ICU). We enrolled 1218 patients treated with continuous RRT (CRRT) or intermittent RRT (IRRT) for ARF in 54 ICUs in 23 countries. We obtained demographic, biochemical and clinical data and followed patients to either death or hospital discharge. Information was analyzed to assess the independent impact of treatment choice on survival and renal recovery. Patients treated first with CRRT (N=1006, 82.6%) required vasopressor drugs and mechanical ventilation more frequently compared to those receiving IRRT (N=212, 17.4%), (p<0.0001). Unadjusted hospital survival was lower (35.8% vs. 51.9%, p<0.0001). However, unadjusted dialysis-independence at hospital discharge was higher after CRRT (85.5% vs. 66.2%, p<0.0001). Multivariable logistic regression showed that choice of CRRT was not an independent predictor of hospital survival or dialysis-free hospital survival. However, the choice of CRRT was a predictor of dialysis independence at hospital discharge among survivors (OR: 3.333, 95% CI: 1.845 - 6.024, p<0.0001). Further adjustment using a propensity score did not significantly change these results. We conclude that worldwide, the choice of CRRT as initial therapy is not a predictor of hospital survival or dialysis-free hospital survival but is an independent predictor of renal recovery among survivors.

Abstract: Hemorrhagic shock followed by resuscitation (HSR) causes neutrophil sequestration in the lung which leads to acute lung injury (ALI). Neutrophil elastase (NE) is thought to play a pivotal role in the pathogenesis of ALI. This study investigated whether sivelestat, a specific NE inhibitor, can attenuate ALI induced by HSR in rats. Male Sprague-Dawley rats were subjected to hemorrhagic shock by withdrawing blood so as to maintain a mean arterial blood pressure of 30+/-5 mm Hg for 60 min followed by resuscitation with the shed blood. HSR-treated animals received a bolus injection of sivelestat (10 mg/kg) intravenously at the start of resuscitation followed by continuous infusion for 60 min (10 mg/kg/h) during the resuscitation phase, or the vehicle. Lung injury was assessed by pulmonary histology, lung wet-weight to dry-weight (W/D) ratio, myeloperoxidase (MPO) activity, gene expression of tumor necrosis factor (TNF)-alpha and inducible nitric oxide synthase (iNOS), DNA binding activity of nuclear factor (NF)-kappaB, and immunohistochemical analysis of intercellular adhesion molecule (ICAM)-1. HSR treatment induced lung injury, as demonstrated by pulmonary edema with infiltration of neutrophils, the increase in lung W/D ratio, MPO activity, gene expression of TNF-alpha and iNOS, and DNA-binding activity of NF-kappaB, and enhanced expression of ICAM-1. In contrast, sivelestat treatment significantly ameliorated the HSR-induced lung injury, as judged by the marked improvement in all these indices. These results indicate that sivelestat attenuated HSR-induced lung injury at least in part through an inhibition of the inflammatory signaling pathway, in addition to the direct inhibitory effect on NE.

Abstract: It has been reported that exhaled carbon monoxide (CO) concentrations and arterial carboxyhemoglobin (CO-Hb) concentration in blood may be increased in critically ill patients. However, there was no study that examined correlation among amount of CO in exhaled air, CO-Hb concentrations in erythrocytes, and bilirubin IXalpha (BR) in serum, i.e., the three major indexes of heme catabolism, within the same subject. Here, we examined CO concentrations in exhaled air, CO-Hb concentrations in arterial blood, and BR levels in serum in 29 critically ill patients. Measurements of exhaled CO, arterial CO-Hb, and serum total BR have been done in the intensive care unit. As control, exhaled CO concentration was also measured in eight healthy volunteers. A median exhaled CO concentration was significantly higher in critically ill patients compared with control. There was significant correlation between CO and CO-Hb and CO and total BR level. We also found CO concentrations correlated with indirect BR but not direct BR. Multivariate linear regression analysis for amount of exhaled CO concentrations also showed significant correlation with CO-Hb and total BR, despite the fact that respiratory variables of study subjects were markedly heterogeneous. We found no correlation among exhaled CO, patients' severity, and degree of inflammation, but we found a strong trend of a higher exhaled CO concentration in survivors than in nonsurvivors. These findings suggest there is an increased heme breakdown in critically ill patients and that exhaled CO concentration, arterial CO-Hb, and serum total BR concentrations may be useful markers in critically ill conditions.

Abstract: BACKGROUND: Continuous renal replacement therapy (CRRT) affects acid-base balance but the influence of severe hepatic failure (SHF) on this effect is unknown. AIM: To assess the effect of SHF on acid-base balance in patients receiving CVVH. DESIGN: Retrospective laboratory investigation. SUBJECTS: Forty patients with SHF and acute renal failure (ARF) treated with CVVH and 42 critically ill patients with severe ARF but no liver disease also treated with CVVH (controls). Intervention: Retrieval of clinical and laboratory data from prospective unit and laboratory databases. METHODS: Quantitative acid-base status assessment using the Stewart-Figge methodology. Comparison of findings between the two groups. RESULTS: Although CVVH had a major effect on acid base balance in both groups, patients with SHF had a higher mean lactate concentrations (4.8 vs. 3.1 mmol/L; p<0.0005), a greater base deficit compared to controls (-1 vs. 4.1 mEq/L; p<0.0001) and a lower PaCO 2 tension (36.8 vs. 42.5 mmHg; p<0.0001), despite the use of bicarbonate replacement fluid. The acidifying effect of hyperlactatemia was slightly worsened by an increased strong ion gap (9.3 vs. 4.9 mEq/L; p<0.0001). It was, however, attenuated by an increased strong ion difference apparent (SIDa) (43.6 vs. 41.9 mEq/L; p<0.05) secondary to hypochloremia (96 vs. 100 mmol/L; p<0.0001) and by hypoalbuminemia, although hypoalbuminemia in SHF patients (26 vs. 23; p<0.005) was less pronounced than in controls. CONCLUSION: The use of CVVH does not fully correct the independent acidifying effect of liver failure on acid-base status. Increased lactate and strong ion gap values maintain a persistent base deficit despite the alkalinizing effects of hypoalbuminemia and hypochloremia. The correction of acidosis in SHF patients may require more intensive CVVH.

Abstract: The effect of low-dose vasopressin (AVP) on vital regional circulations may be clinically relevant but has not been fully described. We sought to determine the effect of low-dose AVP on systemic haemodynamics, coronary, mesenteric and renal circulations in the conscious normal and septic mammal. We studied seven Merino sheep using a prospective randomized cross-over double-blind placebo-controlled animal design. We inserted flow probes around aorta, coronary, mesenteric and renal arteries and, three weeks later, we infused low-dose AVP (0.02 IU/min) or placebo in the normal and septic state induced by intravenous E. coli. In normal sheep, AVP (0.02 IU/min) induced a 17% decrease in mesenteric blood flow (393.0+/-134.9 vs 472.1+/-163.8 ml/min, P<0.05) and a 14% decrease in mesenteric conductance (P<0.05). In septic sheep, AVP decreased heart rate and cardiac output by 28% and 22%, respectively (P<0.05). It also decreased mesenteric blood flow and mesenteric conductance by 23% (flow: 468.5+/-159.7 vs 611.3+/-136.3 ml/min, P<0.05; conductance: 6.3+/-2.7 vs 8.2+/-2.7 ml/min/mmHg; P<0.05). Renal blood flow was unchanged but urine output and creatinine clearance increased (P<0.05). We conclude that low-dose AVP infusion has similar effects in the normal and septic mammalian circulation: bradycardia, decreased cardiac output, decreased mesenteric blood flow and conductance and increased urine output and creatinine clearance. This information is important to clinicians considering its administration in humans.

