Early isovolaemic haemofiltration in oliguric patients with septic shock.

OBJECTIVE: To evaluate the effects of early short-term, isovolaemic haemofiltration at 45 ml/kg/h on physiological and clinical outcomes in patients with septic shock. DESIGN: Retrospective study before and after a change of unit protocol (study period 8 years). SETTING: Intensive care unit of metropolitan hospital. PATIENTS: Eighty patients with septic shock. INTERVENTIONS: Introduction of a new septic shock protocol based on early isovolaemic haemofiltration (EIHF). In the pre-EIHF period (before), 40 patients received conventional supportive therapy. In the post-EIHF period (after), 40 patients received EIHF at 45 ml/kg/h of plasma-water exchange over 6 h followed by conventional continuous venovenous haemofiltration (CVVH). Anticoagulation policy remained unchanged. MEASUREMENTS AND MAIN RESULTS: The two groups were comparable for age, gender and baseline APACHE II score. Delivered haemofiltration dose was above 85% of prescription in all patients. PaO2/FiO2 ratio increased from 117+/-59 to 240+/-50 in EIHF, while it changed from 125+/-55 to 160+/-50 in the control group (p<0.05). In EIHF patients, mean arterial pressure increased (95+/-10 vs 60+/-12 mmHg; p<0.05), and norepinephrine dose decreased (0.20+/-2 vs 0.02+/-0.2 microg/kg/min; p<0.05). Among EIHF patients, 28 (70%) were successfully weaned from the ventilator compared with 15 (37%) in the control group (p<0.01). Similarly, 28-day survival was 55% compared with 27.5% (p<0.05). Length of stay in the ICU was 9+/-5 days compared with 16+/-4 days (p<0.002). CONCLUSIONS: In patients with septic shock, EIHF was associated with improved gas exchange, haemodynamics, greater likelihood of successful weaning and greater 28-day survival compared with conventional therapy.

Effect of daily hemodialysis on monocytes apoptosis.

Uremia is associated with a state of immune dysfunction with increased susceptibility to infection and malignancy possibly related to dysregulation of immune system cell apoptosis. Peritoneal dialysis can restore plasma apoptosis activity on monocytes compared to intermittent hemodialysis. Whether the continuous modality or diverse clearance mechanisms involved are responsible is unknown. Apoptosis rates correlate with phagocytic function highlighting the benefit of efficient toxin clearance. The plasma of 16 patients on daily hemodialysis (D-HD) was incubated with U937 monocytes and compared to 18 hemodialysis (HD) patients, 5 chronic renal failure (CRF) subjects and 5 healthy volunteers (controls). Apoptosis was evaluated by immunofluorescence microscopy dyes (Hoechst 33342, propidium iodide) and annexin V cytoflowmetry at 96 h. Plasma-induced U937 apoptosis (mean values) was significantly enhanced in D-HD (18.8 +/- 4.1), HD (19.67 +/- 5.5) and CRF patients (20.8 +/- 4.7) compared to controls (9.6 +/- 3.6; p < 0.05 for CRF vs. controls, HD vs. controls and D-HD vs. controls). No significant differences were observed between D-HD, HD and CRF sera on apoptosis rate, caspase-3 activity and phagocytic capacity of U937 monocytes. This study demonstrates that the plasma of various HD schedules was unable to reduce monocyte apoptosis induced by uremia.

Monocyte apoptosis in uremia is normalized with continuous blood purification modalities.

Uremia is associated with a state of immune dysfunction. Dysregulation of homeostasis may be directly related to abnormal apoptosis regulation in uremia, which is crucial for the maintenance of the biological system. We demonstrated that plasma from three groups of uremic subjects, i.e. hemodialysis (HD) patients, peritoneal dialysis (PD) patients and patients with predialysis chronic renal failure (CRF), has different apoptotic potential on U937 monocytes. The plasma of HD and CRF subjects when incubated with U937 cells induced higher levels of apoptosis compared with that of PD and control subjects (HD 26.08 +/- 11.39, CRF 24.87 +/- 9.07, PD 12.13 +/- 4.51, controls 11.69 +/- 4.02). Furthermore, the phagocytic ability of U937 cells incubated with the various plasma demonstrated an impaired response in the HD and CRF subjects (HD 27.56 +/- 6.67, CRF 30.24 +/- 9.08, PD 36.55 +/- 9.80, controls 40.04 +/- 6.98). These results suggest that continuous blood purification, such as in PD, may have advantages over intermittent therapies in removing uremic apoptotic molecules and potentially maintaining biological function and homeostasis.

Extracorporeal therapies in non-renal disease: treatment of sepsis and the peak concentration hypothesis.

In the setting of intensive care, patients with acute renal failure often present a clinical picture of the systemic inflammatory response syndrome (SIRS). SIRS can be caused by bacterial stimuli or by non-microbiological stimuli that induce a significant inflammatory response. When this response is exaggerated, the patient experiences multiple organ system failure and a condition of sepsis also defined as a systemic malignant inflammation. This is mostly characterized by an invasion of cytokines and other pro-inflammatory mediators into the systemic circulation where major biological effects take place, including vasopermeabilization, hypotension and shock. At the same time, the monocyte of the septic patient seems to be hyporesponsive to inflammatory stimuli to a certain extent. In this condition, the patient faces a situation of hyperinflammation but at the same time of immunodepression expressing a clinical entity defined as counter anti-inflammatory response syndrome. The general picture of the clinical disorder is therefore better characterized by an immunodysregulation than by a simple pro- or anti-inflammatory disorder. Due to the short half-life of cytokines and other mediators spilled over into the circulation, it is extremely difficult to approach the problem at the right moment with the right pharmacological agent. For these reasons, the peak concentration hypothesis suggests that continuous renal replacement therapies, due to their continuity and unspecific capacity of removal, might be beneficial in cutting the peaks of the concentrations of both pro- and anti-inflammatory mediators, restoring a situation of immunohomeostasis. Thus the patient may benefit from a lesser degree of immunodysregulation and he/she may restore a close-to-normal capacity of response to exogenous stimuli.

Longitudinal study of apoptosis in chronic uremic patients.

Uremia is associated with a state of immune dysfunction, increasing infection and malignancy rates. Dysregulation of homeostasis may be directly related to abnormal apoptosis regulation, a process which is crucial for the maintenance of the biologic system. Abnormal apoptosis rates (ARs) have been reported in the literature. We performed a longitudinal study over a 10-week period in three groups of uremic subjects-hemodialysis (HD), peritoneal dialysis (PD), and predialysis chronic renal failure (CRF). Our results showed that ARs were consistent over the observed period. Monocytes extracted from HD and CRF subjects had higher ARs compared to PD and controls (HD: 26.06 +/- 8.82; CRF: 26.96 +/- 12.81; PD: 14.77 +/- 5.87; C: 11.42 +/- 4.60) when placed in culture medium. The plasma of HD and CRF subjects when incubated with U937 cells had a stronger apoptogenic potential compared with PD and controls (HD: 26.08 +/- 11.39; CRF: 24.87 +/- 9.07; PD: 12.13 +/- 4.51; C: 11.69 +/- 4.02). Inflammatory markers (C-reactive protein [CRP], procalcitonin) and cytokines (interleukin [IL]-1beta, IL-2, IL-10) had a generally poor correlation except for tumor necrosis factor (TNF)-alpha (p < 0.001). The phagocytic ability of U937 cells when incubated with the various plasma demonstrated impaired response in the HD and CRF subjects (HD: 27.56 +/- 6.67; CRF: 30.24 +/- 9.08; PD: 36.55 +/- 9.80; C: 40.04 +/- 6.98). These results suggest continuous renal purification, such as in continuous ambulatory peritoneal dialysis (CAPD), may have advantages over intermittent therapies in regulating apoptosis and maintaining biologic function and homeostasis.

Coupled plasma filtration adsorption: rationale, technical development and early clinical experience.

The adjuvant treatment of sepsis remains a major therapeutic challenge. Blood purification is theoretically appealing if the humoral theory of sepsis is accepted as the basis for intervention. In this setting, blood purification would provide a broad-based restoration of humoral homeostasis thereby avoiding both excessive inflammation and counterinflammation. Several techniques of blood purification have been tried or are under active investigation. One of these is the so-called coupled plasma filtration adsorption (CPFA). CPFA is a novel extracorporeal blood purification therapy aimed at nonselectively reducing the circulating levels and activities of both pro- and anti-inflammatory mediators during sepsis and multiorgan failure. In vitro studies have shown CPFA to be effective in binding a broad range of such mediators proving its technical efficacy. Subsequent animal models have shown a beneficial effect on survival in endotoxemia. These studies have provided the necessary technical developments and biologic rationale for initial human studies. Two phase I/IIa clinical studies have now been performed. Both studies have shown that CPFA improves blood pressure and restores immune function in patients with severe sepsis and multiorgan dysfunction. In this article, we will discuss some of the basic principles involved in sorbent technology, and how these may contribute to treatment efficacy, review animal experiments with CPFA and finally discuss the results of recent human studies and their implications.

Mononuclear leukocyte apoptosis in haemodialysis patients: the role of cell thiols and vitamin E.

BACKGROUND: An increased apoptotic rate of peripheral blood mononuclear leukocytes (PBMLs) in haemodialysis (HD) patients has been reported in several studies, but its underlying mechanisms remain poorly understood. Oxidant stress is a well known cause of cell damage, and several lines of evidence suggest that it might influence the induction and signalling steps of mononuclear cell apoptosis through different mechanisms so as to provoke disturbances of the intracellular pool of thiols (SHi). In this study, we investigated the in vitro apoptotic rate and SHi of PBMLs in end-stage renal disease (ESRD) patients on HD or peritoneal dialysis (PD). METHODS: Apoptosis and SHi were evaluated in vitro in PBMLs obtained from 40 ESRD patients (HD, n = 30 and PD, n = 10) and 10 healthy controls. A subgroup of HD patients was also studied before and after 1 month of treatment with a vitamin E-coated dialyser (CL-E). Cell thiols and viability were also assessed in the monocyte-like cell line U937 and PBMLs after incubation in the presence of uraemic plasma with or without supplementation of the antioxidants vitamin E (70 micro M) or N-acetyl-cysteine (NAC) (0.5 mM). RESULTS: After 24 h in culture, the PBMLs of HD patients, but not those of CAPD patients, showed an apoptotic rate twice that of healthy controls and a 40% decrease of SHi levels (P < 0.01 in both). A negative correlation between the apoptotic rate and SHi was observed in both patients and controls (r = 0.648, P < 0.001). Plasma and ultrafiltrate samples from HD patients contained solutes (mainly in the low-middle molecular weight range) able to trigger apoptosis and oxidative stress in U937 cells. The treatment of HD patients with CL-E, as well as the in vitro supplementation of U937 cells with vitamin E or NAC during the exposure to uraemic plasma, decreased the rate of apoptosis and partially restored SHi. CONCLUSIONS: This study showed an association between an increased apoptotic rate and decreased SHi in PBML of HD patients, but not of CAPD patients. These changes are partially due to different pro-apoptogens that accumulate in the plasma and are at least partially prevented by exogenous antioxidants able to restore SHi, such as vitamin E or thiol suppliers.

Noninvasive transcutaneous access flow measurement before and after hemodialysis: impact of hematocrit and blood pressure.

BACKGROUND/AIMS: The dialysis outcome is strongly affected by the function of the vascular access. It has been suggested that access clotting may be related to increased hematocrit (Hct) or excessive ultrafiltration during dialysis. The present study was designed to evaluate the changes of vascular access flow during hemodialysis in 18 end-stage renal disease patients with native arteriovenous fistulas and the possible correlations with Hct and mean arterial pressure (MAP). METHODS: We utilized a noninvasive vascular access flow measurement technique, based on a transcutaneous optical sensor, to evaluate the flow in the access before and after a single hemodialysis session. At the beginning and at the end of the session, the blood flow was measured noninvasively, placing the sensor approximately 2 in from the point of insertion of the arterial needle. At the same time, Hct and MAP were measured directly. All patients were on hemodialysis for more than 3 months. RESULTS: There was a significant increase in Hct, likely due to ultrafiltration and consequent hemoconcentration, from the beginning to the end of the dialysis session. In detail, the Hct increased from 32.6 +/- 1.9 to 35.4 +/- 1.8% (p < 0.001), while the MAP did not present significant variations. The blood flow did not show significant variations, increasing from 780 +/- 312 to 919 +/- 411 ml/min after the session. Because of the stability of the MAP, we could dissociate the effects of the Hct from those of the MAP on blood flow variations. CONCLUSION: Our study suggests that the blood flow in native fistulas is not affected by the acute rise in Hct due to ultrafiltration during hemodialysis. The transcutaneous access flow measurement technique appears to be reliable and accurate, and it could represent an important diagnostic tool.

In vitro removal of therapeutic drugs with a novel adsorbent system.

BACKGROUND/AIMS: Substances in the middle molecular weight range have been shown to play a significant pathogenetic role in as diverse disorders as end-stage renal disease and multiple organ failure. To overcome the limitations in the amount removed by hemofilters, new sorbents with a high biocompatibility are actively being developed. Furthermore, biocompatible sorbents by their nonspecific adsorptive behavior could have great impact on detoxification treatment in exogenous intoxications. We performed an in vitro evaluation of a newly developed highly biocompatible sorbent cartridge (Betasorb((R))), examining its adsorptive capacity concerning therapeutic drugs. METHODS: Uremic blood spiked with a range of therapeutic drugs was recirculated for 2 h in an in vitro hemoperfusion circuit containing a Betasorb device for hemoperfusion. The drug concentrations before and after the passage of the cartridge were measured, and the total amount removed was calculated. RESULTS: The sorbent showed effective removal of glycopeptide antibiotics, digoxin, theophylline, phenobarbital, phenytoin, carbamazepine, and valproic acid. Moderate removal could be demonstrated for tacrolimus and cyclosporine A; aminoglycosides were removed to a small extent only. CONCLUSION: Betasorb hemoperfusion shows a potent adsorptive capacity concerning therapeutic drugs (except aminoglycosides) and could be of major value in the treatment of intoxications. On the other hand, drug monitoring and possible adjustments are necessary during Betasorb hemoperfusion to maintain the therapeutic ranges of the drugs in blood.