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

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

Clearance of vancomycin during high-volume haemofiltration: impact of pre-dilution

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.     

A pilot randomized study comparing high and low volume hemofiltration on vasopressor use in septic shock

OBJECTIVE: High volume hemofiltration (HVHF) has shown potential benefits in septic animals and a few reports suggested a hemodynamic improvement in humans. However, randomized studies are still lacking. Our goal was to evaluate the hemodynamic effects of HVHF in septic shock patients with acute renal failure (ARF). DESIGN AND SETTING: Prospective randomized study in an intensive care unit (ICU). PATIENTS: Twenty patients with septic shock and ARF. INTERVENTIONS: Patients were randomized to either high volume hemofiltration [HVHF 65 ml/(kg h)] or low volume hemofiltration [LVHF 35 ml/(kg h). Vasopressor dose was adjusted to reach a mean arterial pressure (MAP) > 65 mmHg. MEASUREMENTS AND RESULTS: We performed six hourly measurements of MAP, norepinephrine dose, PaO(2)/FiO(2) and lactate, and four daily urine output and logistic organ dysfunction (LOD) score. Baseline characteristics of the two groups were comparable on randomization. Mean norepinephrine dose decreased more rapidly after 24 h of HVHF treatment compared to LVHF treatment (P = 0.004) whereas lactate and PaO(2)/FiO(2) did not differ between the two treatment groups. During the 4-day follow-up, urine output was slightly increased in the HVHF group (P = 0.059) but the LOD score evolution was not different. Duration of mechanical ventilation, renal replacement therapy and ICU length of stay were also comparable. Survival on day 28 was not affected. CONCLUSION: HVHF decreased vasopressor requirement and tended to increase urine output in septic shock patients with renal failure. However, a larger trial is required to confirm our results and perhaps to show a benefit in survival.     

High-volume versus standard-volume haemofiltration for septic shock patients with acute kidney injury (IVOIRE study): a multicentre randomized controlled trial

Purpose

Septic shock is a leading cause of death among critically ill patients, in particular when complicated by acute kidney injury (AKI). Small experimental and human clinical studies have suggested that high-volume haemofiltration (HVHF) may improve haemodynamic profile and mortality. We sought to determine the impact of HVHF on 28-day mortality in critically ill patients with septic shock and AKI.

Methods

This was a prospective, randomized, open, multicentre clinical trial conducted at 18 intensive care units in France, Belgium and the Netherlands. A total of 140 critically ill patients with septic shock and AKI for less than 24 h were enrolled from October 2005 through March 2010. Patients were randomized to either HVHF at 70 mL/kg/h or standard-volume haemofiltration (SVHF) at 35 mL/kg/h, for a 96-h period.

Results

Primary endpoint was 28-day mortality. The trial was stopped prematurely after enrolment of 140 patients because of slow patient accrual and resources no longer being available. A total of 137 patients were analysed (two withdrew consent, one was excluded); 66 patients in the HVHF group and 71 in the SVHF group. Mortality at 28 days was lower than expected but not different between groups (HVHF 37.9 % vs. SVHF 40.8 %, log-rank test p = 0.94). There were no statistically significant differences in any of the secondary endpoints between treatment groups.

Conclusions

In the IVOIRE trial, there was no evidence that HVHF at 70 mL/kg/h, when compared with contemporary SVHF at 35 mL/kg/h, leads to a reduction of 28-day mortality or contributes to early improvements in haemodynamic profile or organ function. HVHF, as applied in this trial, cannot be recommended for treatment of septic shock complicated by AKI.     

High versus standard-volume haemofiltration in hyperdynamic porcine peritonitis: effects beyond haemodynamics?