Abstract: Decreases in plasma bicarbonate are associated with hyperchloremic acidosis and lactic acidosis. According to the Stewart approach to acid-base physiology, the strong-ion difference regulates plasma bicarbonate, with chloride and lactate being the only strong anions routinely measured in clinical chemistry. We hypothesized that the plasma strong-ion difference, both with and without lactate, would have a stronger association with plasma bicarbonate than plasma chloride alone would have with bicarbonate. We used plasma acid-base data from 300 critically ill patients. The correlation with bicarbonate became progressively weaker (P < 0.001): all measured strong ions, r = 0.60; measured strong ions without lactate, r = 0.42; chloride alone, r = -0.27. In a subgroup of 26 patients with traditional hyperchloremic acidosis (base excess < -2 mmol/L and anion gap <17 mmol/L), the measured strong-ion difference (without lactate) had a stronger correlation (P < 0.001) with bicarbonate than chloride had: r = 0.85 versus r = -0.60. We conclude that hyperchloremic acidosis and lactic acidosis are strong-ion acidoses. Hyperchloremia should be viewed relative to the plasma strong cations. A practical conclusion is that both managing and preventing acid-base disorders with IV fluid therapy involves manipulating each of the plasma strong ions, particularly sodium and chloride.

Abstract: Hemorrhagic shock followed by resuscitation (HSR) induces oxidative stress that leads to acute lung injury. Heme oxygenase-1 (HO-1), the rate-limiting enzyme in heme catabolism, is induced by oxidative stress and is thought to play an important role in the protection from oxidative tissue injuries. We previously demonstrated that HO-1 induction by heme arginate (HA), a strong inducer of HO-1, ameliorated HSR-induced lung injury and inflammation. Cellular redox state is known to modulate the DNA biding activity of the transcription factors; nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1). In the present study, we treated rats with HA (30 mg/kg of hemin) 18 h prior to HSR and examined its effect on the DNA binding activity of NF-kappaB and AP-1 at 1.5 h after HSR. HSR significantly increased the DNA binding activity of NF-kappaB as well as AP-1, while HA pretreatment markedly attenuated the activities of these transcription factors. In contrast, administration of tin mesoporphyrin, a specific competitive inhibitor of HO activity, to HA-pretreated animals abolished the suppressive effect of HA on the activities of NF-kappaB and AP-1, and increased these activities to almost the same level as those in HSR animals. Our findings indicate that HA pretreatment can significantly suppress the increased activity of NF-kappaB and AP-1 induced by HSR by virtue of its ability to induce HO-1. Our findings also suggest that HO-1 induced by HA pretreatment ameliorates HSR-induced lung injury at least in part mediated through the suppression of the activities of these transcription factors.

Abstract: OBJECTIVE: To test whether fluid resuscitation with normal saline or 4% albumin is associated with differential changes in acid-base status and serum electrolytes. DESIGN: Nested cohort study. SETTING: Three general intensive care units. PATIENTS: Six hundred and ninety-one critically ill patients. INTERVENTIONS: Randomization of patients to receive blinded solutions of either 4% human albumin or normal saline for fluid resuscitation. MEASUREMENTS AND MAIN RESULTS: Albumin was given to 339 patients and saline to 352. At baseline, both groups had a similar serum bicarbonate, albumin, and base excess levels. After randomization, bicarbonate and base excess increased significantly and similarly over time (p < .0001). On multivariate analysis, fluid resuscitation with albumin predicted a smaller increase in pH (p = .0051), bicarbonate (p = .034), and base excess (p = .015). The amount of fluid was an independent predictor of pH (p < .0001), serum chloride (p < .0001), calcium (p = .0001), bicarbonate (p = .0002), and base excess (p < .0001) on the first day of treatment. In patients who received >3 L of fluids in the first 24 hrs, albumin administration was associated with a significantly greater increase in serum chloride (p = .0026). Acute Physiology and Chronic Health Evaluation II score and the presence of sepsis also independently predicted changes in several electrolytes and acid-base variables. CONCLUSIONS: When comparing albumin and saline, the choice and amount of resuscitation fluid are independent predictors of acid-base status and serum electrolytes. When large volumes are given, albumin administration leads to a higher chloride concentration. However, overall differences between the types of fluid are minor, whereas the volume of fluid administered is a much stronger predictor of such changes, which are also influenced by illness severity and the passage of time.

Abstract: INTRODUCTION: The choice of invasive systemic haemodynamic monitoring in critically ill patients remains controversial as no multicentre comparative clinical data exist. Accordingly, we sought to study and compare the features and outcomes of patients who receive haemodynamic monitoring with either the pulmonary artery catheter (PAC) or pulse contour cardiac output (PiCCO) technology. METHODS: We conducted a prospective multicentre, multinational epidemiological study in a cohort of 331 critically ill patients who received haemodynamic monitoring by PAC or PiCCO according to physician preference in intensive care units (ICUs) of eight hospitals in four countries. We collected data on haemodynamics, demographic features, daily fluid balance, mechanical ventilation days, ICU days, hospital days, and hospital mortality. We statistically compared the two techniques. RESULTS: Three hundred and forty-two catheters (PiCCO 192 and PAC 150) were inserted in 331 patients. On direct comparison, patients with PAC were older (68 versus 64 years of age; p = 0.0037), were given inotropic drugs more frequently (37.3% versus 13%; p < 0.0001), and had a lower cardiac index (2.6 versus 3.2 litres/minute per square meter; p < 0.0001). Mean daily fluid balance was significantly greater during PiCCO monitoring (+659 versus +350 ml/day; p = 0.017) and mechanical ventilation-free days were fewer (12 for PiCCO versus 21 for PAC; p = 0.045). However, after multiple regression analysis, we found no significant effect of monitoring technique on mean daily fluid balance, mechanical ventilation-free days, ICU-free days, or hospital mortality. A secondary multiple logistic regression analysis for hospital mortality which included mean daily fluid balance showed that positive fluid balance was a significant predictor of hospital mortality (odds ratio = 1.0002 for each ml/day; p = 0.0073). CONCLUSION: On direct comparison, the use of PiCCO was associated with a greater positive fluid balance and fewer ventilator-free days. After correction for confounding factors, the choice of monitoring did not influence major outcomes, whereas a positive fluid balance was a significant independent predictor of outcome. Future studies may best be targeted at understanding the effect of pursuing different fluid balance regimens rather than monitoring techniques per se.

Abstract: A 13-year-old boy with epidermolysis bullosa underwent a repair of pseudosyndactyly. He had a long history of bullae formation in the oral cavity and on the pharynx and body surface, and some were active at the time of surgery. We chose inhalational general anesthesia with tracheal intubation using sevoflurane and nitrous oxide. The trachea was successfully extubated after the surgery, and no major bulla formation was observed. General anesthesia with tracheal intubation may be chosen as anesthesia for patients with epidermolysis bullosa.

Abstract: We experienced the anesthetic management of a child with epidermolysis bullosa undergoing esophageal dilatation. Anesthesia was induced with oxygen/nitrous oxide mixture and sevoflurane. Oral tracheal intubation was with a lubricated laryngoscope blade using vecuronium 0.1 mg x kg(-1) and fentanyl 0.1 microg x kg(-1). To avoid friction and shearing forces on the skin, endotracheal tube was tied with a tape without adhesion and fixed around the neck. We removed adhesive parts of pulse-oximetry probe and electrocardiogram electrodes, then attached to the patient's skin covered with Vaseline. Peripheral venous access was secured in the left ankle and sutured. These methods were effective to avoid new blisters and to keep patient safe.

