Effect of ultrafiltration on extravascular lung water assessed by lung ultrasound in children undergoing cardiac surgery: a randomized prospective study.

BACKGROUND: Increased lung water and the resultant atelectasis are significant pulmonary complications after cardiopulmonary bypass (CPB) in children undergoing cardiac surgery; these complications are observed after CPB than after anaesthesia alone. Ultrafiltration has been shown to decrease total body water and postoperative blood loss and improve the alveolar to arterial oxygen gradient and pulmonary compliance. This study investigated whether conventional ultrafiltration during CPB in paediatric heart surgeries influences post-bypass extravascular lung water (EVLW) assessed by lung ultrasound (LUS). METHODS: This randomized controlled study included 60 patients with congenital heart disease (ASA II-III), aged 1 to 48 months, with a body weight > 3 kg. Conventional ultrafiltration targeting a haematocrit (HCT) level of 28% was performed on the ultrafiltration group, while the control group did not receive ultrafiltration. LUS scores were recorded at baseline and at the end of surgery. The PaO2/FiO2 ratio (arterial oxygen tension divided by the fraction of inspired oxygen), urine output, and haemodynamic parameters were also recorded. RESULTS: LUS scores were comparable between the two groups both at baseline (p = 0.92) and at the end of surgery (p = 0.95); however, within the same group, the scores at the end of surgery significantly differed from their baseline values in both the ultrafiltration (p = 0.01) and non-ultrafiltration groups (p = 0.02). The baseline PaO2/FiO2 ratio was comparable between both groups. at the end of surgery, The PaO2/FiO2 ratio increased in the ultrafiltration group compared to that in the non-ultrafiltration group, albeit insignificant (p = 0.16). no correlation between the PaO2/FiO2 ratio and LUS score was found at baseline (r = - 0.21, p = 0.31). On the other hand, post-surgical measurements were negatively correlated (r = - 0.41, p = 0.045). CONCLUSION: Conventional ultrafiltration did not alter the EVLW when assessed by LUS and oxygenation state. Similarly, ultrafiltration did not affect the urea and creatinine levels, intensive care unit (ICU) stays, ventilation days, or mortality. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT03146143 registered on 29-April-2017.

Pharmaceutical applications of affinity-ultrafiltration mass spectrometry: Recent advances and future prospects.

The immunoaffinity of protein with ligand is broadly involved in many bioanalytical methods. Affinity-ultrafiltration mass spectrometry (AUF-MS), a platform based on interaction of protein-ligand affinity, has been developed to fish out interesting molecules from complex matrixes. Here we reviewed the basics of AUF-MS and its recent applications to pharmaceutical field, i.e. target-oriented discovery of lead compounds from combinatorial libraries and natural product extracts, and determination of free drug concentration in biosamples. Selected practical examples were highlighted to illustrate the advances of AUF-MS in pharmaceutical fields. The future prospects were also presented.

Association of haemodynamic changes measured by serial central venous saturation during ultrafiltration for acutely decompensated heart failure with diuretic resistance and change in renal function.

BACKGROUND: Patients with acute decompensated heart failure with diuretic resistance (ADHF-DR) have a poor prognosis. The aim of this study was to assess in patients with ADHF-DR, whether haemodynamic changes during ultrafiltration (UF) are associated with changes in renal function (Δcreatinine) and whether Δcreatinine post UF is associated with mortality. METHODS: Seventeen patients with ADHF-DR underwent 20 treatments with UF. Serial bloods (4-6 hourly) from the onset of UF treatment were measured for renal function, electrolytes and central venous saturation (CVO2). Univariate and multivariate analysis were performed to assess the relationship between changes in markers of haemodynamics [heart rate (HR), systolic blood pressure (SBP), packed cell volume (PCV) and CVO2] and Δcreatinine. Patients were followed up and mortality recorded. Cox-regression survival analysis was performed to determine covariates associated with mortality. RESULTS: Renal function worsened after UF in 17 of the 20 UF treatments (baseline vs. post UF creatinine: 164±58 vs. 185±69µmol/l, P<0.01). ΔCVO2 was significantly associated with Δcreatinine [ß-coefficient of -1.3 95%CI (-1.8 to -0.7), P<0.001] and remained significantly associated with Δcreatinine after considering changes in SBP, HR and PCV [P<0.001]. Ten (59%) patients died at 1-year and 15(88%) by 2-years. Δcreatinine was independently associated with mortality (adjusted-hazard ratio 1.03 (1.01 to 1.07) per 1µmol/l increase in creatinine; P=0.02). CONCLUSIONS: Haemodynamic changes during UF as measured by the surrogate of cardiac output was associated with Δcreatinine. Worsening renal function at end of UF treatment occurred in the majority of patients and was associated with mortality.