Objective  The role of haemofiltration as an adjunctive treatment of sepsis remains a contentious issue. To address the role of dose and to explore the biological effects of haemofiltration we compared the effects of standard and high-volume haemofiltration (HVHF) in a peritonitis-induced model of porcine septic shock. Design and setting  Randomized, controlled experimental study. Subjects  Twenty-one anesthetized and mechanically ventilated pigs. Interventions  After 12 h of hyperdynamic peritonitis, animals were randomized to receive either supportive treatment (Control, n = 7) or standard haemofiltration (HF 35 ml/kg per h, n = 7) or HVHF (100 ml/kg per hour, n = 7). Measurements and results  Systemic and hepatosplanchnic haemodynamics, oxygen exchange, energy metabolism (lactate/pyruvate, ketone body ratios), ileal and renal cortex microcirculation and systemic inflammation (TNF-α, IL-6), nitrosative/oxidative stress (TBARS, nitrates, GSH/GSSG) and endothelial/coagulation dysfunction (von Willebrand factor, asymmetric dimethylarginine, platelet count) were assessed before, 12, 18, and 22 h of peritonitis. Although fewer haemofiltration-treated animals required noradrenaline support (86, 43 and 29% animals in the control, HF and HVHF groups, respectively), neither of haemofiltration doses reversed hyperdynamic circulation, lung dysfunction and ameliorated alterations in gut and kidney microvascular perfusion. Both HF and HVHF failed to attenuate sepsis-induced alterations in surrogate markers of cellular energetics, nitrosative/oxidative stress, endothelial injury or systemic inflammation. Conclusions  In this porcine model of septic shock early HVHF proved superior in preventing the development of septic hypotension. However, neither of haemofiltration doses was capable of reversing the progressive disturbances in microvascular, metabolic, endothelial and lung function, at least within the timeframe of the study and severity of the model. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users. Roman Sykora and Jiri Chvojka contributed equally to this study.     

Continuous is not continuous: the incidence and impact of circuit "down-time" on uraemic control during continuous veno-venous haemofiltration

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.     

不同置换量血液滤过对脓毒症患者Toll样受体表达的影响

目的 前瞻性的研究不同置换量血液滤过对严重脓毒症患者外周血单核细胞Toll样受体表达及其内在功能的影响.方法对2006年3月至2009年2月入住绍兴市人民医院ICU符合纳入标准的严重脓毒症患者30例,在脓毒症集束化治疗策略的基础上联合血液滤过治疗,并随机分为高通量血液滤过组(HVHF)(置换量4 I/h,15例)与常规通量血液滤过组(置换量2 L/h,15例).①血液滤过治疗0 h,6 h,12 h,24 h,48 h各时相点,分离外周血单核细胞,采用半定量RT-PCR法和流式细胞仪检测单核细胞表面Toll样受体-4(TLR4)和Toll样受体-2(TLR4)mRNA和蛋白表达变化.②血液滤过治疗24 h后分离患者外周血单核细胞于体外培养,以内毒素(LPS)刺激,在6 h,12 h,24 h,48 h各时相点检测单核细胞表面TLR4和TLR2受体mRNA和蛋白的变化,及ELISA法检测单核细胞培养液肿瘤坏死因子-α(TNF-α),白介素-6(IL-6),白介素-8(IL-8)细胞因子水平.统计学方法:对计量资料采用均数±标准差描述,采用t检验或Oneway ANOVA分析.结果 高通最血液滤过较常规通量可显著下调单核细胞TLR2和TLR4 mRNA及蛋白表达水平(P<0.05).不同置换量血滤治疗处理后孵育的单核细胞,其TNF-α,IL-6,IL-8分泌水平各时相点呈现:常规通量组>高通量组>正常对照,P<0.05;ILR4和TLR2 mRNA各时相点表达上调水平.呈现:正常对照>高通量组>常规通量组,P<0.05;其TLR2和TLR4蛋白表达亦呈现mRNA相同趋势,筹异无统计学意义.结论 高通量血液滤过能改善脓毒症患者单核细胞功能,使部分细胞免疫功能得到恢复,对重建机体免疫内稳状态起一定作用.     

