High-volume hemofiltration as salvage therapy in severe hyperdynamic septic shock

Objectives To evaluate the effect of short-term (12-h) high-volume hemofiltration (HVHF) in reversing progressive refractory hypotension and hypoperfusion in patients with severe hyperdynamic septic shock. To evaluate feasibility and tolerance and to compare observed vs. expected hospital mortality.Design and setting Prospective, interventional, nonrandomized study in the surgical-medical intensive care unit of an academic tertiary center.Patients Twenty patients with severe septic shock, previously unresponsive to a multi-intervention approach within a goal-directed, norepinephrine-based algorithm, with increasing norepinephrine (NE) requirements (> 0.3 μg kg^–1 min^–1) and lactic acidosis.Interventions Single session of 12-h HVHF.Measurements and results We measured changes in NE requirements and perfusion parameters every 4 h during HVHF and 6 h thereafter. Eleven patients showed decreased NE requirements and lactate levels (responders). Nine patients did not fulfill these criteria (nonresponders). The NE dose, lactate levels, and heart rates decreased and arterial pH increased significantly in responders. Hospital mortality (40%) was significantly lower than predicted (60%): 67% (6/9) in nonresponders vs. 18% (2/11) in responders. Of 12 survivors 7 required only a single 12-h HVHF session. On logistic regression analysis the only statistically significant predictor of survival was theresponse to HVHF (odds ratio 9).Conclusions A single session of HVHF as salvage therapy in the setting of a goal-directed hemodynamic management algorithm may be beneficial in severe refractory hyperdynamic septic-shock patients. This approach may improve hemodynamics and perfusion parameters, acid-base status, and ultimately hospital survival. Moreover, it is feasible, and safe.Electronic supplementary material The electronic reference of this article is . The online full-text version of this article includes electronic supplementary material. This material is available to authorised users and can be accessed by means of the ESM button beneath the abstract or in the structured full-text article. To cite or link to this article you can use the above reference.     

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.     

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.     

Effects on management and outcome of severe sepsis and septic shock patients admitted to the intensive care unit after implementation of a sepsis program: a pilot study

Introduction  

The application in clinical practice of evidence-based guidelines for the management of patients with severe sepsis/septic shock is still poor in the emergency department, while little data are available for patients admitted to the intensive care unit (ICU). The aim of this study was to evaluate the effect of an in-hospital sepsis program on the adherence to evidence-based guidelines and outcome of patients with severe sepsis/septic shock admitted to the ICU.     

Concomitant arginine-vasopressin and hydrocortisone therapy in severe septic shock: association with mortality

Purpose  

To evaluate the association between concomitant arginine-vasopressin (AVP)/hydrocortisone therapy and mortality in severe septic shock patients.     

Activated protein C in septic shock: a propensity-matched analysis

Introduction  

The use of human recombinant activated protein C (rhAPC) for the treatment of severe sepsis remains controversial despite multiple reported trials. The efficacy of rhAPC remains a matter of dispute. We hypothesized that patients with septic shock who were treated with rhAPC had an improved in-hospital mortality compared to patients with septic shock with similar acuity who did not receive rhAPC.     

Updating the evidence for the role of corticosteroids in severe sepsis and septic shock: a Bayesian meta-analytic perspective

Introduction  

Current low (stress) dose corticosteroid regimens may have therapeutic advantage in severe sepsis and septic shock despite conflicting results from two landmark randomised controlled trials (RCT). We systematically reviewed the efficacy of corticosteroid therapy in severe sepsis and septic shock.     