Continuous ultrafiltration in acute decompensated heart failure: current issues and future directions.

Most patients hospitalized for acutely decompensated heart failure (ADHF) present with symptoms and signs of volume overload, which are also associated with high rates of death and re-hospitalization. Several studies have investigated the possible use of extracorporeal ultrafiltration in the management of ADHF, evaluating potential clinical benefits in terms of hospitalization and survival rates versus those of conventional diuretic therapy. Though ultrafiltration remains an extremely appealing therapeutic option for patients with AHDF, some of the most recent studies have reported conflicting results. Differences in the selection of study population, heterogeneity of the indications for the use of ultrafiltration, disparity in the ultrafiltration protocols, and high variability in the pharmacologic therapies used for the control group could explain some of these contradictory findings. The purpose of the present review is to provide an overview and an update on the mechanisms and clinical effects of ultrafiltration and on currently available evidence supporting its use in ADHF.

Worsening renal function in patients with acute decompensated heart failure treated with ultrafiltration: predictors and outcomes.

BACKGROUND: Ultrafiltration (UF) is used to treat patients with diuretic-resistant acute decompensated heart failure. The aim of this study was to identify predictors and the effect of worsening renal failure(WRF) on mortality in patients treated with UF. METHODS AND RESULTS: Based on changes in serum creatinine, 99 patients treated with UF were divided into WRF and control groups. Overall creatinine increased from 1.9 ± 0.7 to 1.2 ± 1.0 mg/dL (P!.001),and WRF developed in 41% of the subjects. The peak UF rate was higher in the WRF group in univariate analysis (174 ± 75 vs 144 ± 52 mL/h; P = .03). Based on multivariate analysis, aldosterone antagonist treatment (odds ratio [OR] 3.38, 95% confidence interval [CI] 1.17-13.46, P = .04), heart rate ≤65 beats/min (OR 6.03, 95% CI 1.48-48.42; P = .03), and E/E0 ≥ 15 (OR 3.78, 95% CI 1.26-17.55; P 5 .04) at hospital admission were associated with WRF. Patients with baseline glomerular filtration rate (GFR) ≤60mg/dL who developed WRF during UF had a 75% 1-year mortality rate. CONCLUSIONS: WRF occurred frequently during UF. Increased LV filling pressures, lower heart rate, and treatment with aldosterone antagonist at hospital admission can identify patients at increased risk for WRF. Patients with baseline GFR ≤60 mg/dL and WRF during UF have an extremely high 1-year mortality rate.

Worsening renal function in patients with acute decompensated heart failure treated with ultrafiltration: predictors and outcomes.

BACKGROUND: Ultrafiltration (UF) is used to treat patients with diuretic-resistant acute decompensated heart failure. The aim of this study was to identify predictors and the effect of worsening renal failure (WRF) on mortality in patients treated with UF. METHODS AND RESULTS: Based on changes in serum creatinine, 99 patients treated with UF were divided into WRF and control groups. Overall creatinine increased from 1.9 ± 9.7 to 2.2 ± 2.0 mg/dL (P < .001), and WRF developed in 41% of the subjects. The peak UF rate was higher in the WRF group in univariate analysis (174 ± 45 vs 144 ± 42 mL/h; P = .03). Based on multivariate analysis, aldosterone antagonist treatment (odds ratio [OR] 3.38, 95% confidence interval [CI] 1.17-13.46, P = .04), heart rate ≤65 beats/min (OR 6.03, 95% CI 1.48-48.42; P = .03), and E/E' ≥15 (OR 3.78, 95% CI 1.26-17.55; P = .04) at hospital admission were associated with WRF. Patients with baseline glomerular filtration rate (GFR) ≤60 mg/dL who developed WRF during UF had a 75% 1-year mortality rate. CONCLUSIONS: WRF occurred frequently during UF. Increased LV filling pressures, lower heart rate, and treatment with aldosterone antagonist at hospital admission can identify patients at increased risk for WRF. Patients with baseline GFR ≤60 mg/dL and WRF during UF have an extremely high 1-year mortality rate.

Recent advances in the monitoring and control of haemodynamic variables during haemodialysis: a review.