高容量血液滤过对多器官功能障碍综合征患者肿瘤坏死因子及其受体的影响

目的　探讨高容量血液滤过 (HVHF)和连续性静静脉血液滤过 (CVVH)对多器官功能障碍综合征 (MODS)患者肿瘤坏死因子 α(TNFα)及可溶性 TNF受体 (s TNF R1和 s TNF R2 )水平的影响。方法　将 12例确诊为合并急性肾衰竭 (ARF)的 MODS患者随机分为两组 ,分别应用 CVVH和 HVHF方式治疗 ;用酶联免疫吸附法 (EL ISA)测定 CVVH和 HVHF治疗过程中血清 TNFα、s TNF R1和 s TNF R2水平。结果　 HVHF和 CVVH治疗 8h后 ,患者血浆中肌酐 (SCr)和尿素氮 (BU N)均降低 (P均 <0 .0 5 )。在 HVHF治疗期间 ,血清 TNFα水平逐渐降低 ,以治疗后 8h下降最明显 ,与治疗前、治疗后 1h和 4 h血清TNFα水平比较均有显著性差异 (P均 <0 .0 0 1)。在 CVVH治疗期间血清 TNFα水平以及 CVVH和HVHF治疗过程中血清 s TNF R1、s TNF R2水平均无明显的变化 (P均 >0 .0 5 )。结论　 HVHF治疗能明显增加 MODS患者的血清 TNFα清除能力 ,其对 s TNF R1和 s TNF R2等抗炎介质的影响较小。在MODS患者连续性肾脏替代 (CRRT)治疗方式选择上 ,更宜选用 HVHF治疗。     

高容量血液滤过对感染性休克所致急性肾损伤影响的实验研究

目的研究高容量血液滤过(High Volume Hemofiltration,HVHF)对感染性休克所致急性肾损伤(Acute Kidney Injury,AKI)的影响,并探讨其可能机制。方法 18只猪随机分为对照组、连续性肾脏替代治疗(continuous renal replacement therapy,CRRT)组和HVHF组,静脉注射大肠杆菌脂多糖(lipopolysaccharide,LPS)诱导感染性休克模型。各组给予液体复苏及血管活性药物维持保证组织灌注,复苏成功后根据分组给予不同处理:对照组不予特殊处理,CRRT组和HVHF组分别行超滤率为25ml/(kg·h)和85ml/(kg·h)的血液滤过治疗。记录各组血流动力学指标、血管活性药物用量及维持时间,检测血浆中IL-6和IL-10浓度、肾组织NF-k B表达水平,并观察肾组织病理改变。结果各组在给入LPS后约40~60min成功复制出休克模型;各组血流动力学指标在30min、40min、50min及60min时间点与基础相比差异均有统计学意义(P0.05);HVHF组CO值在T6时下降较少,高于基础正常值,与其它两组相比具有统计学差异(P0.05);HVHF组的d Pmax在T4、T5、T6时较其它两组有明显升高(P0.05);HVHF组的补液量较其它两组明显减少(P0.01),CRRT组较对照组减少(P0.05);在T4、T5、T6时间点HVHF组去甲肾上腺素用量较前下降,与其它两组相比有明显统计学差异(P0.01);与CRRT组相比,HVHF组IL-6在T3-T6下降明显,IL-10在T2-T6下降明显,差异均有统计学意义(P0.05);HVHF组肾NF-k B的m RNA相对表达量明显低于其它两组(P0.01),CRRT组低于对照组(P0.05);与对照组及CRRT组相比,HVHF组肾脏病理评分明显降低(P0.01)。结论 HVHF能够减少血管活性药物的用量和液体复苏量,有效降低血浆IL-6、IL-10浓度及肾组织NF-k B的表达水平,改善肾组织病理改变,对感染性AKI具有一定的肾保护作用。     

Pulse high-volume haemofiltration for treatment of severe sepsis: effects on hemodynamics and survival

Introduction

Severe sepsis is the leading cause of mortality in critically ill patients. Abnormal concentrations of inflammatory mediators appear to be involved in the pathogenesis of sepsis. Based on the humoral theory of sepsis, a potential therapeutic approach involves high-volume haemofiltration (HVHF), which has exhibited beneficial effects in severe sepsis, improving haemodynamics and unselectively removing proinflammatory and anti-inflammatory mediators. However, concerns have been expressed about the feasibility and costs of continuous HVHF. Here we evaluate a new modality, namely pulse HVHF (PHVHF; 24-hour schedule: HVHF 85 ml/kg per hour for 6–8 hours followed by continuous venovenous haemofiltration 35 ml/kg per hour for 16–18 hours).