Abstract: INTRODUCTION: Metabolic acidosis is common in patients with cardiac arrest and is conventionally considered to be essentially due to hyperlactatemia. However, hyperlactatemia alone fails to explain the cause of metabolic acidosis. Recently, the Stewart-Figge methodology has been found to be useful in explaining and quantifying acid-base changes in various clinical situations. This novel quantitative methodology might also provide useful insight into the factors responsible for the acidosis of cardiac arrest. We proposed that hyperlactatemia is not the sole cause of cardiac arrest acidosis and that other factors participate significantly in its development. METHODS: One hundred and five patients with out-of-hospital cardiac arrest and 28 patients with minor injuries (comparison group) who were admitted to the Emergency Department of a tertiary hospital in Tokyo were prospectively included in this study. Serum sodium, potassium, ionized calcium, magnesium, chloride, lactate, albumin, phosphate and blood gases were measured as soon as feasible upon arrival to the emergency department and were later analyzed using the Stewart-Figge methodology. RESULTS: Patients with cardiac arrest had a severe metabolic acidosis (standard base excess -19.1 versus -1.5; P < 0.0001) compared with the control patients. They were also hyperkalemic, hypochloremic, hyperlactatemic and hyperphosphatemic. Anion gap and strong ion gap were also higher in cardiac arrest patients. With the comparison group as a reference, lactate was found to be the strongest determinant of acidosis (-11.8 meq/l), followed by strong ion gap (-7.3 meq/l) and phosphate (-2.9 meq/l). This metabolic acidosis was attenuated by the alkalinizing effect of hypochloremia (+4.6 meq/l), hyperkalemia (+3.6 meq/l) and hypoalbuminemia (+3.5 meq/l). CONCLUSION: The cause of metabolic acidosis in patients with out-of-hospital cardiac arrest is complex and is not due to hyperlactatemia alone. Furthermore, compensating changes occur spontaneously, attenuating its severity.

Abstract: Anesthesiologists are increasingly asked to involve in administering general anesthesia outside the operating room for such procedures as computed tomography, magnetic resonance imaging or angiography. Especially, pediatric patients require some kind of sedation or general anesthesia during these procedures. We report general anesthesia outside the operating room in patients with Pierre-Robin syndrome, who are expected to have possible difficult airway. A one-year-old girl and a 16-year-old boy were anesthetized for cardiac catheterization. General anesthesia was given at the angiography room which was located outside the operating room. Anesthesia was induced with oxygen, nitrous oxide and sevoflurane while portable storage unit for difficult airway was prepared including various types and size of laryngoscopes, laryngeal mask airway, fiberoptic intubation equipment and surgical airway access. Fortunately, tracheas were successfully intubated without using special devices, although cautious care during induction was taken. According to development of medical and surgical procedures, it is readily presumed that anesthesiologists will be more often involved in the sedation or anesthesia conducted outside the operating room in future. Anesthesiologists should always ensure enough staffing, proper monitoring and equipment when sedation or anesthesia is conducted outside the operating room, particularly if patients have anesthetic risks.

Abstract: OBJECTIVE: Several different severity scoring systems specific to acute renal failure have been proposed. However, most validation studies of these scoring systems were conducted in a single center or in a small number of centers, often the same ones used for their development. Therefore, it is not known whether such severity scoring systems may be widely applied. DESIGN: Prospective clinical investigation. SETTING: Intensive care units. PATIENTS: One thousand seven hundred and forty-two intensive care unit patients with acute renal failure who were either treated with renal replacement therapy or fulfilled predefined criteria. INTERVENTIONS: Demographic and clinical information and outcomes were measured. MEASUREMENTS AND MAIN RESULTS: Scores for four acute renal failure-specific scoring systems and two general scoring systems (Simplified Acute Physiology Score II and Sequential Organ Failure Assessment) were calculated, and their discrimination and calibration were tested with receiver operating characteristic curves and Hosmer-Lemeshow goodness-of fit-tests. For the receiver operating characteristic curves, blood lactate levels were also used as a reference. All scores had an area under the receiver operating characteristic curve <0.7 (Mehta 0.670, Liano 0.698, Chertow 0.610, Paganini 0.643, Simplified Acute Physiology Score II 0.645, Sequential Organ Failure Assessment 0.675, lactate 0.639). For scores that can calculate predicted mortality, the Hosmer-Lemeshow goodness-of-fit test showed poor calibration. CONCLUSIONS: None of the scoring systems tested had a high level of discrimination or calibration to predict mortality for patients with acute renal failure when tested in a broad cohort of patients from multiple countries. A large, multiple-center database might be needed to improve the discrimination and calibration of acute renal failure scoring system.

Abstract: We investigated whether perioperative extensive epidural block (C3-L) affects postoperative immune response in patients undergoing radical esophagectomy. Patients undergoing radical esophagectomy were randomly assigned to either general anesthesia with continuous epidural infusion via 2 epidural catheters that was continued for postoperative analgesia (group E, n = 15) or intraoperative general anesthesia and postoperative IV morphine analgesia (group G, n = 15). Plasma levels of stress hormones, cytokines, C-reactive protein (CRP), leukocyte counts, and distribution of lymphocyte subsets were assessed before and after surgery and on postoperative days (PODs) 1 and 3. In comparison with group E, significant increases in plasma epinephrine level at the end of surgery (P < 0.05) and norepinephrine level at the end of surgery (P < 0.01) and on POD1 (P < 0.01) and POD3 (P < 0.01) and significant decrease in cluster of differentiation (CD4/CD8 ratio) at the end of surgery (P < 0.05) were observed in group G. However, there were no significant differences in other variables between groups. In both groups, plasma cortisol, adrenocorticotropic hormone, interleukin (IL)-1beta, IL-6, IL-10, and CRP levels were increased after surgery (each group P < 0.01) and IL-1beta, IL-6, IL-10, and CRP were still increased on POD1 and POD3 (each change, each group P < 0.01). Leukocyte counts were increased on POD1 (each group P < 0.05) and POD3 (each group P < 0.01). The proportion of lymphocytes decreased from the end of surgery to POD3 (each group P < 0.01). The proportion of B cells was increased on POD1 (each group P < 0.01); that of natural killer cells was decreased at POD1 and POD3 (each group P < 0.01). We conclude that tissue damage and inflammation apparently overcome the effects of extensive epidural block on stress response and immune function in radical esophagectomy.

Abstract: CONTEXT: Although acute renal failure (ARF) is believed to be common in the setting of critical illness and is associated with a high risk of death, little is known about its epidemiology and outcome or how these vary in different regions of the world. OBJECTIVES: To determine the period prevalence of ARF in intensive care unit (ICU) patients in multiple countries; to characterize differences in etiology, illness severity, and clinical practice; and to determine the impact of these differences on patient outcomes. DESIGN, SETTING, AND PATIENTS: Prospective observational study of ICU patients who either were treated with renal replacement therapy (RRT) or fulfilled at least 1 of the predefined criteria for ARF from September 2000 to December 2001 at 54 hospitals in 23 countries. MAIN OUTCOME MEASURES: Occurrence of ARF, factors contributing to etiology, illness severity, treatment, need for renal support after hospital discharge, and hospital mortality. RESULTS: Of 29 269 critically ill patients admitted during the study period, 1738 (5.7%; 95% confidence interval [CI], 5.5%-6.0%) had ARF during their ICU stay, including 1260 who were treated with RRT. The most common contributing factor to ARF was septic shock (47.5%; 95% CI, 45.2%-49.5%). Approximately 30% of patients had preadmission renal dysfunction. Overall hospital mortality was 60.3% (95% CI, 58.0%-62.6%). Dialysis dependence at hospital discharge was 13.8% (95% CI, 11.2%-16.3%) for survivors. Independent risk factors for hospital mortality included use of vasopressors (odds ratio [OR], 1.95; 95% CI, 1.50-2.55; P<.001), mechanical ventilation (OR, 2.11; 95% CI, 1.58-2.82; P<.001), septic shock (OR, 1.36; 95% CI, 1.03-1.79; P = .03), cardiogenic shock (OR, 1.41; 95% CI, 1.05-1.90; P = .02), and hepatorenal syndrome (OR, 1.87; 95% CI, 1.07-3.28; P = .03). CONCLUSION: In this multinational study, the period prevalence of ARF requiring RRT in the ICU was between 5% and 6% and was associated with a high hospital mortality rate.