The human body possesses a unique set of organs that are responsible for providing homeostatic balance to the body's fluids. Of these, the kidneys regulate fluid and electrolyte balance in order to maintain the intracellular and extracellular fluid volumes and ion composition within tight limits. When kidneys fail to function normally, fluid is retained and several ions and solutes accumulate. The consequences may be life threatening. Many kidney failure patients rely on haemodialysis (HD) as a life sustaining therapy to remove the waste products and excess fluid from the circulating blood. HD is based on the principle of diffusion of solutes and ultrafiltration of fluid across a semi-permeable membrane. Fluid removal during HD results in relative hypovolaemia during which the stability of a patient relies on compensatory mechanisms to maintain blood pressure (BP). The major compensatory mechanisms include sympathetic nervous system activation of peripheral vasoconstriction together with modest heart rate acceleration to ensure the haemodynamic stability of the patient. Over the years, many monitoring tools have been developed in the hope of predicting intra-dialytic hypotensive episodes. Similarly many methods have been utilized to prevent dialysis-induced complications: ultrafiltration and dialysate sodium profiling, varying ultrafiltration based on frequent BP measurements, etc. This paper provides a comprehensive review of those monitoring and control tools. It starts with a brief introduction to human kidneys and dialysis for non-specialized readers. The paper then reviews the monitoring tools that have been applied to assess the physiological response of patients during HD. This is followed by control techniques used to prevent dialysis-induced complications.

Ultrafiltration is associated with fewer rehospitalizations than continuous diuretic infusion in patients with decompensated heart failure: results from UNLOAD.

BACKGROUND: Compare outcomes of ultrafiltration (UF) versus standard intravenous (IV) diuretics by continuous infusion or bolus injection in volume overloaded heart failure (HF) patients. In the Ultrafiltration versus Intravenous Diuretics for Patients Hospitalized for Acute Decompensated heart Failure (UNLOAD) study, UF produced greater fluid reduction and fewer HF rehospitalizations than IV diuretics in 200 hospitalized HF patients. Outcomes may be due to greater fluid removal, but UF removes more sodium/unit volume than diuretics. METHODS AND RESULTS: Outcomes of 100 patients randomized to UF were compared with those of patients randomized to standard IV diuretic therapy with continuous infusion (32) or bolus injections (68). Choice of diuretic therapy was by the treating physician. Forty-eight hour weight loss (kg): 5.0 +/- 3.1 UF, 3.6 +/- 3.5 continuous infusion, and 2.9 +/- 3.5 bolus diuretics (P = .001 UF versus bolus diuretic; P > .05 for the other comparisons). Net fluid loss (L): 4.6 +/- 2.6 UF, 3.9 +/- 2.7 continuous infusion, and 3.1 +/- 2.6 bolus diuretics (P < .001 UF versus bolus diuretic; P > .05 for the other comparisons). At 90 days, rehospitalizations plus unscheduled visits for HF/patient (rehospitalization equivalents) were fewer in UF group (0.65 +/- 1.36) than in continuous infusion (2.29 +/- 3.23; P = .016 versus UF) and bolus diuretics (1.31 +/- 1.87; P = .050 versus UF) groups. No serum creatinine differences occurred between groups up to 90 days. CONCLUSIONS: Despite similar fluid loss with UF and continuous diuretic infusion, fewer HF rehospitalizations equivalents occurred only with UF. Removal of isotonic fluid by UF compared with hypotonic urine by diuretics more effectively reduces total body sodium in congested HF patients.

Membrane processes and devices for separation of bioactive peptides.

In recent years, functional foods and nutraceuticals has attracted much attention, particularly for their impact on human health and prevention of certain diseases. Consequently, the production and properties of bioactive peptides has received an increasing scientific interest over the past few years. Considering that most functional peptides are present in complex matrices containing a large number of hydrolyzed protein fractions, their separation and purification are required. Conventional pressure-driven processes can be used for amino acids and peptides separation but are limited by their fouling problems and their low selectivity when separating similar sized biomolecules. To improve the separation efficiency, an external electric field was applied during pressure-driven filtration. However, the pressure gradient brings about the accumulation of peptides at the nearby membrane surface and affects the membrane transport selectivity. Processes combining an electrical field as a driving force to porous membranes have been developed for the separation of biopeptides to obtain better purified products. Compounds of higher molecular weights than the membrane cut-off can be separated. The first trials were carried-out to perform the separation of amino acids and peptides with a filtration module specially designed and using one ultrafiltration membrane. More recently, electrodialysis with ultrafiltration membranes has been developed to fractionate simultaneously acidic and basic peptides, using a conventional electrodialysis cell, in which some ion exchange membranes are replaced by ultrafiltration ones. The perspectives in this field will be the understanding of the interactions of peptides and membrane as well as the development of new membrane materials limitating or increasing these interactions to improve the selectivity and the yield of production of specific peptides. This review article also discusses recent patents related to bioactive peptides.