Method

Fifteen critically ill patients (seven male; mean Acute Physiology and Chronic Health Evaluation [APACHE] II score 31.2, mean Simplified Acute Physiology Score [SAPS] II 62, and mean Sequential Organ Failure Assessment 14.2) with severe sepsis underwent daily PHVHF. We measured changes in haemodynamic variables and evaluated the dose of noradrenaline required to maintain mean arterial pressure above 70 mmHg during and after pulse therapy at 6 and 12 hours. PHVHF was performed with 250 ml/min blood flow rate. The bicarbonate-based replacement fluid was used at a 1:1 ratio in simultaneous pre-dilution and post-dilution.

Results

No treatment was prematurely discontinued. Haemodynamics were improved by PHVHF, allowing a significant reduction in noradrenaline dose during and at the end of the PHVHF session; this reduction was maintained at 6 and 12 hours after pulse treatment (P = 0.001). There was also an improvement in systolic blood pressure (P = 0.04). There were no changes in temperature, cardiac index, oxygenation, arterial pH or urine output during the period of observation. The mean daily Kt/V was 1.92. Predicted mortality rates were 72% (based on APACHE II score) and 68% (based on SAPS II score), and the observed 28-day mortality was 47%.

Conclusion

PHVHF is a feasible modality and improves haemodynamics both during and after therapy. It may be a beneficial adjuvant treatment for severe sepsis/septic shock in terms of patient survival, and it represents a compromise between continuous renal replacement therapy and HVHF.     

An open-label dose escalation study of the nitric oxide synthase inhibitor, N(G)-methyl-L-arginine hydrochloride (546C88), in patients with septic shock. Glaxo Wellcome International Septic Shock Study Group.

OBJECTIVE: To assess the effects of the nitric oxide synthase inhibitor, 546C88, in patients with septic shock and to evaluate the range of dose rates that sustain mean arterial pressure (MAP) of > or =70 mmHg. DESIGN: Multicenter, open-label, uncontrolled, dose range finding study. SETTING: Ten intensive care units in Europe and the United States. PATIENTS: Thirty-two patients with septic shock diagnosed within <24 hrs. INTERVENTIONS: Patients received a fixed dose rate of 546C88 at either 1(n = 6), 2.5 (n = 6), 5 (n = 4), 10 (n = 5), or 20 mg/kg/hr (n = 11) by intravenous infusion for up to 8 hrs. Conventional vasoactive therapy was restricted to norepinephrine and/or dobutamine. During 546C88 therapy, MAP was to be maintained between 70 and 90 mm Hg, while attempting to withdraw any concurrent norepinephrine. MEASUREMENTS AND MAIN RESULTS: Systemic and pulmonary hemodynamics, blood gases, and plasma nitrate were assessed. Infusion of 546C88 (1-20 mg/kg/hr) for up to 8 hrs enabled a 60 to 80% reduction of the norepinephrine dose rate in all cohorts, while MAP was sustained at >70 mm Hg. There was an increase in vascular tone and a decrease in cardiac index within the 1st hr of therapy. Systemic vascular resistance returned toward baseline with reduction of concomitant administration of norepinephrine. The decline in oxygen delivery was associated with an increase in extraction and, therefore, the maintenance of oxygen consumption. There was a sustained reduction of venous admixture within the 1st hr of therapy. 546C88 was not associated with any major or dose-dependent adverse effect on pulmonary, hepatic, or renal function. CONCLUSIONS: Treatment with the nitric oxide synthase inhibitor, 546C88, can restore the balance of vasomotor tone, thereby, maintaining blood pressure and reducing or eliminating the requirement for norepinephrine therapy in patients with septic shock. Infusion of 546C88 (1-20 mg/kg/hr) appears to have a satisfactory overall safety profile.     