Abstract: OBJECTIVE: According to recent research, diuretics may increase mortality in acute renal failure patients. The administration of diuretics in such patients has been discouraged. Our objective was to determine the impact of diuretics on the mortality rate of critically ill patients with acute renal failure. DESIGN: Prospective, multiple-center, multinational epidemiologic study. SETTING: Intensive care units from 54 centers and 23 countries. PATIENTS: Patients were 1,743 consecutive patients who either were treated with renal replacement therapy or fulfilled predefined criteria for acute renal failure. INTERVENTIONS: Three distinct multivariate models were developed to assess the relationship between diuretic use and subsequent mortality: a) a propensity score adjusted multivariate model containing terms previously identified to be important predictors of outcome; b) a new propensity score adjusted multivariate model; and c) a multivariate model developed using standard methods, compensating for collinearity. MEASUREMENTS AND MAIN RESULTS: Approximately 70% of patients were treated with diuretics at study inclusion. Mean age was 68 and mean Simplified Acute Physiology Score II was 47. Severe sepsis/septic shock (43.8%), major surgery (39.1), low cardiac output (29.7), and hypovolemia (28.2%) were the most common conditions associated with the development of acute renal failure. Furosemide was the most common diuretic used (98.3%). Combination therapy was used in 98 patients only. In all three models, diuretic use was not associated with a significantly increased risk of mortality. CONCLUSIONS: Diuretics are commonly prescribed in critically ill patients with acute renal failure, and their use is not associated with higher mortality. There is full equipoise for a randomized controlled trial of diuretics in critically ill patients with renal dysfunction.

Abstract: BACKGROUND: The timing and use of norepinephrine (noradrenaline) (NE) in septic shock remain a matter of controversy. AIM: To study the outcome of septic patients treated with early and exclusive NE. SETTING: Tertiary Intensive Care Unit. PATIENTS: 142 patients with septic shock. INTERVENTION: Exclusive NE infusion within 24 hours of admission to ICU. METHODS AND MAIN RESULTS: Retrospective analysis of data from a unit database identified 142 patients. Their median admission simplified acute physiology score (SAPS II) score was 46 [38, 56] with 98 (69%) receiving mechanical ventilation. Mean arterial pressure (MAP) at the start of NE infusion was 60 [58, 68]mmHg. NE infusion was started at a median of 1.3 [0.3, 5.0]h after ICU admission. Restoration and maintenance of target MAP was achieved initially in all patients and, in 61.3%, within 30 min. The median peak dose of NE was 0.28 [0.14, 0.61]microg/(kg min) and the duration of infusion was 88 [42, 175]h. SAPS II predicted mortality was 40.8%, however, only 34.5% (P = 0.27) died. Among the most severely ill patients (SAPS II score >56) actual mortality was 50.0% versus 74.7% predicted (P = 0.07). CONCLUSIONS: Early and exclusive use of NE in hyperdynamic septic shock achieved a stable MAP >75 mmHg in all patients. Survival compared favorably with that predicted by illness severity scores.

Abstract: Heme oxygenase-1 (HO-1) is induced by oxidative stress and is thought to confer protection against oxidative tissue injuries. HO-1 catalyzes the conversion of the heme moiety of hemeproteins, such as hemoglobin, myoglobin, and cytochrome P450, to biliverdin, liberating carbon monoxide (CO) in the process. CO reacts with hemoglobin to form carboxyhemoglobin. In this study, to examine the effect of anesthesia and/or surgery on endogenous CO production, we measured the amount of exhaled CO and the arterial carboxyhemoglobin concentration of patients who underwent surgery under general or spinal anesthesia. Both CO and carboxyhemoglobin concentrations were significantly larger on the day after surgery than during the preoperative period (P < 0.05) and in the recovery room (P < 0.05), regardless of anesthesia. However, neither index differed between general and spinal anesthesia. These results suggest that oxidative stress caused by anesthesia and/or surgery may induce HO-1, which catalyzes heme to produce CO, leading to increased exhaled CO concentration.

Abstract: BACKGROUND AND OBJECTIVES: Many clinicians believe that low-dose dopamine (LDD) [2 micro g/kg/min] increases renal blood flow (RBF) and medium-dose norepinephrine (MD-NE) [0.4 micro g/kg/min] decreases RBF. They also believe that MD-NE might induce mesenteric and/or coronary ischemia. In fact, the effects of these drugs on renal and vital organ blood flow are poorly understood. The aim of this study was to compare the effects of 6 h of IV LDD and MD-NE infusion on mammalian renal, coronary, mesenteric, and sagittal blood flow. DESIGN: Randomized, controlled, experimental animal study. SETTING: Animal laboratory of tertiary physiology institute. SUBJECTS: Seven Merino cross sheep were studied. MEASUREMENTS AND RESULTS: We performed a staged insertion of transit-time flow probes around ascending aorta, sagittal sinus and circumflex coronary, superior mesenteric, and left renal arteries. We then randomized these animal with long-term embedded flow probes to either 6 h of placebo (saline solution) or drugs (MD-NE at 0.4 micro g/kg/min or LDD at 2 micro g/kg/min), and performed continuous measurement of systemic pressures, cardiac output (CO), and flow to vital organs. We also sampled blood and urine for the measurement of lactate, creatinine, and creatinine clearances at preset intervals. RESULTS: Compared to placebo, LDD did not affect systemic hemodynamics. However, it increased mean RBF by 20% (267.3 +/- 87.6 mL/min vs 222.0 +/- 74.4 mL/min, p = 0.028) without a detectable effect on other vital regional circulations. MD-NE, however, increased mean arterial pressure (101.0 +/- 8.3 mL/min vs 84.2 +/- 5.2 mL/min, p = 0.018) [mean +/- SD] and CO (4.93 +/- 1.45 L/min vs 3.81 +/- 0.57 L/min, p = 0.028). It also increased coronary blood flow (36.0 +/- 15.7 mL/min vs 23.0 +/- 10.7 mL/min, p = 0.018) and RBF (286.5 +/- 79.0 mL/min vs 222.0 +/- 74.4 mL/min, p = 0.018). MD-NE had no detectable effect on mesenteric or sagittal sinus flow. LDD infusion increased urine output, but did not change creatinine clearance. MD-NE infusion increased urine output significantly more than LDD but not creatinine clearance. CONCLUSIONS: Both LDD (2 micro g/kg/min) and MD-NE (0.4 micro g/kg/min) increased RBF and urine output. However, the effect of MD-NE was more pronounced. LDD did not affect other vital organ flows, but MD-NE increased coronary blood flow without any changes in mesenteric and sagittal sinus blood flow.

Abstract: We conducted a prospective observational study to assess the efficacy of continuous venovenous hemofiltration (CVVH) with no anticoagulation. A standard anticoagulation protocol for CVVH, which prescribed no anticoagulation for patients at risk of bleeding, was applied to 48 critically ill patients treated with CVVH. Circuit life was prospectively observed, and the following data were obtained for each circuit: heparin use and dose, protamine use, daily prothrombin time-international normalized ratio, activated partial thromboplastin time, and platelet count. Out of 300 consecutive circuits, 143 (47.6%) received no anticoagulation, 31 (10.3%) received regional anticoagulation, and 126 received low dose heparin. No patients experienced bleeding complications secondary to CVVH. Platelet count was significantly lower in the no anticoagulation group (73 x 10(3)/microl) compared with the low dose heparin group (119 x 10(3)/microl) and the protamine group (104 x 10(3)/microl) (p < 0.01 for both comparisons). There was no significant difference in mean circuit life among the three groups (heparin, 20.9 hours; no anticoagulation, 19.3 hours; protamine, 21.2 hours; not significant). In conclusion, for a group of patients deemed to be at risk of bleeding, CVVH without anticoagulation achieved an acceptable circuit life, which was similar to that obtained in other patients with low dose heparin anticoagulation or regional anticoagulation with heparin/protamine.