High-volume haemofiltration in human septic shock

OBJECTIVE: To evaluate whether high volume haemofiltration improves haemodynamics and affects serum cytokine and complement concentrations in human septic shock. DESIGN AND SETTING: Randomized cross-over clinical trial in a tertiary intensive care unit. PATIENTS: Eleven patients with septic shock and multi-organ failure. INTERVENTIONS: Patients were assigned to either 8 h of high-volume haemofiltration (HVHF; 6 l/h) or 8 h of standard continuous veno-venous haemofiltration (CVVH; 1 l/h) in random order. MEASUREMENTS AND MAIN RESULTS: We measured changes in haemodynamic variables, dose of norepinephrine required to maintain a mean arterial pressure greater than 70 mmHg and plasma concentrations of complement anaphylatoxins and several cytokines. An 8-h period of HVHF was associated with a greater reduction in norepinephrine requirements than a similar period of CVVH (median reduction: 10.5 vs. 1.0 microg/min; p = 0.01; median percentage reduction: 68 vs. 7%; p = 0.02). Both therapies were associated with a temporary reduction (p < 0.01) in the plasma concentration of C3a, C5a, and interleukin 10 within 2 h of initiation. HVHF was associated with a greater reduction in the area under the curve for C3a and C5a (p < 0.01). The concentration of the measured soluble mediators in the ultrafiltrate was negligible. CONCLUSIONS: HVHF decreases vasopressor requirements in human septic shock and affects anaphylatoxin levels differently than standard CVVH.     

Predictive value of procalcitonin decrease in patients with severe sepsis: a prospective observational study

Introduction  

This prospective study investigated the predictive value of procalcitonin (PCT) for survival in 242 adult patients with severe sepsis and septic shock treated in intensive care.     

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.     

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 central venous oxygen saturation in the latter stages of septic shock is associated with increased mortality

Introduction  

Current guidelines recommend maintaining central venous oxygen saturation (ScvO₂) higher than 70% in patients with severe sepsis and septic shock. As high levels of ScvO₂ may reflect an inadequate use of oxygen, our aim was to evaluate the relation between maximal ScvO₂ levels (ScvO_2max ) and survival among intensive care unit (ICU) patients with septic shock.     

Critical illness-related corticosteroid insufficiency in cancer patients

Purpose  

Critically ill cancer patients with sepsis represent a high-risk sub-group for the development of critical illness-related corticosteroid insufficiency (CIRCI); however, the incidence of CIRCI in this population is unknown. The purpose of this study was to determine the incidence of CIRCI in cancer patients with severe sepsis or septic shock.     

Incidence of severe sepsis and septic shock in German intensive care units: the prospective,multicentre INSEP study

Purpose

To estimate the incidence density, point prevalence and outcome of severe sepsis and septic shock in German intensive care units (ICUs).

Methods

In a prospective, multicentre, longitudinal observational study, all patients already on the ICU at 0:00 on 4 November 2013 and all patients admitted to a participating ICU between 0:00 on 4 November 2013 and 2359 hours on 1 December 2013 were included. The patients were followed up for the occurrence of severe sepsis or septic shock (SEPSIS-1 definitions) during their ICU stay.

Results

A total of 11,883 patients from 133 ICUs at 95 German hospitals were included in the study, of whom 1503 (12.6 %) were diagnosed with severe sepsis or septic shock. In 860 cases (57.2 %) the infections were of nosocomial origin. The point prevalence was 17.9 % (95 % CI 16.3–19.7).The calculated incidence rate of severe sepsis or septic shock was 11.64 (95 % CI 10.51–12.86) per 1000 ICU days. ICU mortality in patients with severe sepsis/septic shock was 34.3 %, compared with 6 % in those without sepsis. Total hospital mortality of patients with severe sepsis or septic shock was 40.4 %. Classification of the septic shock patients using the new SEPSIS-3 definitions showed higher ICU and hospital mortality (44.3 and 50.9 %).

Conclusions

Severe sepsis and septic shock continue to be a frequent syndrome associated with high hospital mortality. Nosocomial infections play a major role in the development of sepsis. This study presents a pragmatic, affordable and feasible method for the surveillance of sepsis epidemiology. Implementation of the new SEPSIS-3 definitions may have a major effect on future epidemiological data.

     

Assessment of pro-vasopressin and pro-adrenomedullin as predictors of 28-day mortality in septic shock patients

Purpose  

Improvements in survival after septic shock will most likely rely on our capacity to manage individualized therapies based on the measurement of rapidly accessible biomarkers. As the early phase of septic shock is dominated by severe alterations of the cardiovascular system, the predictive value for mortality of pro-vasopressin (pro-AVP) and pro-adrenomedullin (pro-ADM), two vasoactive pro-hormones, was assessed.     

Are clinical trials dealing with severe infection fitting routine practices? Insights from a large registry

Introduction

Guidelines dealing with severe sepsis and septic shock mostly rely on randomized controlled trials (RCTs) to ensure the best standards of care for patients. However, patients included in high-quality studies may differ from the routine population and alter external validity of recommendations. We aimed to determine to what extent non-inclusion criteria of RCTs dealing with severe sepsis and septic shock may affect application of their conclusions in routine care.