Liberal vs. conservative vasopressor use to maintain mean arterial blood pressure during resuscitation of septic shock: an observational study

OBJECTIVE: The optimal role of vasopressor therapy in septic shock is not known. We hypothesized that the variability in the use of vasopressors to treat hypotension is associated with subsequent organ failures. DESIGN: Retrospective observational single-center cohort study. SETTING: Tertiary care hospital. PATIENTS AND PARTICIPANTS: Consecutive patients with septic shock. MEASUREMENT AND RESULTS: Ninety-five patients were enrolled. Serial blood pressure recordings and vasopressor use were collected during the first 12h of septic shock. Median duration of hypotension that was not treated with vasopressors was 1.37h (interquartile range [IQR] 0.62-2.66). Based on the observed variability, we evaluated liberal (duration of untreated hypotension < median) vs. conservative (duration of untreated hypotensionn > median) vasopressor therapy. Compared with patients who received conservative vasopressor therapy, patients treated liberally had similar baseline organ impairment [median Sequential Organ Failure Assessment (SOFA) score 8 vs. 8, p = 0.438] were more likely to be younger (median age 70 vs. 77 years, p = 0.049), to require ventilator support (78 vs. 49%, p < 0.001), and to have progression of organ failures after 24h (59 vs. 37%, p = 0.032). When adjusted for age and mechanical ventilation, early therapy aimed at achieving global tissue perfusion [odds ratio (OR) 0.33, 95% confidence interval (CI) 0.11-0.88), and early adequate antibiotic therapy (OR 0.27, 95% CI 0.09-0.76), but not liberal vasopressor use (OR 2.13, 95% CI 0.80-5.84), prevented progression of organ failures. CONCLUSIONS: In our retrospective study, early adequate antibiotics and achieving adequate global perfusion, but not liberal vasopressor therapy, were associated with improved organ failures after septic shock. Clinical trials which compare conservative vs. liberal vasopressor therapy are warranted.     

High-volume hemofiltration for septic acute kidney injury: a systematic review and meta-analysis

Introduction

High-volume hemofiltration (HVHF) is an attractive therapy for the treatment of septic acute kidney injury (AKI). Small experimental and uncontrolled studies have suggested hemodynamic and survival benefits at higher doses of HVHF than those used for the high-intensity arms of the RENAL and ATN studies. Our aim was to evaluate the effects of high-volume hemofiltration (HVHF) compared with standard-volume hemofiltration (SVHF) for septic AKI.

Methods

A systematic review and meta-analysis of publications between 1966 and 2013 was performed. The review was limited to randomized-controlled trials that compared HVHF (effluent rate greater than 50 ml/kg per hour) versus SVHF in the treatment of sepsis and septic shock. The primary outcome assessed was 28-day mortality. Other outcomes assessed were recovery of kidney function, lengths of ICU and hospital stays, vasopressor dose reduction, and adverse events.

Results

Four trials, including 470 total participants, were included. Pooled analysis for 28-day mortality did not show any meaningful difference between HVHF compared with SVHF (OR, 0.76; 95% CI, 0.45 to 1.29). No included studies reported statistically significant differences between groups for any of the secondary outcomes. Adverse events, including hypophosphatemia and hypokalemia, were more commonly observed in HVHF-treated patients, although reporting was inconsistent across studies.

Conclusions

Insufficient evidence exists of a therapeutic benefit for routine use of HVHF for septic AKI, other than on an experimental basis. Given the logistic challenges related to patient recruitment along with an incomplete understanding of the biologic mechanisms by which HVHF may modify outcomes, further trials should focus on alternative extracorporeal therapies as an adjuvant therapy for septic AKI rather than HVHF.     