Abstract: BACKGROUND: The Fencl-Stewart approach to acid-base disorders uses five equations of varying complexity to estimate the base excess effects of the important components: the strong ion difference (sodium and chloride), the total weak acid concentration (albumin) and unmeasured ions. Although this approach is straightforward, most people would need a calculator to use the equations. We proposed four simpler equations that require only mental arithmetic and tested the hypothesis that these simpler equations would have good agreement with more complex Fencl-Stewart equations. METHODS: We reduced two complex equations for the sodium-chloride effect on base excess to one simple equation: sodium-chloride effect (meq litre(-1))=[Na(+)]-[Cl(-)]-38. We simplified the equation of the albumin effect on base excess to an equation with two constants: albumin effect (meq litre(-1))=0.25x(42-[albumin]g litre(-1)). Using 300 blood samples from critically ill patients, we examined the agreement between the more complex Fencl-Stewart equations and our simplified versions with Bland-Altman analyses. RESULTS: The estimates of the sodium-chloride effect on base excess agreed well, with no bias and limits of agreement of -0.5 to 0.5 meq litre(-1). The albumin effect estimates required log transformation. The simplified estimate was, on average, 90% of the Fencl-Stewart estimate. The limits of agreement for this percentage were 82-98%. CONCLUSIONS: The simplified equations agree well with the previous, more complex equations. Our findings suggest a useful, simple way to use the Fencl-Stewart approach to analyse acid-base disorders in clinical practice.

Abstract: A young woman with primary pulmonary hypertension developed severe interstitial pneumonia (IP) 5 days after induction of epoprostenol infusion. Although the pathogen involved was not identified, her IP was initially responsive to steroids, and discontinuation of steroid therapy caused the redevelopment of IP. After intensive treatment, including steroid therapy and inhaled nitric oxide, epoprostenol was successfully switched to prostaglandin E(1) infusion and she recovered. Epoprostenol infusion can cause a rapid severe IP, even soon after the induction of therapy. Clinicians should keep this syndrome in mind, especially when treating a severe case of IP.

Abstract: OBJECTIVE: To evaluate the effect of changing the amount of pre-dilution replacement fluid on the sieving coefficient (SC) and mass transfer of small solutes during isovolaemic high-volume haemofiltration (HVHF). DESIGN AND SETTING: Prospective interventional study in the intensive care unit of a tertiary university hospital. PATIENTS: Eight patients with septic shock. INTERVENTIONS: Isovolaemic HVHF (6 l/h of replacement fluid) was performed. The proportion of replacement fluid delivered in pre-filter was altered to progressively decrease it from 6 to 0 l/h. Samples were simultaneously taken from the "pre-filter", "post-filter" and ultrafiltrate (UF) sampling ports. MEASUREMENTS AND RESULTS: Sodium, potassium, chloride, total calcium, total magnesium, phosphate, total CO(2), urea, creatinine and glucose concentrations were measured in each sample. The sieving coefficients of chloride, total CO(2), phosphate, urea and glucose were higher than 1 in most pre-dilution states. The sieving coefficients of sodium, potassium, calcium, magnesium, total CO(2) and urea decreased significantly with decreasing pre-dilution fluid rate. The sieving coefficients of chloride and glucose increased with decreasing pre-dilution fluid rate. There was a significant mass gain of sodium and glucose under all pre-dilution conditions. Mass chloride gains decreased with decreasing pre-dilution rates and changed into chloride loss during 6 l/h of post-dilution. Decreasing pre-dilution improved urea and creatinine mass removal. CONCLUSIONS: Small solute SC and mass transfer during isovolaemic HVHF are significantly affected by the proportion of replacement fluid administered pre-filter. Isovolaemic HVHF is neither isonatraemic nor isochloraemic.

Abstract: OBJECTIVE: To determine whether base excess, base excess caused by unmeasured anions, and anion gap can predict lactate in adult critically ill patients, and also to determine whether acid-base variables can predict mortality in these patients. DESIGN: Retrospective study. SETTING: Adult intensive care unit of tertiary hospital. PATIENTS: Three hundred adult critically ill patients admitted to the intensive care unit. INTERVENTIONS: Retrieval of admission biochemical data from computerized records, quantitative biophysical analysis of data with the Stewart-Figge methodology, and statistical analysis. MEASUREMENTS AND MAIN RESULTS: We measured plasma Na+, K+, Mg2+, Cl-, HCO3-, phosphate, ionized Ca2+, albumin, lactate, and arterial pH and Paco2. All three variables (base excess, base excess caused by unmeasured anions, anion gap) were significantly correlated with lactate (r2 =.21, p <.0001; r2 =.30, p <.0001; and r2 =.31. p <.0001, respectively). Logistic regression analysis showed that the area under the receiver operating characteristic (AUROC) curves had moderate to high accuracy for the prediction of a lactate concentration >5 mmol/L: AUROC curves, 0.86 (95% confidence interval [CI], 0.78-0.94), 0.86 (95% CI, 0.78-0.93), and 0.85 (95% CI, 0.77-0.92), respectively.Logistic regression analysis showed that hospital mortality rate correlated significantly with Acute Physiology and Chronic Health Evaluation (APACHE) II score, anion gap corrected (anion gap corrected by albumin), age, lactate, anion gap, chloride, base excess caused by unmeasured anions, strong ion gap, sodium, bicarbonate, strong ion difference effective, and base excess. However, except for APACHE II score, AUROC curves for mortality prediction were relatively small: 0.78 (95% CI, 0.72-0.84) for APACHE II, 0.66 (95% CI, 0.59-0.73) for lactate, 0.64 (95% CI, 0.57-0.71) for base excess caused by unmeasured anions, and 0.63 (95% CI, 0.56-0.70) for strong ion gap. CONCLUSIONS: Base excess, base excess caused by unmeasured anions, and anion gap are good predictors of hyperlactatemia (>5 mmol/L). Acid-base variables and, specifically, "unmeasured anions" (anion gap, anion gap corrected, base excess caused by unmeasured anions, strong ion gap), irrespective of the methods used to calculate them, are not accurate predictors of hospital mortality rate in critically ill patients.