Ultrafiltration for the management of acute decompensated heart failure.

Heart failure is a major public health problem and is increasing in incidence throughout the industrialized world. Despite recent advances in pharmacotherapy, the overall mortality remains high and largely unchanged. Ultrafiltration has received increased attention in the treatment of acute decompensated congestive heart failure, and recent clinical trials suggest its usefulness in removing volume while preserving renal function. This review will focus on the background of ultrafiltration in the treatment of acute decompensated heart failure as well as the current evidence regarding its efficacy and safety.

Outcomes of volume-overloaded cardiovascular patients treated with ultrafiltration.

BACKGROUND: Ultrafiltration (UF) can rapidly and predictably remove extracellular and intravascular fluid volume. To date, assessment of UF in patients with cardiovascular disease has been confined to short- and medium-term studies in patients with a principal diagnosis of acute heart failure. METHODS: In-hospital and long-term outcomes were reviewed from consecutive patients with cardiovascular disorders and recognized pulmonary and systemic volume overload treated with a simplified UF system with the capability for peripheral venovenous access. Trained abstractors reviewed both paper and electronic medical records. Patients with a principal diagnosis of heart failure versus other primary hospital discharge diagnoses were identified according to International Classification of Diseases, 9th Revision standards by independent coders. RESULTS: For a period of 43 months, 100 patients (76 male/24 female, 65 +/- 14.0 years of age, systolic dysfunction 64%) were treated with UF during 130 hospitalizations. Baseline systolic blood pressure was 119 +/- 23 mm Hg. Before UF, 53% were receiving intravenous vasoactive therapy. By using UF, 7.1 +/- 3.9 L of ultrafiltrate were removed during 2.0 +/- 1.2 treatments per hospitalization. Baseline creatinine was 1.8 +/- 0.8 and 1.9 +/- 1.2 (not significant) at discharge. Of the 15 in-hospital deaths, 14 occurred during the initial hospitalization. Left ventricular dysfunction was related to 13 (87%) of the 15 deaths; no deaths were related to UF use. In hospitalizations with a principal diagnosis of heart failure (n = 79), in-hospital mortality was 7.6% compared with an ADHERE risk tree estimated mortality of 7.5%. Multivariate logistic regression identified a trend for decreased systolic blood pressure to predict patient initial hospitalization mortality (P = .06). Kaplan-Meier survivals for all patients were 71% at 1 year and 67% at 2 years. Cox regression found decreased systolic blood pressure as a predictor of long-term mortality (P = .025). Total volume of ultrafiltrate removed, ejection fraction, history of coronary artery disease, creatinine clearance, gender, age, and principal diagnosis of heart failure were not significantly associated with long-term mortality. CONCLUSION: This series extends the spectrum of patients previously reported to be treated with UF. Despite marked volume overload, UF-treated patients with a principal diagnosis of heart failure had inpatient outcomes similar to the ADHERE registry. UF should be considered for a broad range of patients who present with volume overload.

Bioseparation in antibody manufacturing: the good, the bad and the ugly.

Improvements in upstream production have boosted productivity in the biomanufacturing industry, but this is leading to bottlenecks in downstream processing as current technology platforms reach their limits of throughput and scalability. Although chromatography remains an indispensible component of downstream processing due to its simplicity and high resolving power (The Good), there is virtually no economy of scale effect so more product translates almost linearly into greater production costs. Bind-and-elute processes (such as the initial capture step in antibody manufacturing) are volume-driven and therefore have knock-on effects that impact on the entire production facility since the space required for preparation, storage, and cleaning steps has to be similarly adapted (The Bad). During long-term operations with multiple cycles, thorough cleaning is necessary to prevent progressive fouling and microbial contamination (The Ugly). Innovative solutions are required, which may include revisiting simpler and less expensive separation technologies, the use of disposable modules, and the integration of improved processes that are scalable to cope with increased demands. Among the alternatives that have been put forward, membrane adsorbers are beginning to make a real impact on the industry, particularly for flow-through applications such as polishing and viral clearance.