Endothelial dysfunction in critically ill patients: the effect of haemofiltration

Objectives: To examine the effect of a single episode of continuous venovenous haemofiltration (CVVH) on indicators of endothelial injury and the protein C/S system in critically ill patients. Design: Observational study. Setting: University teaching hospital intensive care unit. Patients: 12 critically ill patients with acute renal failure receiving their first episode of CVVH. Interventions: Blood samples were collected prior to starting CVVH and at 15 min and 1, 3–4, 8–12, and 24 h, and at 24-h intervals thereafter until the filter clotted. Measurements and results: Soluble tissue factor, soluble thrombomodulin, E-selectin and endothelin-1 were measured as indicators of endothelial injury. Changes in the protein C/S system were assessed by measurement of protein C (PC) and both free and total protein S (PS). Levels of PC and both free and total PS were subnormal in 6 and 11 patients, respectively, prior to CVVH, but there were no further changes during CVVH. Levels of tissue factor, thrombomodulin, E-selectin, and endothelin-1 were raised prior to haemofiltration in 9, 10, 9 and 9 patients, respectively. There were further increases during CVVH in at least one, but not all, of the markers of endothelial injury in most patients. There was no consistency between the changes in different markers of endothelial injury during haemofiltration in individual patients. Conclusions: The PC/PS system and endothelial integrity is compromised in critically ill patients prior to haemofiltration, but a single episode of CVVH has little effect on the PC/PS system. The increase in markers of endothelial dysfunction seen during CVVH is more likely to be related to the underlying condition of the patient rather than any specific consequence arising from the technique itself. Received: 5 May 1998 Accepted: 18 September 1998     

Effect of norepinephrine on the outcome of septic shock

OBJECTIVE: Despite increasingly sophisticated critical care, the mortality of septic shock remains elevated. Accordingly, care remains supportive. Volume resuscitation combined with vasopressor support remains the standard of care as adjuvant therapy, and many consider dopamine to be the pressor of choice. Because of fear of excessive vasoconstriction, norepinephrine is considered to be deleterious. The present study was designed to identify factors associated with outcome in a cohort of septic shock patients. Special attention was paid to hemodynamic management and to the choice of vasopressor used, to determine whether the use of norepinephrine was associated with increased mortality. DESIGN: Prospective, observational, cohort study. SETTING: Intensive care unit of a university hospital. PATIENTS: Ninety-seven adult patients with septic shock. MEASUREMENTS AND MAIN RESULTS: Data from these patients were examined to select variables independently and significantly associated with outcome during the hospital stay. Nineteen clinical, biological, and hemodynamic variables were collected at study entry or during the first 48-72 hrs and analyzed for each patient. A stepwise logistic regression analysis and a model building strategy were used to identify variables independently and significantly associated with outcome. The overall hospital mortality was 73% (71 patients). Five variables were significantly associated with outcome. One factor was strongly associated with a favorable outcome: the use of norepinephrine as part of the hemodynamic support of the patients. The 57 patients who were treated with norepinephrine had significantly lower hospital mortality (62% vs. 82%, p < .001; relative risk = 0.68; 95% confidence interval = 0.54-0.87) than the 40 patients treated with vasopressors other than norepinephrine (high-dose dopamine and/or epinephrine). Four variables were associated with a poor outcome and significantly higher hospital mortality: pneumonia as a cause of septic shock (82% vs. 61%, p < .03; relative risk = 1.47; 95% confidence interval = 1.07-1.77), organ system failure index < or = 3 (92% vs. 60%, p < .001; relative risk = 1.47; 95% confidence interval = 1.17-1.82), low urine output at entry to the study (88% vs. 60%, p < .01; relative risk = 1.44; 95% confidence interval = 1.06-1.87), and admission blood lactate concentration > 4 mmol/L (91% vs. 63%, p < .01; relative risk = 1.60; 95% confidence interval = 1.27-1.84). CONCLUSIONS: Our results indicate that the use of norepinephrine as part of hemodynamic management may influence outcome favorably in septic shock patients. The data contradict the notion that norepinephrine potentiates end-organ hypoperfusion, thereby contributing to increased mortality. However, the present study suffers from some limitation because of its nonrandomized, open-label, observational design. Hence, a randomized clinical trial is needed to clearly establish that norepinephrine improves mortality of patients with septic shock, as compared with high-dose dopamine or epinephrine. Pneumonia as the cause of septic shock, high blood lactate concentration, and low urine output on admission are strong indicators of a poor prognosis. Multiple organ failure is confirmed as a reliable predictor of mortality in septic patients.     

Randomized, double-blind, placebo-controlled crossover pilot study of a potassium channel blocker in patients with septic shock

BACKGROUND: Marked potassium efflux prevents calcium entry into vascular smooth muscle cells and may be responsible for the "vasoplegia" of septic shock. Blockade of adenosine triphosphate (ATP)-sensitive potassium channels restores vascular tone in animal studies of septic shock. The effect of such potassium channel blockade has not been previously studied in humans. OBJECTIVE: To test whether the administration of an ATP-sensitive potassium (K(ATP)) channel blocker restores norepinephrine responsiveness in patients with septic shock. DESIGN: Randomized, double-blind, placebo-controlled crossover pilot study. SETTING: Intensive care unit of a university hospital. PATIENTS: Ten patients with septic shock requiring invasive hemodynamic monitoring and infusion of norepinephrine to maintain adequate mean arterial pressure. INTERVENTION: In addition to standard therapy, patients were randomized to initially receive either the K(ATP) channel blocker glibenclamide (20 mg) or placebo. Then, after 24 hrs, each patient crossed over to receive the alternative therapy. MEASUREMENTS AND MAIN RESULTS: After the administration of the K(ATP) channel blocker glibenclamide, median norepinephrine requirements decreased from 13 to 4 microg/min compared with a change from 19 to 7 microg/min after placebo. The two changes represented a decrease of 78.9% and 71.1% in dose, respectively (p = .57, not significant). There were also no significant changes in heart rate, mean arterial blood pressure, and lactate concentration when comparing the study drug with placebo. Glibenclamide, however, induced a significant decrease in median blood glucose concentration (5.4 [inter-quartile range, 4.5-7.0] vs. 7.0 mmol/L [5.2-9.3], p < .0001) compared with placebo and increased the need for parenteral glucose administration. CONCLUSIONS: The K(ATP) channel blocker glibenclamide failed to achieve a greater reduction in norepinephrine dose than placebo in septic shock patients, although it caused a reduced glucose concentration. Our observations suggest that, in such patients, blockade of K(ATP) channels does not have a potent effect on vasomotor tone.     

Sublingual microcirculatory changes during high-volume hemofiltration in hyperdynamic septic shock patients

Introduction  

Previous studies have suggested that high volume hemofiltration (HVHF) may contribute to revert hypotension in severe hyperdynamic septic shock patients. However, arterial pressure stabilization occurs due to an increase in systemic vascular resistance, which could eventually compromise microcirculatory blood flow and perfusion. The goal of this study was to determine if HVHF deteriorates sublingual microcirculation in severe hyperdynamic septic shock patients.     

Solute mass balance during isovolaemic high volume haemofiltration

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 CO₂, urea, creatinine and glucose concentrations were measured in each sample. The sieving coefficients of chloride, total CO₂, phosphate, urea and glucose were higher than 1 in most pre-dilution states. The sieving coefficients of sodium, potassium, calcium, magnesium, total CO₂ 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.     

Complement activation in septic shock patients

To evaluate the status of the complement system and to determine the effects of corticosteroids on complement component levels in septic shock, C3, C4, and Factor B were measured in 42 patients with severe late septic shock. Serum levels of C4 and Factor B correlated with C3 levels (r = 0.48 and 0.64, respectively; p less than .01) in patients in shock for more than 4 h, but only Factor B correlated with C3 (r = 0.85; p less than .01) in patients in shock for 4 h or less. C3 and Factor B levels were significantly (p less than .05) lower in patients who died (12,174 +/- 1,524 CH50 U/ml and 14 +/- 1 mg/dl, respectively) than in patients who survived (18,418 +/- 2,833 CH50 U/ml and 21 +/- 2 mg/dl, respectively). Corticosteroids did not alter complement component levels. The alternative pathway appears to be activated early in septic shock, whereas the classical pathway is activated later. C3 and Factor B levels may predict survival of patients in septic shock. In this study, corticosteroids did not change the complement component levels of patients in late severe septic shock.