Abstract: OBJECTIVES: To measure changes in medullary and cortical renal blood flow during experimental hyperdynamic sepsis and the effect of subsequent norepinephrine infusion on such flows.DESIGN Experimental animal study. SETTING: Animal laboratory of university-affiliated physiology institute.SUBJECTS Eighteen anesthetized merino sheep. INTERVENTIONS: A transit-time flow probe was placed around the left renal artery. Laser Doppler flow probes were inserted in the left renal medulla and cortex by micromanipulation to measure changes in regional intrarenal blood flow. MEASUREMENTS AND MAIN RESULTS: Systemic pressures, cardiac output, renal, and intrarenal blood flows were measured continuously. A bolus of Escherichia coli (7.5 x 10(9) colony forming units) was given intravenously to induce hyperdynamic sepsis. After the onset of hyperdynamic sepsis, all animals were randomly allocated to either norepinephrine (0.4 microg.kg-1.min-1 for 30 mins) or observation for 30 mins in random order. E. coli injection induced a significant decrease in mean arterial pressure (102.2 +/- 15.2 mm Hg to 74.3 +/- 16.1 mm Hg, p <.05) and an increase in mean cardiac output (4.60 +/- 1.62 L/min to 5.93 +/- 1.18 L/min, p <.05). However, renal blood flow did not change significantly (326.4 +/- 139.4 mL/min to 293.1 +/- 117.5 mL/min, not significant) despite a 30% increase in renal conductance (3.27 +/- 1.52 to 4.13 +/- 2.01 mL.min-1.mm Hg-1, p <.05). Cortical blood flow decreased by 15% (not significant) and medullary flow by 5% (not significant) during sepsis, but individual changes were unpredictable. On the other hand, norepinephrine infusion caused a significant improvement in mean arterial pressure (74.3 +/- 16.1 to 105.7 +/- 17.7 mm Hg, p <.05) and a further increase in cardiac output (5.93 +/- 1.18 to 7.13 +/- 1.52 L/min, p <.05). Mean renal blood flow also increased (293.1 +/- 117.5 to 384.5 +/- 168.1 mL/min, p <.05) despite decreased renal conductance (4.13 +/- 2.01 to 3.73 +/- 1.91 mL.min-1.mm Hg-1, p <.05). Infusion of norepinephrine significantly increased medullary blood flow by 35% compared with baseline (p <.05) and by 54% compared with untreated sepsis (p <.05), whereas the increases in cortical blood flow (16 and 53%, respectively) were not significant. CONCLUSIONS: Hyperdynamic sepsis caused renal vasodilation but had limited effects on regional intrarenal blood flow. Norepinephrine infusion (0.4 microg.kg-1.min-1) during sepsis significantly increased global and medullary renal blood flow and restored renal vascular tone toward but not above normal.

Abstract: INTRODUCTION: The aim of the present study is to understand the nature of acid-base disorders in critically ill patients with acute renal failure (ARF) using the biophysical principles described by Stewart and Figge. A retrospective controlled study was carried out in the intensive care unit of a tertiary hospital. MATERIALS AND METHODS: Forty patients with ARF, 40 patients matched for Acute Physiology and Chronic Health Evaluation II score (matched control group), and 60 consecutive critically ill patients without ARF (intensive care unit control group) participated. The study involved the retrieval of biochemical data from computerized records, quantitative biophysical analysis using the Stewart-Figge methodology, and statistical comparison between the three groups. We measured serum sodium, potassium, magnesium, chloride, bicarbonate, phosphate, ionized calcium, albumin, lactate and arterial blood gases. RESULTS: Intensive care unit patients with ARF had a mild acidemia (mean pH 7.30 +/- 0.13) secondary to metabolic acidosis with a mean base excess of -7.5 +/- 7.2 mEq/l. However, one-half of these patients had a normal anion gap. Quantitative acid-base assessment (Stewart-Figge methodology) revealed unique multiple metabolic acid-base processes compared with controls, which contributed to the overall acidosis. The processes included the acidifying effect of high levels of unmeasured anions (13.4 +/- 5.5 mEq/l) and hyperphosphatemia (2.08 +/- 0.92 mEq/l), and the alkalinizing effect of hypoalbuminemia (22.6 +/- 6.3 g/l). CONCLUSIONS: The typical acid-base picture of ARF of critical illness is metabolic acidosis. This acidosis is the result of the balance between the acidifying effect of increased unmeasured anions and hyperphosphatemia and the lesser alkalinizing effect of hypoalbuminemia.

Abstract: OBJECTIVES: Norepinephrine use in patients after cardiac surgery is controversial because of the fear that norepinephrine might decrease kidney function through regional vasoconstriction. Accordingly, we studied the renal effects of norepinephrine use for hypotensive vasodilatation after cardiac surgery. DESIGN AND SETTING: Retrospective controlled study in the cardiothoracic ICU of tertiary hospital. PATIENTS. 100 cardiac surgery patients with post-operative hypotensive vasodilatation and 100 control cardiac surgery patients. INTERVENTION: Treatment of hypotension (MAP<70 mmHg) with continuous norepinephrine infusion. MEASUREMENTS AND RESULTS: We collected data on demographic and surgical characteristics, haemodynamics, serum creatinine and mortality. Just after surgery the norepinephrine group had a significantly higher mean central venous pressure, lower mean arterial pressure, and lower systemic vascular resistance index with a similarly elevated mean cardiac index. Despite norepinephrine administration at a mean peak dose of 7.3+/-6.4 micro g/min the mean post-operative change in creatinine was not different between two groups on days 0, 2 or 4 after surgery. CONCLUSIONS: Norepinephrine does not increase post-operative serum creatinine concentrations in patients with hypotensive vasodilatation after cardiac surgery. Concerns related to its potential adverse effects on the kidney function in this setting appear unjustified.

Abstract: BACKGROUND/AIMS: To determine the impact of replacement fluid infusion site on filter life and azotemic control during continuous veno-venous hemofiltration (CVVH). METHODS: Pre-dilution CVVH was conducted from February 2001 to December 2001 and then practice was changed to post-dilution (from January 2002 to July 2002). Filter life was prospectively observed and the following data obtained for each filter: starting date and time, ending date and time, heparin use, heparin dose and protamine use. Daily creatinine, urea, INR, APTT and platelet count were also collected. RESULTS: Forty-eight patients were studied (33 in pre-dilution and 15 in post-dilution) for a total of 309 filters (202 in pre-dilution and 107 in post-dilution). The median filter life was significantly shorter in the post-dilution period (18.0 vs. 13.0 h, p = 0.021). Multivariate linear regression analysis showed that pre-dilution was a significant independent predictor of increased filter life (p = 0.029), together with platelet count (p = 0.0035) and heparin dose (p = 0.046). There was no significant improvement in daily creatinine and/or urea reduction in the post-dilution period (% Delta creatinine: 7.9 vs. 10.2%/day, p = 0.99, urea: 5.4 vs. 9.7%/ day, p = 0.78). CONCLUSIONS: Post-dilution was associated with reduced filter life without any beneficial effect on daily changes in urea and creatinine levels. Pre-dilution appears a preferable technical approach to CVVH.

Abstract: AIMS: To study incidence, clinical features, and outcome of critically ill patients with end-stage renal failure (ESRF) requiring renal replacement therapy (RRT) in the intensive care unit (ICU) and to test the validity of severity scoring systems for these patients. METHODS: Data for ESRF patients treated with RRT were collected from 81 Australian adult ICUs providing RRT. They were compared with matched controls with acute renal failure. RESULTS: Thirty-eight ESRF patients received RRT in the ICU over 3 months. The mean APACHE II score was 21.8 (predicted mortality: 37%) and the SAPS II score 44.7 (predicted mortality: 37%). The hospital mortality was 34%. Receiver operating characteristic curves showed good discrimination ability for hospital mortality for these two scores (AUC: 0.81 for APACHE II and 0.84 for SAPS II). Using admission diagnosis and SAPS II scores, 32 ESRF patients treated with continuous RRT (CRRT) were matched to 32 acute renal failure patients also treated with CRRT. ICU mortality (22 vs. 38%) and hospital mortality (38 vs. 38%) were comparable between the two groups. CONCLUSIONS: ESRF patients requiring RRT in the ICU were relatively frequent. Severity scores could be used to predict the hospital outcome for these patients. Their mortality, when treated with CRRT, was similar to that of diagnosis- and severity-score-matched patients with acute renal failure.