Advances in primary recovery: centrifugation and membrane technology.

Significant and continual improvements in upstream processing for biologics have resulted in challenges for downstream processing, both primary recovery and purification. Given the high cell densities achievable in both microbial and mammalian cell culture processes, primary recovery can be a significant bottleneck in both clinical and commercial manufacturing. The combination of increased product titer and low viability leads to significant relative increases in the levels of process impurities such as lipids, intracellular proteins and nucleic acid versus the product. In addition, cell culture media components such as soy and yeast hydrolysates have been widely applied to achieve the cell culture densities needed for higher titers. Many of the process impurities can be negatively charged at harvest pH and can form colloids during the cell culture and harvest processes. The wide size distribution of these particles and the potential for additional particles to be generated by shear forces within a centrifuge may result in insufficient clarification to prevent fouling of subsequent filters. The other residual process impurities can lead to precipitation and increased turbidity during processing and even interference with the performance of the capturing chromatographic step. Primary recovery also poses significant challenges owing to the necessity to execute in an expedient manner to minimize both product degradation and bioburden concerns. Both microfiltration and centrifugation coupled with depth filtration have been employed successfully as primary recovery processing steps. Advances in the design and application of membrane technology for microfiltration and dead-end filtration have contributed to significant improvements in process performance and integration, in some cases allowing for a combination of multiple unit operations in a given step. Although these advances have increased productivity and reliability, the net result is that optimization of primary recovery processes has become substantially more complicated. Ironically, the application of classical chemical engineering approaches to overcome issues in primary recovery and purification (e.g., turbidity and trace impurity removal) are just recently gaining attention. Some of these techniques (e.g., membrane cascades, pretreatment, precipitation, and the use of affinity tags) are now seen almost as disruptive technologies. This paper will review the current and potential future state of research on primary recovery, including relevant papers presented at the 234th American Chemical Society (ACS) National Meeting in Boston.

Alternatives to chromatographic separations.

Up to now, the productivity of mammalian cell culture has been perceived as limiting the productivity of the industrial manufacture of therapeutic monoclonal antibodies. Dramatic improvements in cell culture performance have changed this picture, and the throughput of antibody purification processes is gaining increasing attention. Although chromatographic separations currently are the centerpiece of antibody purification, mostly due to their high resolving power, it becomes more and more apparent that there may be limitations at the very large scale. This review will discuss a number of alternatives to chromatographic antibody purification, with a particular emphasis on the ability to increase throughput and overcome traditional drawbacks of column chromatography. Specifically, precipitation, membrane chromatography, high-resolution ultrafiltration, crystallization, and high-pressure refolding will be evaluated as potential large scale unit operations for industrial antibody production.

Ultrafiltration for acute decompensated heart failure.

For the 13th consecutive year, acute decompensated heart failure is the most common reason for admission to American hospitals. Most patients admitted for decompensated heart failure are by definition, diuretic resistant. The therapeutic objective in these patients is volume and sodium removal, and the restoration of diuretic sensitivity. In a significant proportion of patients, this objective is not met, subjecting patients to readmission for recurrent (or continued) heart failure decompensation. Ultrafiltration therapy offers the potential of greater volume and sodium removal as compared with conventional therapies in a more expeditious manner. Ultrafiltration can be accomplished safely, quickly and on a regular telemetry ward in extremely ill patients, but relies on earlier discharge with reduced readmission rates to be economically feasible.

Dialysis modalities in the intensive care unit.

Acute renal failure in the ICU is a clinically diverse entity. Consequently, the indications for initiation of dialysis therapy are varied. In general, the indications are solute control, volume control, or both. A variety of dialysis modalities are available; however, there is no consensus as to the optimal modality for any particular group of patients. A careful understanding of the particular benefits, limitations, and potential complications of each modality coupled with a thorough assessment of the individual patient's need formulate the basis for dialysis modality selection. In certain circumstances, the more conventional intermittent therapies are sufficient, whereas in other settings, CRRT techniques are advantageous. The impact of modality selection on outcome remains an area of significant controversy. Future studies in which more uniformity within specific subgroups of patients with ARF is sought may shed light on the optimal modality for a particular patient group. Newer therapies aimed at more optimal and more specific blood purification may prove promising in the management of complex critically ill patients with ARF and other comorbid conditions.