Methods

In a first step, the MEDLINE database was searched for RCTs treating severe sepsis and septic shock patients between 1992 and 2008, and non-inclusion criteria for these studies were abstracted. Two reviewers independently evaluated the articles, which were checked by a third reviewer. We extracted data on the study design, main intervention, primary endpoint, criteria for inclusion, and criteria for non-inclusion. In a second step, the distribution of the non-inclusion criteria was observed in a prospective multicenter cohort of severe sepsis and septic shock patients (Cub-Rea network, 1992 to 2008).

Results

We identified 96 articles out of 7,012 citations that met the screening criteria. Congestive heart failure (35%) and cancer (30%) were frequent exclusion criteria in selected studies, as well as other frequent disorders such as gastrointestinal and liver diseases and all causes of immune suppression. Of the 67,717 patients with severe sepsis and septic shock in the Cub-Rea database, 40,325 (60%) experienced at least one of the main exclusion criteria, including 11% of congestive heart failure patients and 11% of cancer patients. In addition, we observed a significant trend for increasing number of patients with these criteria along time.

Conclusion

Current exclusion criteria for RCTs dealing with severe sepsis and septic shock excluded most patients encountered in daily practice and limit external validity of the results of high-quality studies.     

Beneficial effects of the heme oxygenase-1/carbon monoxide system in patients with severe sepsis/septic shock

Purpose

We evaluated the relations among the arterial carbon monoxide (CO) concentration, heme oxygenase (HO)-1 expression by monocytes, oxidative stress, plasma levels of cytokines and bilirubin, and the outcome of patients with severe sepsis or septic shock.

Methods

Thirty-six patients who fulfilled the criteria for severe sepsis or septic shock and 21 other patients without sepsis during their stay in the intensive care unit were studied. HO-1 protein expression by monocytes, arterial CO, oxidative stress, bilirubin, and cytokines were measured.

Results

Arterial blood CO, cytokine, and bilirubin levels, and monocyte HO-1 protein expression were higher in patients with severe sepsis/septic shock than in non-septic patients. Increased HO-1 expression was related to the arterial CO concentration and oxidative stress. There was a positive correlation between survival and increased HO-1 protein expression or a higher CO level.

Conclusions

Arterial CO and monocyte HO-1 protein expression were increased in critically ill patients, particularly those with severe sepsis or septic shock, suggesting that oxidative stress is closely related to HO-1 expression. The HO-1/CO system may play an important role in sepsis.     

Neutrophil gelatinase-associated lipocalin in adult septic patients with and without acute kidney injury

Purpose

To study the impact of inflammation/sepsis on the concentrations of neutrophil gelatinase-associated lipocalin (NGAL) in plasma and urine in adult intensive care unit (ICU) patients and to estimate the predictive properties of NGAL in plasma and urine for early detection of acute kidney injury (AKI) in patients with septic shock.

Methods

Sixty-five patients admitted to the general ICU at the Karolinska University Hospital Solna, Sweden, with normal plasma creatinine were assessed for eligibility. Twenty-seven patients with systemic inflammatory response syndrome (SIRS), severe sepsis, or septic shock without AKI and 18 patients with septic shock and concomitant AKI were included in the final analysis. Plasma and urine were analyzed twice daily for plasma NGAL (pNGAL), C-reactive protein (CRP), procalcitonin, myeloperoxidase, plasma cystatin C, plasma creatinine, urine NGAL (uNGAL), urine cystatin C, and urine α1-microglobulin.

Results

Of the 45 patients, 40 had elevated peak levels of pNGAL. Peak levels of pNGAL were not significantly different between septic shock patients with and without AKI. Peak levels of uNGAL were below the upper reference limit in all but four patients without AKI. uNGAL was a good predictor (area under ROC 0.86) whereas pNGAL was a poor predictor (area under ROC 0.67) for AKI within the next 12 h in patients with septic shock.

Conclusions

pNGAL is raised in patients with SIRS, severe sepsis, and septic shock and should be used with caution as a marker of AKI in ICU patients with septic shock. uNGAL is more useful in predicting AKI as the levels are not elevated in septic patients without AKI.