Abstract: BACKGROUND: Clinicians calculate the anion gap (AG) and the strong ion difference (SID) to make acid-base diagnoses. The technology used is assumed to have limited impact. The authors hypothesized that different measurement technologies markedly affect AG and SID values. METHODS: SID and AG were calculated using values from the point-of-care blood gas and electrolyte analyzer and the central hospital laboratory automated blood biochemistry analyzer. Simultaneously measured plasma sodium, potassium, and chloride concentrations were also compared. RESULTS: Mean values for central laboratory and point-of-care plasma sodium concentration were significantly different (140.4 +/- 5.6 vs. 138.3 +/- 5.9 mm; P < 0.0001), as were those for plasma chloride concentration (102.4 +/- 6.5 vs. 103.4 +/- 6.0 mm; P < 0.0001) but not potassium. Mean AG values calculated with the two different measurement techniques differed significantly (17.6 +/- 6.2 mEq/l for central laboratory vs. 14.5 +/- 6.0 mEq/l for point-of-care blood gas analyzer; P < 0.0001). Using the Stewart-Figge methodology, SID values also differed significantly (43.7 +/- 4.8 vs. 40.7 +/- 5.6 mEq/l; P < 0.0001), with mean difference of 3.1 mEq/l (95% limits of agreement, -3.4, 9.5 mEq/l). For 83 patients (27.6%), differences in AG values were as high as 5 mEq/l or more, and for 46% of patients whose AG value was outside the reference range with one technology, a value within normal limits was recorded with the other. CONCLUSIONS: Results with two different measurement technologies differed significantly for plasma sodium and chloride concentrations. These differences significantly affected the calculated AG and SID values and might lead clinicians to different assessments of acid-base and electrolyte status.

Abstract: OBJECTIVE: There is little information on the duration of time that patients spend off therapy (down-time) during continuous veno-venous haemofiltration (CVVH) and the effect of this treatment free time on azotaemic control. DESIGN AND SETTING: Prospective observational study in the ICU of tertiary hospital. PATIENTS AND PARTICIPANTS: 48 critically ill patients treated with CVVH at 2 l/h of ultrafiltration. INTERVENTIONS: Prospective collection of demographic and biochemical data. MEASUREMENTS AND RESULTS: Two hundred and sixty-six filters were observed. Start and end times were collected for each filter. Creatinine and urea were measured daily and percentage of reduction of these two solutes was calculated (%Delta creatinine and urea). The median period when CVVH was not applied to a patient (down-time) was 3 h per day. There was a significant inverse correlation between down-time and %Delta creatinine and urea over each 24-h time cycle. On average at least 16 h per day of CVVH was required to maintain creatinine and urea concentration for each 24-h cycle. CONCLUSIONS: "Continuous" therapy is not truly continuous. Down-time adversely affects azotaemic control. Physicians prescribing CRRT should be aware of the consequences of such down-time on the quality and quantity of renal replacement therapy delivered.

Abstract: BACKGROUND AND OBJECTIVES: Different techniques of continuous renal replacement therapy (CRRT) might have different effects on electrolyte and acid-base control. The aim of this study was to determine whether continuous veno-venous hemodiafiltration (CVVHDF) or continuous veno-venous hemofiltration (CVVH) achieve better control of serum sodium, potassium and bicarbonate concentrations. DESIGN: Retrospective controlled study. SETTING: Two tertiary intensive care units. PATIENTS: Critically ill patients with acute renal failure (ARF) treated with CVVHDF (n=49) or CVVH (n=50). INTERVENTIONS: Retrieval of daily morning sodium and potassium values and arterial bicarbonate levels from computerized biochemical records before and after the initiation of CRRT for up to 2 weeks of treatment. Statistical comparison of findings. MEASUREMENTS AND RESULTS: Before treatment, abnormal (high or low) values were frequently observed for sodium (65.1% for CVVHDF vs. 80.0% for CVVH; NS), potassium (45.9% vs. 34.0%; NS), and bicarbonate (73.3% vs. 68.0%; NS). After treatment, however, CVVHDF was more likely to achieve serum sodium concentrations within the normal range (74.1% vs. 62.9%; p=0.0026). Both treatments decreased the mean serum potassium concentration over the first 48 h (p=0.0059 and p<0.0001, respectively), but there was no difference in terms of the normalization of serum potassium concentration during the entire treatment period (88.3% vs. 90.5%; NS). Both treatments increased the mean arterial bicarbonate concentration over the first 48 hours (p=0.011 and p<0.0001, respectively). However, CVVH was associated with a lower incidence of metabolic acidosis (13.8% for CVVH vs. 34.5% for CVVHDF; p<0.0001) and a higher incidence of metabolic alkalosis (38.9% vs. 1.1%; p<0.0001) during the entire treatment period. CONCLUSIONS: CRRT strategies based on different techniques have a significantly different impact on sodium and bicarbonate control.

Abstract: BACKGROUND: Continuous veno-venous hemofiltration (CVVH) appears to have a significant and variable impact on acid-base balance. However, the pathogenesis of these acid-base effects remains poorly understood. The aim of this study was to understand the nature of acid-base changes in critically ill patients with acute renal failure during continuous veno-venous hemofiltration by applying quantitative methods of biophysical analysis (Stewart-Figge methodology). METHODS: We studied forty patients with ARF receiving CVVH in the intensive care unit. We retrieved the biochemical data from computerized records and conducted quantitative biophysical analysis. We measured serum Na+, K+, Mg2+, Cl-, HCO3-, phosphate, ionized Ca2+, albumin, lactate and arterial blood gases and calculated the following Stewart-Figge variables: Strong Ion Difference apparent (SIDa), Strong Ion Difference Effective (SIDe) and Strong Ion Gap (SIG). RESULTS: Before treatment, patients had mild acidemia (pH: 7.31) secondary to metabolic acidosis (bicarbonate: 19.8 mmol/L and base excess: -5.9 mEq/L). This acidosis was due to increased unmeasured anions (SIG: 12.3 mEq/L), hyperphosphatemia (1.86 mmol/L) and hyperlactatemia (2.08 mmol/L). It was attenuated by the alkalinizing effect of hypoalbuminemia (22.5 g/L). After commencing CVVH, the acidemia was corrected within 24 hours (pH 7.31 vs 7.41, p<0.0001). This correction was associated with a decreased strong ion gap (SIG) (12.3 vs. 8.8 mEq/L, p<0.0001), phosphate concentration (1.86 vs. 1.49 mmol/L, p<0.0001) and serum chloride concentration (102 vs. 98.5 mmol/L, p<0.0001). After 3 days of CVVH, however, patients developed alkalemia (pH: 7.46) secondary to metabolic alkalosis (bicarbonate: 29.8 mmol/L, base excess: 6.7 mEq/L). This alkalemia appeared secondary to a further decrease in SIG to 6.7 mEq/L (p<0.0001) and a further decrease in serum phosphate to 0.77 mmol/L (p<0.0001) in the setting of persistent hypoalbuminemia (21.0 g/L; p=0.56). CONCLUSIONS: CVVH corrects metabolic acidosis in acute renal failure patients through its effect on unmeasured anions, phosphate and chloride. Such correction coupled with the effect of hypoalbuminemia, results in the development of a metabolic alkalosis after 72 hours of treatment.

Abstract: BACKGROUND: The epidemiology, pathogenesis and prognosis of severe ischemic early liver injury (SIELI) after cardiac surgery are poorly understood. Accordingly, we studied patients whose alanine transaminase (ALT) concentration acutely increased above 500 IU/l in the immediate postoperative period and compared these patients to two control groups matched for preoperative and immediate postoperative characteristics. METHODS: We used a prospective database of 1,800 consecutive cardiac surgical cases to identify the study groups. Group I was made up of 20 patients with ALT levels above 500 IU/L in the acute postoperative stage (SIELI). Preoperative liver tests were normal in all these patients. Group II was obtained by identifying 20 control cases whose age, type of surgery, NYHA classification, and Parsonnet score matched Group I (preoperative controls). Group III was obtained by identifying 20 patients who developed postoperative acute renal failure and shock (ARF/shock; postoperative controls) but no enzyme evidence of hepatic injury. RESULTS: Acute renal failure, a low cardiac index (CI) state, and mortality were more common in SIELI and ARF/Shock patients compared with preoperative controls (all p values less than 0.01). Peak postoperative pulmonary artery occlusion (PAOP) and central venous (CVP) pressures were also higher in SIELI and ARF/Shock patients than controls (all p values less than 0.02). A higher dose of norepinephrine and milrinone were required to maintain blood pressure and cardiac output in SIELI and ARF/shock patients than preoperative controls (all p values less than 0.005). SIELI patients, however, differed from ARF/Shock patients in that they had a higher preoperative NYHA class and a greater incidence of hypertension and diabetes. Stepwise linear regression analysis identified a postoperative low CI and the presence of diabetes as the only predictors of peak ALT value (p less than 0.05). Multivariate logistic regression analysis identified female gender as being associated with a higher likelihood of SIELI (odds ratio: 6.13; 95% CI 1.08 to 34.82) CONCLUSIONS: SIELI after cardiac surgery carries a high mortality and is strongly associated with a low cardiac output and increased filling pressures, suggesting that liver ischemia induced by a combination of decreased perfusion and congestion is fundamental to its pathogenesis. A history of cardiac failure, diabetes, hypertension, and female gender may represent risk factors for its development and severity in the setting of a postoperative low cardiac output state.

Abstract: OBJECTIVE: To measure the sieving coefficient (SC) and clearance of vancomycin during high-volume haemofiltration (HVHF) and to evaluate the impact of different pre-dilution regimens on these variables. DESIGN AND SETTING: Prospective interventional study in the intensive care unit in a tertiary university hospital. PATIENTS: Seven patients with septic shock and multi-organ dysfunction. INTERVENTIONS: HVHF (6 l/h fluid exchange) was performed in septic shock patients using variable proportions of their replacement fluid in pre- and post-dilution mode. MEASUREMENTS AND RESULTS: Pre-filter, post-filter and ultrafiltrate vancomycin concentrations were measured simultaneously, and SC and clearance calculated. The measurements were repeated following each change in the proportion of pre-dilution fluid. SC steadily decreased as the proportion of pre-dilution decreased, changing from 0.76 in pure pre-dilution to 0.57 in pure post-dilution (p=0.0004). Clearance, however, increased with decreasing pre-dilution fluid rate, from 53.9 ml/min at pure pre-dilution to 67.2 ml/min at 2 l/h pre-dilution with 4 l/h post-dilution. CONCLUSIONS: HVHF achieves high vancomycin clearances, which despite some deterioration in SC increase with the proportion of replacement fluid given post-filter. Clinicians applying HVHF need to be aware of such clearances to avoid inadequate vancomycin dosing and to adjust therapy according to variations in HVHF technique.

Abstract: To test the hypothesis that dialysis using a new large pore membrane would achieve effective cytokine removal, blood from six volunteers was incubated with endotoxin (1 mg) and then circulated through a closed circuit with a polyamide membrane (nominal cut-off: 100 kDa). Hemodialysis was conducted at 1 or 9 L/hr of dialysate flow at the start of circulation and after 2 and 4 hours. The peak dialysate/plasma concentration ratios were 0.92 for interleukin (IL)-1beta, 0.67 for IL-6, 0.94 for IL-8, 0.33 for tumor necrosis factor (TNF)-a, and 0.11 for albumin. The dialysate/plasma ratios for all cytokines and albumin were decreased with increased dialysate flow from 1 to 9 L/hr (p < 0.05). Clearances for IL-1beta, IL-6, and IL-8, however, were significantly improved with increased dialysate flow (p < 0.01). There was no increase in TNF-a clearance (not significant) and a decrease in albumin clearance (p < 0.01). The peak clearance at 9 L/hr was 33 ml/min for IL-1beta, 19 for IL-6, 51 for IL-8, 11 for TNF-alpha, and 1.2 for albumin. No adsorption of cytokines was observed. We conclude that cytokine dialysis is achievable through a membrane with a high cut-off point with negligible albumin loss. These findings support the technical feasibility of this new approach to blood purification in sepsis.

Abstract: BACKGROUND AND OBJECTIVES: Different techniques of continuous renal replacement therapy (CRRT) might have different effects on azotemic control. Accordingly, we tested whether continuous veno-venous hemodiafiltration (CVVHDF) or continuous veno-venous hemofiltration (CVVH) would achieve better control of serum creatinine and plasma urea levels. DESIGN: Retrospective controlled study. SETTING: Two tertiary Intensive Care Units. PATIENTS: Critically ill patients with acute renal failure (ARF) treated with CVVHDF (n = 49) or CVVH (n = 50). Interventions: Retrieval of daily morning urea and creatinine values before and after the initiation of CRRT for up to 2 weeks of treatment. MEASUREMENTS AND RESULTS: Before treatment, serum urea and creatinine concentrations were significantly lower in the CVVH group than in CVVHDF group (urea: 31.0 +/- 15.0 mmol/L for CVVHDF and 24.7 +/- 16.1 mmol/L for CVVH, p = 0.01, creatinine: 547 +/- 308 micromol/L vs. 326 +/- 250 micromol/L, p < 0.0001). These differences were still significant after 48 h of treatment (urea: 20.1 +/- 8.3 mmol/L vs. 14.1 +/- 6.1 mmol/L; p = 0.0003, creatinine: 360 +/- 189pmol/L vs. 215 +/- 118 micromol/L; p < 0.0001). Throughout the duration of therapy, mean urea levels (22.3 +/- 9.0 mmol/L for CVVHDF vs. 16.7 +/- 7.8 mmol/L for CVVH, p < 0.0001) and mean creatinine levels (302 +/- 167 vs. 211 +/- 103 micromol/L, p < 0.0001) were better controlled in the CVVH group. CONCLUSIONS: CRRT strategies based on different techniques might have a significantly different impact on azotemic control.

Abstract: BACKGROUND AND OBJECTIVES: Different techniques of continuous renal replacement therapy (CRRT) might have different effects on calcium, phosphate and magnesium concentrations. Accordingly, we tested whether continuous veno-venous hemodia filtration (CVVHDF) or continuous venovenous hemofiltration (CVVH) would achieve better control of these electrolytes. DESIGN: Retrospective controlled study SETTING: Two tertiary Intensive Care Units PATIENTS: Critically ill patients with acute renal failure (ARF) treated with CVVHDF (n=49) or CVVH (n=50) INTERVENTIONS: Retrieval of daily morning ionized calcium, phosphate and magnesium before and after the initiation of CRRT for up to 2 weeks of treatment. MEASUREMENTS AND RESULTS: Before treatment, both groups had a high incidence of abnormal ionized calcium concentrations (57.2% for CVVHDF vs 46.0% for CVVH; NS). After treatment, both groups showed a significant increase in serum calcium concentration over the first 48 h (p=0.041 vs p=0.0048) but hypercalcemia was more common during CVVHDF (15.3% vs 0.4%; p<0.0001). However, in both groups, hypocalcemia remained common (30.9% vs 36.7%; NS). Before treatment, abnormal serum phosphate concentrations were also common (65.1% for CVVHDF vs 78.1% for CVVH; NS). After treatment, both groups achieved a significant reduction of serum phosphate within 48 hours (p<0.0001 in both groups). There was no difference in the prevalence of abnormal phosphate levels during treatment (45.5% vs 42.4%; NS). Before treatment, both groups had a high incidence of abnormal magnesium concentrations (50.0% for CVVHDF vs 51.2% for CVVH; NS). During treatment, there was no significant change in serum magnesium concentrations during the first 48 hours or in the prevalence of abnormal magnesium concentrations (56.3% vs 63.4%; p=0.13). However CVVHDF was associated with a higher prevalence of hypomagnesemia (8.1% vs 0.4%; p<0.0001) and a lower incidence of hypermagnesemia (48.2% vs. 63.0%; p=0.0014). CONCLUSIONS: In critically ill patients with ARF, calcium, phosphate and magnesium were commonly abnormal and they were only partly corrected by CRRT. CVVH and CVVHDF had a different effect on serum magnesium concentrations.

Abstract: