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Pyruvate Preserves Neutrophilic Superoxide Production in Acidic, High Glucose‐Enriched Peritoneal Dialysis Solutions
Abstract
To investigate effects of pyruvate (Py)-based peritoneal dialysis solutions (P-PDS) on neutrophilic superoxide (O2-) production against high glucose (HG) concentrations at acidic or physiologic pH value, and explore potential mechanisms.
Human neutrophils were incubated with both dl-lactate (La, 40 mM)-based PDS (L-PDS) and equimolar P-PDS at various pH and HG levels, respectively. Hanks' balanced salt solution (HBSS) served as controls. O2- generation was determined by the reduction of ferricytochrome c.
Acidic pH and high La induced acute and substantial inhibitions of O2- production. HG in both PDS and HBSS resulted in a suppression of O2- in a dose-dependent manner. P-PDS generated near twofold O2- formation of L-PDS counterparts at various pH and HG levels. P-PDS with HG produced significantly more O2- than Py-free HBSS counterparts.
Py in PDS effectively protected neutrophils from HG-induced inhibition of O2- production, even at a physiological pH. The Py cytoprotection may be associated with the preservation of carbohydrate metabolic pathways in addition to its alkalization.
... Increasing evidence suggests that the ketone pyruvic acid (the simplest a-keto acid) may have immunonutritional significance in the modulation of PMN host defence mechanisms and granulocytic immunoregulation because of its relevant role in cellular energetics and metabolism (i.e. as an important source of respiratory cellular fuel or further metabolic precursors). Indeed, in all prokaryotic or eukaryotic cells its carboxylate anion (known as pyruvate) is certainly an important chemical compound in biochemistry and therefore it is no particular surprise that pyruvate not only can be produced by different pathways (i.e. via glycolysis in which one molecule of glucose breaks down into two molecules of pyruvate or reversible transamination reactions, etc.), but also unites several key metabolic processes (Agam and Gutman 1972; Curi et al. 1989, 1988; Fauth et al. 1993 and 1990; Frei et al. 1975; Fuchs et al. 1994; Homem de Bittencourt et al. 1993; Ing et al. 1997; Newsholme et al. 1987; Wu et al. 2005 and 2003). ...
... Thus indirect regulation of arginine, ornithine or aspartate (i.e. via oxalacetate) metabolism (for example used as a substrate for the enzymes of the urea cycle or formation of phosphoserine and serine), the synthesis of @BULLETNO required for PMN activation and ultimately the formation of glutamine, glutamate or a-ketoglutarate metabolism (i.e. used for glutathione, proline, purine and pyrimidine synthesis, export of glutamate in exchange for import of cystine and following conversion to cysteine, synthesis of glucosamines or NAD?, etc.) can all be modulated by pyruvateenriched immunonutrition in PMN (Agam and Gutman 1972; Curi et al. 1989, 1988; Fink 2008; Frei et al. 1975; Fuchs et al. 1994; Engel et al. 2009a, b; Mühling et al. 2010, 2005; Newsholme et al. 1987; Serrano and Curi 1989; Wu et al. 2005, 2003). Nevertheless, the conversion of pyruvate does not just supply important precursors for the above-mentioned metabolic pathways, since it also provides energy-rich molecules such as nicotinamide adenine dinucleotide phosphate (NADPH) or guanosine-5 0 -triphosphate (GTP). ...
... It primarily generates superoxide, a highly reactive free radical, by transferring electrons from NADPH inside the cell across the membrane and coupling these to molecular oxygen. In phagosomes or outside the cell, superoxide can spontaneously form hydrogen peroxide that will undergo further reactions to generate reactive oxygen species (ROS) (Newsholme et al. 1987; Wu et al. 2005, 2003; Zhou and Yu 1998). Superoxide is capable of killing bacteria and fungi by mechanisms that are not yet fully understood. ...
For the first time the immunonutritional role of pyruvate on neutrophils (PMN), free α-keto and amino acid profiles, important reactive oxygen species (ROS) produced [superoxide anion (O(2) (-)), hydrogen peroxide (H(2)O(2))] as well as released myeloperoxidase (MPO) acitivity has been investigated. Exogenous pyruvate significantly increased PMN pyruvate, α-ketoglutarate, asparagine, glutamine, aspartate, glutamate, arginine, citrulline, alanine, glycine and serine in a dose as well as duration of exposure dependent manner. Moreover, increases in O(2) (-) formation, H(2)O(2)-generation and MPO acitivity in parallel with intracellular pyruvate changes have also been detected. Regarding the interesting findings presented here we believe, that pyruvate fulfils considerably the criteria for a potent immunonutritional molecule in the regulation of the PMN dynamic α-keto and amino acid pools. Moreover it also plays an important role in parallel modulation of the granulocyte-dependent innate immune regulation. Although further research is necessary to clarify pyruvate's sole therapeutical role in critically ill patients' immunonutrition, the first scientific successes seem to be very promising.
... Furthermore, early studies documented that pyruvatebased PDS (P-PDS) was much more effective than regular commercial lactate-based PDS (L-PDS) in improving human blood neutrophils' intracellular pH and superoxide generation (79,80). Regarding direct peritoneal resuscitation, recent animal studies also found that P-PDS was significantly advantageous over L-PDS in reversing visceral hypoperfusion, correcting metabolic acidosis, and protecting the intestinal barrier (81)(82)(83). ...
... At present, if pyruvate solutions were compassionately used in severe COVID-19 patients, clinical outcomes might have greatly improved (86,87). In the future, pyruvate-enriched fluids may encompass other medical solutions specifically used for RBC storage, cell salvage, organ preservation, cardioplegia, peritoneal dialysis, priming fluid for cardiopulmonary bypass circuits, and others (24,27,77,80,88). ...
There have been ongoing debates about resuscitation fluids because each of the current fluids has its own disadvantages. The debates essentially reflect an embarrassing clinical status quo that all fluids are not quite ideal in most clinical settings. Therefore, a novel fluid that overcomes the limitations of most fluids is necessary for most patients, particularly diabetic and older patients. Pyruvate is a natural potent antioxidant/nitrosative and anti-inflammatory agent. Exogenous pyruvate as an alkalizer can increase cellular hypoxia and anoxia tolerance with the preservation of classic glycolytic pathways and the reactivation of pyruvate dehydrogenase activity to promote oxidative metabolism and reverse the Warburg effect, robustly preventing and treating hypoxic lactic acidosis, which is one of the fatal complications in critically ill patients. In animal studies and clinical reports, pyruvate has been shown to play a protective role in multi-organ functions, especially the heart, brain, kidney, and intestine, demonstrating a great potential to improve patient survival. Pyruvate-enriched fluids including crystalloids and colloids and oral rehydration solution (ORS) may be ideal due to the unique beneficial properties of pyruvate relative to anions in contemporary existing fluids, such as acetate, bicarbonate, chloride, citrate, lactate, and even malate. Preclinical studies have demonstrated that pyruvate-enriched saline is superior to 0.9% sodium chloride. Moreover, pyruvate-enriched Ringer’s solution is advantageous over lactated Ringer’s solution. Furthermore, pyruvate as a carrier in colloids, such as hydroxyethyl starch 130/0.4, is more beneficial than its commercial counterparts. Similarly, pyruvate-enriched ORS is more favorable than WHO-ORS in organ protection and shock resuscitation. It is critical that attention first be paid to improving abnormal saline with pyruvate for ICU patients. Many clinical trials with a high dose of intravenous or oral pyruvate were conducted over the past half century, and results indicated its effectiveness and safety in humans. The long-term instability of pyruvate aqueous solutions and para-pyruvate cytotoxicity is not a barrier to the pharmaceutical manufacturing of pyruvate-enriched fluids for ICU patients. Clinical trials with sodium pyruvate-enriched solutions are urgently warranted.
... The impact of Pyr on systemic acidosis, however, at present has not been well appreciated [31] , and potential mechanisms whereby Pyr preferably corrected severe acidosis have not been fully elucidated either [6,34] . There are several likely bio-chemical sites on which the metabolism of exogenous Pyr consumes intracellular protons, indicating that Pyr is of particular signifi cance in the pHi modulation [32,[35][36][37] ( fi g. 1 ): ...
... In addition, Pyr might be also a promising buffer to correct uremic acidosis in patients undergoing peritoneal dialysis (PD), which markedly improves the biocompatibility of PD solutions [5,36] . It may effi ciently correct chronic acidotic status in hemodialysis patients as well, which is not satisfactorily treated at present [60] . ...
The review focuses on biochemical metabolisms of conventional buffers and emphasizes advantages of sodium pyruvate (Pyr) in the correction of intracellular acidosis. Exogenous lactate (Lac) as an alternative of natural buffer, bicarbonate, consumes intracellular protons on an equimolar basis, regenerating bicarbonate anions in plasma while the completion of gluconeogenesis and/or oxidation occurs via tricarboxylic-acid cycle in mitochondria mainly in liver and kidney, or heart. The general assumption that Lac is 'metabolized to bicarbonate' in liver to serve as a buffer has been questioned. Pyr as a novel buffer would be superior to conventional ones in the correction of metabolic acidosis. Several likely biochemical mechanisms of Pyr action are discussed. Experimental evidence, in vivo, strongly suggested that Pyr would be particularly efficient in the correction of severe acidemia: type A lactic acidosis, hypercapnia with cardiac arrest, and diabetic and alcoholic ketoacidosis in animal experiments and clinic settings. Because of its multi-cytoprotection, Pyrs not only correct acidosis, but also benefit theunderlying dysfunction of vital organs. In addition, Pyr is also a potential buffer component of dialysis solutions. However, the instability of Pyr in aqueous solutions restricts its clinical applications as a therapeutic agent. Attempts to create a stable Pyr preparation are needed.
... Therefore I do not believe the beneficial effects of pyruvate are a function of energy-substrate availability since the high glucose concentration in non-pyruvate medium would have compensated for the lack of pyruvate-derived energy. It is worth mentioning that high glucose in combination with pyruvate has previously been shown to improve neutrophil cell function(Wu et al. 2003).10.4.5The Concept of "PigmentationMedium" for culture of RPE: should all future RPE culture use RPE-optimized medium? ...
Retinal Pigment Epithelium (RPE) transplantation efforts have been ongoing for three decades . To this day no feasible cure exists for diseases such as age-related macular degeneration (AMD). The key to treatment of AMD is to replenish the RPE. Establishing cells that accurately represent their native tissue is a considerable challenge. RPE cells undergo de-differentiation in culture losing important characteristics after repeated passage. Furthermore, RPE cells are anchorage-dependant and require a substrate for survival. Attempts at replenishing the RPE using suspensions have been met with scepticism due to the high degree of apoptosis. ARPE-19, a human RPE line, retains several phenotypic characteristics of primary RPE although current passages have lost some established features. A variety of polymers with diverse chemistries, specialised coatings, and optimised media were tested to optimally grow ARPE-19 cells. Using information gathered from these experiments, optimal conditions were selected for Human Embryonic Stem Cell (HESC)-derived RPE cells. Cell/substrate composites were transplanted in pigs to validate their efficacy. Differentiation of ARPE-19 cells was enhanced by utilising a superior substrate, polyester filter, together with an optimal growth medium containing pyruvate. HESCderived RPE grown in optimal conditions developed differentiation characteristics identical to native RPE. This was assessed by morphology, immunohistochemical profile, trans-epithelial resistance, electron-microscopy, and growth factor secretion. A higher porosity version of this filter supported growth and differentiation of HESC-RPE and this was chosen as the basis for a transplantation project due to its good permeability. Transplanted HESC-RPE/polyester composites survived surgical delivery in a pig model and were eventually chosen for a phase I clinical trial. Conclusion: This thesis investigated optimal conditions for the human RPE line ARPE- 19. Optimal growth conditions were then applied to HESC-RPE cells which achieved a high level of differentiation. Composites were transplanted in pigs and led to their selection for use in clinical trials.
... 16 Although it is clear that exercise increases lactate concentrations in horses, it remains unknown whether the increased extracellular lactate concentrations associated with strenuous exercise are directly involved in alteration of equine PMN functions. However, there are some reports [17][18][19] that extracellular lactate affects ROS production and phagocytosis of human PMNs and macrophages. Similarly, the synergistic effect of extracellular lactate and pH on ROS production by equine PMNs is not as clear as reported in human PMNs. ...
To evaluate effects of extracellular lactate on viability, shape change, lactate metabolism, and reactive oxygen species (ROS) production in equine polymorphonuclear leukocytes (PMNs).
PMNs isolated from equine venous blood samples.
PMNs were incubated with 0 to 300mM lactate for 30 minutes before each experiment. Viability was assessed via trypan blue exclusion. Shape change was assessed via flow cytometry and light microscopy. Relative quantification of monocarboxylic acid transporter and lactate dehydrogenase lactate dehydrogenase (LDH) isotype mRNAs was performed with a real-time PCR assay. Effects of lactate at a pH of 7.4 to 6.0 on ROS production in response to phorbol 12-myristate 13-acetate, opsonized zymosan, or N-formyl-methionyl-leucyl-phenylalanine was assessed by luminol-dependent chemiluminescence.
Lactate had no effect on viability of PMNs but did alter their size and density. Monocarboxylic acid transporter 1 and lactate dehydrogenase B mRNA values were not altered. Monocarboxylic acid transporter 4 and lactate dehydrogenase A mRNA values were significantly decreased. Lactate incubation of cells significantly decreased PMN-derived luminol-dependent chemiluminescence and induced different sensitivities to stimulants (phorbol 12-myristate 13-acetate, opsonized zymosan, and N-formyl-methionyl-leucyl-phenylalanine). The response ratio to N-formyl-methionyl-leucyl-phenylalanine revealed that PMNs were primed by incubation with up to 50mM lactate, significantly increasing the production of ROS. Incubation with lactate and acidic pH caused a synergistic effect on ROS production.
Extracellular lactate potentially has a direct effect on the capacity to produce ROS by equine PMNs, which may be associated with alterations in innate immune functions within a short period after high-intensity exercise.
... Despite the greater complexity, carboxylic acid salts of the dialysate appear to be just as integral to the toxicity to HPMC and neutrophils as they were to bacteria. While lactate-based solutions buffered with bicarbonate modulate the levels of putative markers of peritoneal membrane integrity and inflammation (70), the substitution of pyruvate as a base to dialysate appears to neutralize the adverse effects of dialysate on both HPMC (71) and neutrophils (72)(73)(74). The authors attribute the findings to the Crabtree Effect, where high glucose concentrations inhibit respiratory metabolism and produce ethanol under aerobic conditions (as opposed to the normal Pasteur Effect, where the product of glycolysis, pyruvate, is metabolized into ethanol only in the presence of low oxygen concentrations). ...
Although it was first described over a quarter of a century ago, the mechanisms behind the antimicrobial activity of fresh peritoneal dialysate have been poorly understood. Recent insight into the biochemistry appears to suggest that at least part of the effect resides in the salts of the carboxylic acids. An understanding of the metabolic pathways of both sensitive and resistant organisms has not only led to an understanding of the mechanisms of the antimicrobial effect, but also may have provided the insight for future studies to reduce toxicity to the peritoneal membrane. While our knowledge base in this area is still evolving, an improved understanding of the biochemical basis of both the antibacterial effect and toxicity of the salts of carboxylic acids in peritoneal dialysate can only prove useful.
... Exposure of peripheral blood neutrophils to an acidic pyruvate solution caused less decrease in intracellular pH than a similar lactate-buffered fluid (33). Also, a better preservation of neutrophilic superoxide production and nitric oxide generation (34,35) has been described. A study in peritoneal macrophages showed similar results (36). ...
Conventional lactate-buffered peritoneal dialysis (PD) fluids containing glucose and glucose degradation products are believed to contribute to the development of fibrosis and angiogenesis in the dialyzed peritoneum. To reduce potential negative effects of lactate, pyruvate was substituted as a buffer and its effects on peritoneal pathological alterations were studied in a chronic peritoneal exposure model in the rat.
20 Wistar rats were infused intraperitoneally with pyruvate-buffered (n = 9) or lactate-buffered PD fluid. After 20 weeks of daily infusion, peritoneal function was assessed. In omental peritoneal tissue, the number of blood vessels was analyzed following alpha-smooth muscle actin staining. The degree of fibrosis was quantitated in Picro Sirius Red-stained sections and by assessment of the hydroxyproline content. Plasma lactate/pyruvate and betahydroxybutyrate/acetoacetate (BBA/AA) ratios were determined. Plasma and dialysate vascular endothelial growth factor (VEGF) levels were quantitated by ELISA.
The mass transfer area coefficient of creatinine was higher and the dialysate-to-plasma ratio of sodium was lower in pyruvate-treated animals compared to the lactate-treated group (0.11 vs 0.05 mL/min, p < 0.05, and 78% vs 89%, p < 0.05). The BBA/AA ratio tended to be lower in the pyruvate animals (p = 0.07). The number of blood vessels was lower in pyruvate-treated animals (16 vs 37 per field, p < 0.001). Total surface area, luminal area, and wall/total area of the vessels were larger in the pyruvate group. The degree of fibrosis was lower in intersegmental and perivascular areas of pyruvate-exposed animals. Effluent VEGF was higher in the pyruvate group.
Replacement of lactate by pyruvate resulted in changes in peritoneal solute transport, accompanied by a reduction in both peritoneal membrane angiogenesis and fibrosis, suggesting potentially novel mechanisms to reduce glucose-driven alterations to the peritoneal membrane in PD patients.
We applied the Revised Soil Loss Equation (RUSLE) to assess levels of soil loss in a Geographic Information System (GIS). In this study, we used the k-NN technique to estimate vegetation cover by integrating Landsat ETM+ scenes and field data with optimal parameters. We evaluated the root mean square errors and significance of biases at the pixel level in order to determine the optimal parameters. The accuracy of vegetation cover estimation by the k-NN technique was compared to that predicted by a regression function using Landsat ETM+ bands and field measurements as well as to that predicted by the Normalized Difference Vegetation Index (NDVI). We used a regression equation to calculate the cover management (C) factor of the RUSLE from vegetation cover data. On the basis of the quantitative model of soil erosion, we explored the relationship between soil loss and its influencing factors, and identified areas at high erosion risk. The results showed that the k-NN method can predict vegetation cover more accurately for image pixels at the landscape level than can the other two methods examined in this study. Of those factors, the C-factor is one of the most important affecting soil erosion in the region. Scenarios with different vegetation cover on high-risk areas showed that greater vegetation cover can considerably reduce the loss of soil erosion. The k-NN technique provides a new method to estimate the C-factor for RUSLE erosion mapping. The quantitative model of different vegetation cover scenarios provides information on how vegetation restoration could reduce erosion.
Hypotension is an important complication of hemodialysis. The pathogenesis of this complication remains unclear. The role of chronic inflammation in chronic dialysis-associated hypotension has not been investigated. A total of 38 dialysis patients with chronic hypotension were identified. Their demographic and biochemical data, inflammatory markers (high sensitivity C-reactive protein [hs-CRP] and interleukin-6 [IL-6]), hepatocyte growth factor (HGF), leptin, and adiponectin levels were measured and compared with those of another 87 nonhypotensive dialysis patients. No between-group differences in their clinical features, underlying renal disease were found. Levels of serum albumin, leptin, adiponectin, and HGF were similar between the two groups. The serum albumin levels were inversely correlated with hs-CRP and IL-6. Adiponectin was negatively correlated with hs-CRP and leptin. HGF showed a positive relation with hs-CRP. No association was found between adiponectin and HGF. Therefore, chronic inflammation is prevalent in the dialysis population, and serum HGF level is associated with inflammation but not with chronic dialysis hypotension.
To investigate the effects of pyruvate (Pyr)-based peritoneal dialysis solutions (P-PDS) on neutrophilic nitric oxide (NO) generation, we incubated human peripheral neutrophils in dL-lactate (Lac, 40 mM)-based PDS and equimolar P-PDS, and Hanks' balanced salt solution at various pH and high glucose (HG) levels, respectively. The production of NO in various test solutions was determined based on the Griess reaction. Acidic pH, high Lac, and HG induced an acute and substantial inhibition of neutrophilic NO, whereas Pyr in PDS significantly improved the NO generation in both acidic pH and physiological pH, and also in HG conditions. The Pyr protection may be associated with the improvement of glucose metabolic pathways in addition to its alkalization.
The life expectancy of patients with chronic renal failure who are dependent on dialysis is very poor. This study was undertaken to determine time-related outcomes in dialysis patients requiring cardiac valve replacement.
From 1994 to 2001, 29 end-stage renal disease (ESRD) patients on hemodialysis (HD) program underwent 30 valve replacement operations: 29 received mechanical valves (97%), and one received bioprosthetic valves. The sites of valve replacement were 11 aortic (36.7%), 18 mitral (60%), and one both aortic and mitral (3.3%). Mean age was 42.46 +/- 14.26 years (range 17-75 years). Follow-up was completed in 28 patients (96.5%).
Early postoperative mortality (in the first 30 days) was 3.4% (n = 1). The overall estimated Kaplan-Meier survival was 56.7% at 36 months, 46.7% at 60 months, and 43.3% at 96 months. HD program was discontinued for two patients after renal transplantation in the follow-up period. All patients, except the one with bioprosthesis, used warfarin sodium for anticoagulation and none of them had bleeding. One of the patients had a major cerebrovascular accident (CVA) and another one had a minor CVA at the follow-up (6.7%).
Life quality is better and life expectancy is longer after valve replacement in ESRD patients who have valvular disease. Also, longer life expectancy increases the probability for finding donors for kidney transplantation.
Cardiovascular disease is the major cause of mortality in maintenance hemodialysis patients. Left ventricular dysfunction is present in approximately 80% of these patients and is highly predictive of future ischemic heart disease, cardiac failure, and death. Anemia has been identified as one of several risk factors responsible for cardiac complications. The treatment of renal anemia with recombinant human erythropoietin (rHuEpo) and consequent improvement of cardiac performance may reverse pathological changes in left ventricular geometry. In this study, the acute and chronic effects of rHuEpo administration on 24-hour ambulatory blood pressure recordings and echocardiographic parameters in 30 rHuEpo-naïve maintenance hemodialysis patients were examined. Twenty-four-hour ambulatory blood pressure monitoring was performed prior to and after 1 week and 6 months of rHuEpo administration. The patients underwent echocardiographic examination prior to and after 6 months of rHuEpo administration. One week treatment with rHuEpo did not cause any significant change in 24-hour ambulatory blood pressure recordings. After 6 months of therapy, serum hemoglobin levels increased from 8.8 +/- 0.66 g/dL to 10.8 +/- 0.70 g/dL (P < 0.05). Echocardiographic examination revealed elevation in ejection fraction (62.26 +/- 6.84% vs. 69.90 +/- 8.98%, P < 0.05) with reductions in fractional shortening (36.70 +/- 4.96% vs. 35.96 +/- 6.32%, P < 0.05), interventricular septum thickness (1.21 +/- 0.16 vs. 1.00 +/- 0.16 cm, P < 0.05), and left ventricular mass index (148.2 +/- 46.5 g/m2 vs. 93.6 +/- 17.2 g/m2, P < 0.05). Doppler echocardiography and tissue Doppler imaging provided additional information in comparison with conventional echocardiography. Before treatment, mitral flow E wave (E, 0.64 +/- 0.27 vs. 0.82 +/- 0.17 cm/s), mitral flow A wave (A, 0.80 +/- 0.21 vs. 0.70 +/- 0.21 cm/s), early diastolic velocity of lateral wall (Lateral E', 11.2 +/- 2.8 vs. 12.4 +/- 2.3 cm/s), late diastolic velocity of lateral wall (Lateral A', 6.7 +/- 2.5 vs. 7.8 +/- 2.1 cm/s), early diastolic velocity of septal wall (Septal E', 9.7 +/- 2.9 vs. 11.3 +/- 1.1 cm/s), and late diastolic velocity of septal wall (Septal A', 6.4 +/- 2.1 vs. 7.8 +/- 2.0 cm/s) were significantly lower in patients than in the controls. Patients and controls have similar deceleration time of mitral flow E wave (E Dec, 186 +/- 57.8 vs. 192 +/- 62.4 ms), isovolumic left ventricular relaxation time (IVRT, 111.9 +/- 30.7 vs. 91.1 +/- 32 ms), systolic velocity of lateral wall (Lateral S', 7.8 +/- 2.3 vs. 8.1 +/- 2.0 cm/s), and systolic velocity of septal wall (Septal S', 7.5 +/- 1.9 vs. 7.7 +/- 1.4 cm/s) values. Therapy with rHuEpo did not cause significant changes in E (0.64 +/- 0.27 vs. 0.76 +/- 0.29 cm/s), A (0.80 +/- 0.21 vs. 0.79 +/- 0.23 cm/s), E Dec (186 +/- 57.8 vs. 165.8 +/- 60.1 ms), IVRT (111.9 +/- 30.7 vs. 101.6 +/- 36.2 ms), Lateral E' (11.2 +/- 2.8 vs. 11.5 +/- 4.4 cm/s), Lateral A' (6.7 +/- 2.5 vs. 7.4 +/- 2.1 cm/s), Lateral S' (7.8 +/- 2.3 vs. 8.1 +/- 2.0 cm/s), Septal E' (9.7 +/- 2.9 vs. 10.0 +/- 1.1 cm/s), Septal A' (6.4 +/- 2.1 vs. 6.6 +/- 2.0 cm/s), and Septal S' (7.5 +/- 1.9 vs. 7.9 +/- 1.4 cm/s) indicating persistence of diastolic dysfunction. In 6 months time, 24-hour ambulatory blood pressure recordings, however, tended to be higher (systolic: 125.16 +/- 21.02 mm Hg vs. 134.36 +/- 23.98 mm Hg; diastolic: 77.40 +/- 14.47 mm Hg vs. 83.26 +/- 14.89 mm Hg, P < 0.05). Correction of anemia with rHuEpo results in the elevation of blood pressure and reduction in left ventricular mass index. Myocardial contraction and relaxation velocities did not improve following regression of left ventricular hypertrophy, suggesting the persistance of diastolic dysfunction. Doppler echocardiography with tissue Doppler imaging reflects the real situation of diastolic function in patients on maintenance hemodialysis.
Commercial peritoneal dialysis solution (CDS) is known to have a detrimental effect on the capacity of peritoneal macrophages (PM phi) to kill bacteria and produce acute phase cytokines. This cytotoxic effect is largely caused by the low pH of CDS. Because the cytoplasmic pH (pHi) is an important determinant of cellular function, the effect of CDS on the pHi of PM phi from continuous ambulatory peritoneal dialysis patients was studied. The pHi of PM phi was measured fluorometrically in N-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES)-buffered salt solution (HBSS) or CDS at pH values of 5.3, 6.5, and 7.0, values that represent the pH existing in dialysate during the first 30 min of dwell time. For any given pH of the experimental medium, the pHi was always more acidic in CDS than in HBSS. When PM phi were incubated with a lactate-containing HBSS, a cellular acidification was observed that was similar to that attained by exposure to CDS at the same pH. This supports the hypothesis that the decrease in pHi was due to the influx of lactic acid from the CDS into the PM phi. In order to demonstrate a causal association between the CDS-induced cellular acidification and a defect in phagocytosis and cytokine production, these functions were studied after pHi clamping by means of K+/nigericin. It was found that clamping pHi to values below 6.5 led to a markedly reduced tumor necrosis factor-alpha production and phagocytosis. However, at values of pHi > 6.5, these functions were normal. (ABSTRACT TRUNCATED AT 250 WORDS)
Acidic (pH 5.2) incubation mixtures containing pyruvate-based or lactate-based peritoneal dialysis solutions (PDSN's) induced comparable degrees of intracellular acidosis in neutrophils. However, addition of an acidic (pH 5.2), pyruvate-based PDSN to a pH-7.4, neutrophil/phosphate-buffered saline mixture brought about higher extracellular and intracellular (neutrophil) pH values when compared to the introduction of an equally acidic, lactate-based PDSN. This poor ability of acidic (pH 5.0-5.5), pyruvate-based PDSN's to resist alkalinizing influences is the cause for the above higher pH values. The higher intracellular pH levels so obtained may be a reason behind why acidic, pyruvate-based PDSN's appear to be more biocompatible than their equally acidic, lactate-based counterparts.
An axial-flow ventricular assist device (VAD) under development at the authors' facility is intended for use as a long-term implantable device. At high speeds axial-flow VADs can collapse the native ventricle and damage the heart muscle, lung tissue, and blood. A prototype algorithm was developed to maintain physiologic perfusion to the vital organs while preventing ventricular collapse, through analysis of the electrical current waveform of the motor. The premise of the control algorithm is that the hemodynamics of the patient are reflected in the shape of this waveform. This approach is intended to eliminate the need for invasive sensors, thus effectively using the pump itself as a transducer. The control algorithm regulates the speed of the pump by comparing the motor-current waveform with reference waveforms using a matched filter. The matched filter was evaluated by its classification and differentiation performance. Thus far, the authors have been able to classify the waveforms into one of the four physiologic regions (below, within, or above the optimal range, and ventricular suction) with over 90% reliability. Ongoing work is directed toward improving the detection of ventricular suction, as this condition must be strictly avoided.
Accelerated atherosclerosis resulting in an abnormally high incidence of coronary and cerebrovascular occlusive accidents has been repeatedly reported in dialysis patients, but incidence and risk factors of such complications in chronic renal failure (CRF) predialysis patients are debated.
We prospectively assessed the incidence of first myocardial and cerebral infarction episodes in a cohort of 147 CRF patients (99 male) followed from January 1985 to December 1994. Relevant clinical and laboratory risk factors for atherogenesis were determined at yearly intervals. They included blood pressure, smoking, blood lipids, fibrinogen, and homocysteine which were compared in patients with (CVA+) or without (CVA-) occurrence of cardiovascular (CV) atherosclerotic accidents.
Incidence of CV accidents was nearly three times higher in CRF patients than in the French general population in both genders. In particular, incidence of myocardial infarction in male patients aged 45-55, 55-65 and > 65 years was 7.6, 18.2, and 27.8/1000 patient-years, respectively, compared to 3.4, 8.9, and 10.4/1000 subject-years in the general population. Although age and degree of renal failure at onset of CV events or at end of follow-up did not differ between CVA+ and CVA- groups, cigarette smoking (24.5 [SD 24.3] vs 8.2 [14.7] pack-years, P < 0.0001) and systolic blood pressure (159 [19] vs 148 [19] mmHg, P < 0.001) were markedly higher in CVA+ patients. Similarly, mean plasma HDL-cholesterol was lower, whereas LDL-cholesterol, triglycerides, apoB, Lp(a), fibrinogen, and homocysteine levels all were significantly higher in CVA+ than in CVA- patients. Multivariate Cox analysis identified cigarette smoking, systolic pressure, HDL cholesterol, and fibrinogen as independent risk factors for developing CV accidents.
Incidence of atherosclerotic CV complications is abnormally high in predialysis CRF patients, suggesting that the uraemic state per se is associated with atherogenesis. As several of the identified clinical and metabolic risk factors for such accidents are potentially remediable by specific therapeutic interventions, prophylactic measures should be initiated long before start of renal replacement therapy.
Pyruvate improves cellular and organ function during hypoxia and ischemia and stabilizes the NADH redox state and cytosolic ATP phosphorylation potential. In this in vivo study, we evaluated the effects of intravenous pyruvate on cardiovascular and neocortical function, indexes of the cytosolic redox state (lactate/pyruvate ratio, L/P) and cellular energy state (adenosine and degradative products hypoxanthine and inosine, ADO + HX + Ino) during controlled arterial hemorrhage (40 mmHg) in sedated swine (45 kg). Na+ pyruvate was infused 1 h before (1 g. kg(-1). h(-1)) and 2 h during (0.5 g. kg(-1). h(-1)) hemorrhage to attain arterial pyruvate levels of 6 mM. Volume (0.9% NaCl) and osmotic (10% NaCl) effects were matched in controls. Time to peak hemorrhage (57 min) and peak hemorrhage volume (43 ml/kg) were similar in all groups. The volume and osmotic groups experienced spontaneous cardiovascular decompensation between 60 and 90 min, with an average time until death of 82.7 +/- 5.5 and 74.8 +/- 8.2 min. In contrast, survival in the pyruvate group was 151.2 +/- 10.0 min (P < 0.001). During hemorrhage, the pyruvate group had better cardiovascular and cerebrovascular function with significantly higher systemic and cerebral oxygen consumption and less attenuation of the amplitude and frequency of the electrocorticogram. In addition, pyruvate prevented metabolic acidosis and stabilized the L/P. Pyruvate slowed the rise in neocortical microdialysis levels of ADO + HX + Ino, and prevented the net efflux of ADO + HX + Ino into the sagittal sinus. The findings reveal considerable metabolic and functional enhancement by pyruvate during severe hemorrhagic shock with a 75-min delay in spontaneous cardiovascular decompensation and death.
The successful development of peritoneal dialysis (PD) during the last two decades has been made possible by using well-established glucose-based solutions with lactate as buffer. On the other hand, awareness has been increasing about the potentially negative effects of the high concentrations of glucose and lactate, and the low pH of conventional PD solutions. This awareness has prompted an intensive effort to search for and test alternative solutions.
As a result, three new, more biocompatible solutions— containing either less glucose or less lactate—are available. Amino acid–based solution uses amino acids instead of glucose as the osmotic agent; it is indicated for treatment of malnutrition. The higher pH and absence of glucose in this solution may prevent alterations of the peritoneal membrane caused by acidity and high glucose concentrations. Bicarbonate/lactate–buffered solution contains a physiologic concentration of bicarbonate and a reduced concentration of lactate; it also has a physiologic pH and markedly reduced levels of glucose degradation products (GDPs). Icodextrin-based solution contains icodextrin as the osmotic agent; it is indicated for long dwells, delivering sustained ultrafiltration for more than 16 hours. This iso-osmolar glucose-free solution may reduce peritoneal membrane alterations caused by glucose or the hyperosmolality (or both) of conventional solutions.
Clinical experience of the new solutions is now extensive, and their efficacy and safety are well documented. It therefore seems appropriate to state that we have entered a new era of PD therapy. Each of the new solutions may be less damaging to the peritoneal membrane than conventional solution. In addition, they permit better management of malnutrition and fluid status, and may thus help to improve PD patient survival.
Although the effects of each of these new solutions have been well described, clinical documentation of the combined use of these new biocompatible PD solutions is still insufficient. However, the results of studies are expected, during the coming years, to support the combined use of the new solutions as the preferred standard practice for PD.
Pyruvate, a metabolic product of glycolysis and an oxidizable fuel in myocardium, increases cardiac mechanical performance and energy reserves, especially when supplied at supraphysiological concentrations. The inotropic effects of pyruvate are most impressive in hearts that have been reversibly injured (stunned) by ischemia/reperfusion stress. Glucose appears to be an essential co-substrate for pyruvate's salutary effects in stunned hearts, but other fuels including lactate, acetate, fatty acids, and ketone bodies produce little or no improvement in postischemic function over glucose alone, In contrast to pharmacological inotropism by catecholamines, metabolic inotropism by pyruvate increases cardiac energy reserves and bolsters the endogenous glutathione antioxidant system. Pyruvate enhancement of cardiac function may result from one or more of the following mechanisms: increased cytosolic ATP phosphorylation potential and Gibbs free energy of ATP hydrolysis, enhanced sarcoplasmic reticular calcium ion uptake and release, decreased cytosolic inorganic phosphate concentration, oxyradical scavenging via direct neutralization of peroxides and/or enhancement of the intracellular glutathione/NADPH antioxidant system, and/or closure of mitochondrial permeability transition pores. This review aims to summarize evidence for each of these mechanisms and to consider the potential utility of pyruvate as a therapeutic intervention for clinical management of cardiac insufficiency.
When a continuous- flow artificial heart (CFAH) is installed in the bypass of a pulsating natural heart, the motor current shows pulsatility, which may be dependent on the assisting status. This hypothesis prompted us to investigate the basic characteristics of the pulsatility of the motor current with an in vitro mock circuit. In this study, we used a specially devised mock circuit consisting of a sac-type pulsatile pump, three reservoirs, and our mixed flow pump (MFP) as a CFAH. The motor current waveform was monitored. The pump speed of the MFP was changed from 2000 rpm to 5000 rpm. We calculated the index of motor current amplitude (ICA), which was obtained, by dividing the amplitude of the motor current by the simultaneous mean value. The ICA plotted against the pump speed (ICA-pump speed relationship) showed several characteristic points: the t-i point, the PR0.7 point, the PR0.5 point, and the maxQ point. The t-i points strongly corresponded to the turning point from partial to total left heart assistance. When the contractility, afterload, and preload were changed, the pump flow rate at each point changed, depending on the preload like Starling's law. These data suggest that the assisting status of a CFAH could be estimated by detecting the characteristic points of the ICA-pump speed relationship.
We evaluated our novel method of controlling a continuous flow artificial heart. This method employs the detection of the total-assist and sucking points by means of pump pulsatility. Acute animal experiments were carried, out using beagle dogs and our mixed flow pump. The pump was installed as the left ventricle-descending aorta bypass (LVAD: n = 8) or the right atrium-pulmonary artery bypass (RVAD: n=5) through left thoracotomy. Hemodynamic parameters, pump flow rate, and motor current were monitored. To estimate the pump's pulsatility without any specific sensor, we calculated the index of current amplitude (ICA), which was obtained by dividing the amplitude of the motor current waveform by the simultaneous mean value. In the LVAD, the ICA plotted against the pump speed had a peak point (t-point) which corresponded highly with the turning point from partial to total assistance. The ICA also had a trough (s-point) which in most cases corresponded with the beginning point of severe sucking. Among preload (LVEDP), afterload (mAoP), and contractility (max LV dP/dt), only preload significantly influenced the pump flow rate at the t-point. In the RVAD, the ICA had the s-point but showed no t-point. However the pump assist flow at the s-point was larger than left heart output. These data in the LVAD indicated that the control of the pump speed towards the t-point was preload dependent, allowing us to simulate Starling's law of the natural heart. Control of RVAD by detecting the sucking phenomenon only was considered inappropriate in light of excess assist flow.
Background— Application of pyruvate was shown to improve contractile function in isolated animal myocardium and hemodynamics in patients with congestive heart failure. We assessed the influence of pyruvate on systolic and diastolic myocardial function and its subcellular mode of action in isolated myocardium from end-stage failing human hearts.
Methods and Results— In muscle strip preparations, concentration-dependent effects of pyruvate on developed and diastolic force (n=6), aequorin light emission reflecting intracellular Ca²⁺ transients (n=6), and rapid cooling contractures reflecting sarcoplasmic reticulum (SR) Ca²⁺ content (n=11) were measured. Pyruvate resulted in a concentration-dependent increase in developed force and a decrease in diastolic force, with a maximum effect of 155% and 21%, respectively, at 20 mmol/L pyruvate (P<0.05). This was associated with a dose-dependent prolongation of time to peak tension and relaxation time. Pyruvate increased rapid cooling contractures by 51% and aequorin light signals by 85% (at 15 and 20 mmol/L; P<0.05). This indicates increased SR Ca²⁺ content and increased intracellular Ca²⁺ transients. The inotropic effect of pyruvate was still present after elimination of SR Ca²⁺ storage function with 10 μmol/L cyclopiazonic acid and 1 μmol/L ryanodine (n=8). Pyruvate significantly increased intracellular pH from 7.31±0.03 to 7.40±0.04 by BCECF fluorescence (n=6).
Conclusions— The present findings indicate that pyruvate improves contractile performance of failing human myocardium by increasing intracellular Ca²⁺ transients as well as myofilament Ca²⁺ sensitivity. The former seem to result from increased SR Ca²⁺ accumulation and release, the latter from increased intracellular pH.
Exposure of human neutrophils to a conventional, acidic, lactate-containing peritoneal dialysis solution (PDS) resulted in the development of a prompt and substantial intracellular acidosis. It is possible that this intracellular acidosis contributes to cellular dysfunction.
Direct investigation of the polyol pathway is rarely possible in studies of human diabetes. A spectrophotometric assay has been developed for the measurement of aldose reductase and sorbitol dehydrogenase activity in the neutrophil. Neutrophil aldose reductase activity was increased in patients with Type 1 diabetes with complications (median 40 (interquartile range 28-48) u, where 1 unit of enzyme activity = nmol NADPH min-1 10(8)-cells-1) compared with those without complications (20 (16-36) u, p less than 0.01) and normal control subjects (20 (8-36) u, p less than 0.01). In Type 2 diabetes, patients with complications also had higher aldose reductase activity (40 (28-52) u) than those without complications (24 (16-36) u, p less than 0.01). There were no differences between patients without complications and normal control subjects. Sorbitol dehydrogenase activity was decreased in diabetic patients (p less than 0.02) but not significantly different between diabetic patients with and without complications.
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The pH of conventional peritoneal dialysis solution is normally in the range of 5.0 to 5.5, because acid has been added during the manufacturing process to prevent caramelization of dextrose during sterilization. We studied the effects of normalizing the pH of conventional peritoneal dialysis solution on superoxide production by normal human neutrophils. At a pH of 6.0, superoxide generation was 4.07±2.56 (SD) nanomoles per million cells. With normalization of pH to 7.4, superoxide production was 19.3± 7.3 (p < 0.001).
The results suggest that the unphysiologic acidity of conventional peritoneal dialysis solution has deleterious consequences on neutrophil superoxide formation.
We related risk factors, cardiovascular symptoms, and coronary status to the extent of extracranial carotid atherosclerosis as measured by B-mode ultrasonography in 376 volunteers hospitalized for elective coronary angiography. In a first analysis, we correlated risk factors and cardiovascular symptoms with carotid atherosclerosis. Univariate analysis showed that relations between many continuous risk factors and carotid atherosclerosis were graded and consistent for men and women. Multivariate analysis identified 6 significant variables (age, hypertension, pack-years smoked, and inversely, plasma concentrations of high density lipoprotein cholesterol and uric acid, and Framingham Type A score) that together accounted for 35% of the variability in extent of carotid atherosclerosis. In a second multivariate analysis, addition of coronary status (presence or absence of coronary stenosis as evaluated by coronary angiography) to the roster of candidate independent variables produced a new equation that accounted for an additional 5% of the variability in carotid atherosclerosis extent. Although much of the variability in extent of carotid atherosclerosis remains unexplained, these data define an association between coronary and carotid atherosclerosis that depends partly on shared exposure of both arteries to the same risk factors. They are also consistent with the concept that as yet undiscovered risk factors and/or genetic (e.g., arterial wall) factors common to both arterial beds also contribute to the relation between coronary and carotid atherosclerosis in human beings.
The incidences of cerebral hemorrhage (CH), cerebral infarction (CI) and subarachnoid hemorrhage (SAH) were examined retrospectively in patients with chronic renal failure on maintenance hemodialysis, followed for 13 years in our 26 satellite dialysis centers. During 10,364 patient-years of experience (PYE), CH developed in 66, CI in 16, SAH in 3 and unclassified stroke in 5 cases. The incidence was 637 per 10(5) PYE for CH and 154 for CI, the former being approximately 5 times and the latter one third of the incidence of CH or CI in the general population in Japan. Forty-six percent of fatal CH cases died within 24 hours and 73% within 3 days after the onset, while 13% of CI deaths died within 24 hours and 26% within 3 days. These data suggest that factors such as the regular use of heparin as an anticoagulant in hemodialysis patients or other inherent factors in these patients may increase vulnerability to CH and decrease the probability of CI.
Control of hypertension, labile or fixed, systolic or diastolic, at any age, in either sex appears to be central to prevention of atherothrombotic brain infarction (ABI). Prospectively, hypertension proved the most common and potent precursor of ABI's. Its contribution was direct and could not be attributed to factors related both to stroke and hypertension. Asymptomatic, causal "hypertension" was associated with a risk of ABI about four times that of normotensives. The probability of occurrence of an ABI was predicted no better with both blood pressure measurements or the mean arterial pressure than with systolic alone. Since there was no diminishing impact of systolic pressure with advancing age, the concept that systolic elevations are, even in the aged, innocuous is premature. Comparing normotensives and hypertensives in each sex, women did not tolerate hypertension better than men.
We sought to determine whether artherosclerosis may be accelerated in uremic patients on maintenance hemodialysis and investigated the risk factors for carotid and femoral atherosclerosis in such patients. High-resolution B-mode ultrasonography was used to determine the intima-media thickness (IMT) of the carotid and femoral arteries in 199 hemodialysis patients and 81 age-matched healthy controls subjects. The IMT values of the carotid and femoral arteries in the hemodialysis patients were significantly higher than in age-matched control subjects in most age groups. The IMT values of the carotid or femoral artery were significantly correlated with age in both the hemodialysis patients and the control subjects. There was a significant relationship between the IMT values of the two arteries in the hemodialysis patients (r = 0.418, P = 0.0001) and in the control subjects (r = 0.321, P = 0.0037). Multiple regression analysis showed that age, cigarette smoking, and uremic state were independent risk factors for atherosclerosis of both arteries in the patients and the control subjects (R2 = 0.174, P < 0.0001; R2 = 0.205, P < 0.0001, respectively). In the hemodialysis patients, the independent risk factors associated with the extent of the IMT of the carotid artery were age, cigarette smoking, and serum phosphorus level (R2 = 0.230, P < 0.0001), while those associated with the extent of the IMT of the femoral artery were age, cigarette-smoking, and serum m-PTH level (R2 = 0.230, P < 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)
A new peritoneal dialysate containing pyruvate anions was developed in order to avoid cytotoxic effect of conventional lactate-based dialysate. The dialysate has a final pH of 5.4 to 5.6 and is composed of 1.36-3.86% glucose-monohydrate; 132 mmol/l sodium; 1.75 mmol/l calcium; 0.75 mmol/l magnesium; 102 mmol/l chloride and 35 mmol/l pyruvate. For cytotoxicity testing peritoneal macrophages, and mesothelial cells (MC) were exposed to conventional lactate dialysate, and pyruvate dialysate. We investigated the O2- generation and cytokine synthesis after endotoxin stimulation in peritoneal macrophages and the proliferation of mesothelial cells of cultured human MC. After exposure to lactate dialysate O2- generation and cytokine synthesis in peritoneal macrophages and proliferation of mesothelial cells were inhibited when compared to solution containing pyruvate and the control solution. After preincubation with 3.86% glucose containing solutions, all negative effects became even more pronounced in the lactate group whereas after pre-exposure to pyruvate containing solution the toxic effects were absent. These results suggest that the acute toxic effects of commercially available peritoneal dialysates can be avoided by the use of sodium pyruvate instead of sodium lactate.
These experiments were undertaken to assess the role of sorbitol dehydrogenase in mediating sorbitol pathway-linked neural and vascular dysfunction in rats with streptozocin-induced diabetes. 2-methyl-4-[N,N-dimethylsulfamoyl-piperazino]-pyrimidine (S-0773), a putative inhibitor of sorbitol dehydrogenase, was given in the drinking water to control and diabetic rats. After 5 weeks of diabetes, glycosylated hemoglobin levels were increased twofold and were unaffected by S-0773. Sorbitol levels in diabetic rats were increased 11- to 14-fold in ocular tissues and sciatic nerve; S-0773 increased sorbitol levels another 4-fold or more in these same tissues but had much smaller effects in other tissues. Diabetes-associated increases in fructose levels and lactate:pyruvate ratios in retina and in sciatic nerve were markedly attenuated by S-0773. S-0773 also attenuated, but did not completely normalize, impaired caudal nerve conduction and vascular dysfunction in ocular tissues, sciatic nerve, and aorta in diabetic rats. These observations, together with other evidence, suggest that sorbitol pathway-linked vascular dysfunction (in ocular tissues, peripheral nerve, and aorta) and electrophysiological dysfunction (in peripheral nerve) induced by diabetes are more closely linked to increased oxidation of sorbitol to fructose than to putative osmotic effects of elevated sorbitol levels or redox and metabolic imbalances associated with reduction of glucose to sorbitol by aldose reductase.
The substrate and inhibitor specificity of the lactic acid (Lac) transport system of human neutrophils was investigated. The ability of a variety of compounds to inhibit the influx of [14C]lactate, presumably reflecting competition by substrate analogues for binding at the external translocation site, was taken as an index of affinity for the Lac carrier. pH-state techniques were utilized to assess transportability. Results indicate a relatively low order of selectivity, the neutrophil H+(+)lactate- cotransport system demonstrating a broad acceptance of short-chain unsubstituted and substituted alkyl monocarboxylates as well as aromatic monocarboxylates. There was a slight preference for oxo, Cl, and OH substituents over other groups at the two-position of short chain alkyl fatty acids: all were readily transported across the plasma membrane at rates approaching that of L-lactate itself. Aromatic acids were not transported inward by the carrier although these compounds did permeate via simple nonionic diffusion. The neutrophil Lac carrier can be blocked by a number of cyanocinnamate derivatives, the classical inhibitors of monocarboxylate transport in mitochondria, and by dithiol compounds and sulfhydryl-reactive agents. This constellation of biochemical properties is similar to the features that characterize other well described H+(+)lactate- cotransport systems in red blood cells, Ehrlich ascites tumor cells, hepatocytes, and cardiac sarcolemmal vesicles, although significant differences exist when comparisons are made to the Na(+)-dependent lactate transporter of the kidney proximal tubule.
Studies have been conducted to assess the possible preventive effect of pyruvate against lens protein oxidation and consequent denaturation and insolubilization. Rat lens organ culture system was used for these studies. The content of water insoluble proteins (urea soluble) increased if the lenses were cultured in medium containing hydrogen peroxide. Incorporation of pyruvate in the medium prevented such insolubilization. The insolubilization was associated primarily with loss of gamma crystallin fraction of the soluble proteins. PAGE analysis demonstrated that insolubilization is related to -S-S- bond formation which was preventable by pyruvate. Since pyruvate is a normal tissue metabolite the findings are considered pathophysiologically significant against cataract formation. This was apparent by the prevention of selenite cataract in vivo by intraperitoneal administration of pyruvate.
The purpose of this study was to elucidate the prevalence and degree of asymptomatic occlusive lesions in the carotid and intracranial arteries in Japanese patients with ischemic heart disease (IHD).
We performed carotid and intracranial MR angiography (MRA) on 67 patients (49 men, 18 women; age range, 40 to 78 years; mean age, 60.1 years) who had received selective coronary angiography for the clinical diagnosis of IHD. On the basis of these images, degree of stenosis in the regions of the bilateral carotid artery bifurcation and five regions of the intracranial arteries, ie, bilateral intracranial portions of the internal carotid arteries and the middle cerebral arteries and the basilar artery were estimated.
Stenosis of more than 25% narrowing of the diameter of the target arteries was found in 15 patients (22.4%) in the extracranial carotid arteries and in 11 patients (16.4%) in the intracranial arteries. Most of the stenotic lesions were mild. The incidence of extracranial carotid stenosis and the severity of coronary atherosclerosis showed a significant correlation. The mean age of the patients with intracranial arterial lesions was statistically higher than those without intracranial lesions.
Our data suggest that asymptomatic occlusive lesions in the carotid and intracranial arteries are fairly common in Japanese patients with IHD, although the degree of stenosis is relatively mild. Coexistence of carotid atherosclerosis should be suspected in IHD patients with severe coronary atherosclerosis, and the possibility of atherosclerosis in the intracranial arteries should be considered in aged IHD patients.
A rotary blood pump inherently provides only one noninvasive "observable" parameter (motor current) and allows for only one "controllable" parameter (pump speed.) To maintain the systemic circulation properly, the pump seed must be controlled to sustain appropriate outlet flows and perfusion pressure while preventing pulmonary damage caused by extremes in preload. Steady-state data were collected at repeated intervals during chronic trials of the Nimbus AxiPump (Nimbus, Inc., Rancho Cordova, California, U.S.A.) in sheep (n = 7) and calves (n = 12). For each data set, the pump speed was increased at increments of 500 rpm until left ventricular and left atrial emptying was observed by left atrial pressure diminishing to zero. The effect of decreasing preload was evaluated perioperatively by inferior vena cava occlusion at a constant pump speed. Fourier analysis established a relationship between changes in the pump preload and the power spectra of the pump current waveform. Based on these results, a control method was devised to avoid ventricular collapse and maintain the preload within a physiologic range. The objective of this controller is the minimization of the second and third harmonic of the periodic current waveform. This method is intended to provide a noninvasive regulation of the pump by eliminating the need for extraneous transducers.
To identify the risk factors of stroke in patients receiving maintenance hemodialysis, we conducted a prospective study on patients in Okinawa, Japan. Patients with end-stage renal disease who were treated with maintenance hemodialysis before the end of 1990 and were alive on January 1, 1991 (N = 1,243) were studied. Medical records and pertinent data as of January 1, 1991 were compiled. All occurrences of stroke were recorded throughout the follow-up period, and until the end of 1995. The duration of observation was 5,110.3 patient-years. A total of 90 cases of stroke were observed, including 63 (70.0%) cerebral hemorrhage, 20 (22.2%) cerebral infarction, and 7 (7.8%) subarachnoid hemorrhage. Multiple logistic analysis identified hypertension as an independent predictor of stroke, with an odds ratio of 2.38 and a 95% confidence interval from 1.26 to 4.50. The present study demonstrates that the high incidence of stroke is at least partially explained by insufficient control of hypertension. Every effort to control hypertension is warranted in chronic dialysis patients.
A new peritoneal dialysate containing pyruvate anions has been tested for its effects on cell functions and compared with conventional lactate and bicarbonate based solutions. The dialysate has a final pH of 5.4 to 5.6 and is composed of 1.36 to 3.86% glucose-monohydrate, 132 mmol/liter sodium, 1.75 mmol/liter calcium, 0.75 mmol/liter magnesium, 102 mmol/liter chloride and 35 mmol/liter pyruvate. For cytotoxicity testing peritoneal macrophages and peripheral blood mononuclear cells (PBMC) were exposed to conventional lactate dialysate, pyruvate dialysate, bicarbonate dialysate and a control medium RPMI 1640 (Biochrom KG, Berlin, Germany), followed by activation with different bacterial stimuli. In addition, the study further investigated the effect of varying glucose concentration in the different dialysates ranging from 0 to 3.86% and pH changes between 5.2 and 7.4 on the cytotoxicity effect on the selected cells. Mononuclear cells exposed to pyruvate-based dialysate before stimulation with endotoxin exhibited a tumor necrosis factor (TNF)-mRNA signal comparable to those of cells exposed to RPMI. In contrast, exposure to lactate-based dialysate completely inhibited TNF-mRNA synthesis. In addition, cytokine synthesis in macrophages and PBMCs after exposure to pyruvate was less inhibited when compared to the corresponding levels measured after exposure to lactate. The chemotactic response of polymorphonuclear cells and O-2 generation in all tested cell types after exposure to pyruvate was found not to be inhibited, whereas a complete inhibition was observed after exposure to lactate. The results demonstrate that cytotoxicity effects of peritoneal dialysate on cell lines can be minimized by using a new dialysate formulation containing pyruvate anions instead of lactate.
Indirect measurement of the flow rate of a centrifugal blood pump using the driving motor current was studied. The pump flow rate can be expressed as a function of the motor current under a given motor speed in the absence of energy loss resulting from uncertain mechanical contact friction. The magnetically suspended centrifugal blood pump (MSCP), developed by the collaboration of Kyoto University and NTN Inc., was suitable for the application of this measuring method because the impeller is suspended magnetically inside the pump housing without any mechanical contact. The effect of fluid viscosity on the pump performance was investigated in detail, and it was possible to estimate the pump flow rate and the pressure difference through the pump (from inlet port to outlet port) accurately by monitoring the motor current and speed when the kinematic viscosity of working fluids was known. The kinematic viscosity of working fluids can also be measured with the MSCP. The motor current and motor speed were monitored in a chronic animal experiment, and the estimated flow rate and pressure difference showed good correlation with directly measured data.
In this study, centrifugal pump performance was examined in a mock circulatory loop to derive an automatic pump rotational speed (rpm) control method. The pivot bearing supported sealless centrifugal pump was placed in the left ventricular apex to aorta bypass mode. The pneumatic pulsatile ventricle was used to simulate the natural ventricle. To simulate the suction effect in the ventricle, a collapsible rubber tube was placed in the inflow port of the centrifugal pump in series with the apex of the simulated ventricle. Experimentally, the centrifugal pump speed (rpm) was gradually increased to simulate the suction effect. The pump flow through the centrifugal pump measured by an electromagnetic flowmeter, the aortic pressure, and the motor current were continuously digitized at 100 Hz and stored in a personal computer. The analysis of the cross-spectral density between the pump flow and motor current waveforms revealed that 2 waveforms were highly correlated at the frequency range between 0 and 4 Hz, with the coherence and phase angles being close to 1.0 and 0 degree, respectively. The fast Fourier transform analysis of the motor current indicated that the second harmonic component of the motor current power density increased with the occurrence of the suction effect in the circuit. The ratio of the fundamental to the second harmonic component decreased less than 1.3 as the suction effect developed in the circuit. It is possible to detect and prevent the suction effect of the centrifugal blood pump in the natural ventricle through analysis of the motor current waveform.
In our previous study (Diabetes 44:520-526, 1995), endothelial cells cultured in high glucose condition showed impairment of an oxidant-induced activation of the pentose phosphate pathway (PPP) and a reduced supply of NADPH to the glutathione redox cycle. To gain insight into the mechanisms of this impairment, the protective effect of pyruvate was studied in human umbilical vein endothelial cells cultured in either 5.5 mmol/l glucose (normal glucose [NG] condition) or 33 mmol/l glucose (high glucose [HG] condition). Through pretreatment of cells with 0.2 mmol/l pyruvate for 5-7 days in the HG condition, glucose oxidation through the PPP and total cellular NADPH content in the presence of 0.2 mmol/l H2O2 were increased by 54 (P < 0.05) and 34%, respectively, and glutathione-dependent degradation of H2O2 in HG cells was enhanced by 41% (P < 0.01), when compared with those cells to which pyruvate was not added. The addition of pyruvate significantly reduced the fructose 1,6-bisphosphate (FDP) content and free cytoplasmic NADH/NAD ratio, estimated by increased pyruvate/lactate ratio in NG and HG cells exposed to H2O2. Furthermore, the addition of pyruvate also showed a 46% reduction (P < 0.01) of endothelial cell damage induced by H2O2 in HG cells. These results indicate that abnormalities in PPP activation and glutathione redox cycle activity induced by H2O2 in HG cells are compensated, and that the accentuated reductive stress is improved by an addition of pyruvate. These pyruvate effects are associated with protection against an oxidant-induced endothelial cell injury in the high glucose condition.
Patients with chronic renal failure often show accumulation of intermediate-density lipoprotein (IDL). Because recent studies have emphasized the atherogenicity of IDL in the general population, we evaluated the relationship between this lipoprotein and aortic atherosclerosis in uremic patients treated with hemodialysis. Aortic pulse wave velocity (PWV) was measured as a noninvasive index of sclerotic change of aorta in 205 hemodialysis patients and 184 age- and gender-matched healthy subjects. Fasting plasma lipoproteins were fractionated by ultracentrifugation into very low-density lipoprotein (VLDL), IDL, LDL, and HDL. Plasma lipoprotein (a) (Lp(a)) was measured by a latex immunoturbidimetric assay. Aortic PWV was significantly higher in the hemodialysis patients than in the control subjects. The hemodialysis group showed a significant increase in VLDL and IDL cholesterol, whereas their LDL and HDL cholesterol were lower than the control levels. Lp(a) levels did not differ between the two groups. In the hemodialysis population, VLDL, IDL, and LDL cholesterol correlated positively with aortic PWV adjusted for age, gender, smoking, and BP, whereas Lp(a) did not. Multiple regression analyses indicated that plasma triglycerides, independent of HDL cholesterol, had a significant association with aortic PWV in the hemodialysis patients but not in the control subjects. Further analyses revealed that aortic PWV in the hemodialysis patients had a significant and independent association with IDL cholesterol, whereas aortic PWV in the control subjects had significant and independent associations with HDL cholesterol and Lp(a). These results demonstrate that IDL is the lipoprotein fraction most closely associated with aortic PWV in the hemodialysis patients.
Reperfusion of ischemic adult hearts is associated with increased fatty acid oxidation, reduced pyruvate oxidation, and reduced pyruvate dehydrogenase (PDH) activity, leading to a decrease in cardiac efficiency. These effects may be amplified in newborn hearts because of the immaturity of their PDH pathway. We hypothesize that pyruvate can augment mechanical function in the immature heart by activating the PDH complex (PDC) during reperfusion in severely ischemic hearts.
Seven-day old isolated working rabbit hearts (n = 12) were perfused with modified Krebs solution containing 0.4 mM palmitate. Pyruvate (5 mM) was added for a 10-min period either before or after a 30-min period of normothermic global ischemia. Cardiac functional indices before global ischemia and during reperfusion were correlated with active and total PDC activity measured in 28 additional hearts frozen at the various time points throughout the perfusion protocol.
Addition of pyruvate before ischemia increased the proportion of active PDC but did not affect any measured functional indices. During early reperfusion, aortic flow, cardiac output, and cardiac work were all significantly depressed compared to preischemic values. Addition of pyruvate significantly increased the proportion of active PDC and was also associated with a significant increase in aortic flow, cardiac work, and developed pressure. Removal of pyruvate from the perfusate resulted in a subsequent significant decrease in PDC activity and these functional parameters.
During reperfusion of neonatal rabbit hearts, addition of pyruvate improves cardiac performance in association with activation of PDC.
We investigated the basic characteristics of the pulsatility of motor current with an in vitro mock circuit that consists of a sac-type pulsatile pump (simulating the natural left ventricle), three reservoirs, and our mixed flow pump (MFP). There are three alternatives at the inlet of the MFP: 1) the left atrium (LA), 2) the left ventricle (LV), and 3) both (LALV). The motor current waveform was monitored. The pump speed of the MFP was changed from 0 to 7,000 rpm. We calculated the index of motor current amplitude (ICA), which was obtained from the amplitude of the motor current waveform divided by the simultaneous mean value. The ICA plotted against the pump speed had a peak point (t-point) that highly corresponded with the turning point from partial to total left heart assistance. The ICA also had a second specific point (s-point) that corresponded with the beginning of severe sucking. In LV and LALV aortic bypass, t- and s-points could clearly be detected. In LA aortic bypass, however, early and severe sucking occurred, and t- and s-points were not manifest. These data suggest that the assist status of continuous flow artificial heart can be estimated by detecting the t- and s-points.
Our novel control strategy for a continuous flow artificial heart by detecting the total assist and sucking points based on pump pulsatility was evaluated in acute animal experiments using beagle dogs and our mixed flow pump. The pump was installed as a left ventricular (LV) bypass through a left thoracotomy. To change LV contractility, the left coronary arteries were occluded for 30 min, followed by a 120 min reperfusion. To change LV end diastolic pressure (LVEDP), dextran solution was rapidly infused. To estimate the pump pulsatility without any specific sensor, we calculated the index of current amplitude (ICA), which was obtained from the amplitude of the motor current waveform divided by the simultaneous mean value. To investigate the basic characteristics of the ICA, the pump speed was changed temporarily from 2,300 rpm to 5,000 rpm. In 92% of all measurements, the ICA plotted against the pump speed had a peak point (t-point) that corresponded highly with the turning point from partial to total assistance. The ICA also had a trough (s-point) that corresponded with the beginning of severe sucking in most cases. Only preload significantly influenced pump flow rate at the t-point from among preload (LVEDP), afterload (SAoP), and contractility (max LV dP/dt), by which we can simulate Starling's law of the natural heart. We concluded that a continuous flow artificial heart could be well controlled by detecting the t-point and s-point.
In this study, a detection algorithm for suction and regurgitation of the centrifugal pump during left heart bypass without relying on external flow or pressure sensors was developed and evaluated in acute studies using adult goats. The detection scheme relies on power spectral density (PSD) analysis of the motor current waveform through which the waveform deformation index (WDI) is obtained. This index is defined as the ratio of the fundamental component of the PSD to the higher PSD components, and its value increases with the deformation of the basic waveform. By assuming that the undistorted motor current waveform can be represented by a pure sine waveform, we theoretically synthesized various waveforms which have different second harmonic components. We were able to synthesize the waveform whose shape was close to the distorted motor current waveform under varying suction levels obtained in a mock loop study. From this study, we came to the conclusion that the WDI value of 0.2 can serve as a threshold level in deciding the suction and regurgitation speeds (rpm) during left heart bypass. In the study using adult goats, we were successful in minimizing both regurgitation and suction when the centrifugal pump speed was adjusted based on the WDI algorithm. The resultant bypass flow ranged from 1.5 to 2.0 L/min which was around 60% of the total flow. Further study is underway to evaluate the applicability of the WDI method in optimizing bypass pump flow.
Variable glucose-lactate-based peritoneal dialysates have negative effects on peritoneal macrophages and peripheral blood leukocytes, reducing the capacity of leukocytes for chemotaxis, bacterial killing. But few reports exist on cell apoptosis. To investigate the effects of glucose-lactate-based peritoneal dialysates on cultured phagocytes (monocytes and neutrophils), we focused on studying phagocyte apoptosis after brief exposure to commercial peritoneal dialysates.
Cell apoptosis is measured by flow cytometry (FCM) to detect phosphatidylserine (PS) exposure on early apoptotic cells using fluorescein-labeled annexin V. To mimic the composition of dialysate in vivo, where the freshly instilled solution mixes with the residual dialysate from the previous cycle, we performed the experiments using a mixture of fresh and spent dialysate (9:1). In our transient exposure experiments, monocytes and neutrophils were separately incubated in each of the test solutions (1.5% glucose and 4.25% glucose dialysates) for 10 minutes or 30 minutes and afterward separated and resuspended in RPMI 1640 medium and cultured over the indicated time.
After exposure to 1.5% glucose dialysates for 10 minutes, monocytes and neutrophils exhibited normally spontaneous apoptosis. After exposure to 4.25% glucose dialysate, monocytes underwent apoptosis increasingly, 21%+/-5.0% versus 9.8%+/-3.6% (p < 0.05) at 24 hours and 47%+/-6.2% versus 16%+/-4.0% (p < 0.01) at 72 hours compared with controls. For neutrophils, the results were discouraging: hypertonic dialysate not only increased apoptosis [65.36%+/-2.6% versus 34.17% +/-8.52% (p < 0.01) at 72 hours], but also induced cell necrosis. When Incubation time was prolonged for 30 minutes, 1.5% dialysate acted like 4.25% dialysate, with the rate of apoptosis increasing rapidly [40%+/-4.0% versus 16%+/-4.0% (p < 0.01) at 72 hours for monocytes, and 66.90%+/-5.6% versus 34.17%+/-8.52% (p < 0.01) at 72 hours for neutrophils].
Glucose-lactate-based peritoneal dialysates can induce peripheral blood phagocyte apoptosis in vitro, which indicates that glucose plays an important role in triggering cell apoptosis. Therefore, looking for new, physiologic peritoneal dialysis fluids to replace conventional fluids is reasonable.
Pyruvate, a metabolic product of glycolysis and an oxidizable fuel in myocardium, increases cardiac mechanical performance and energy reserves, especially when supplied at supraphysiological concentrations. The inotropic effects of pyruvate are most impressive in hearts that have been reversibly injured (stunned) by ischemia/reperfusion stress. Glucose appears to be an essential co-substrate for pyruvate's salutary effects in stunned hearts, but other fuels including lactate, acetate, fatty acids, and ketone bodies produce little or no improvement in postischemic function over glucose alone. In contrast to pharmacological inotropism by catecholamines, metabolic inotropism by pyruvate increases cardiac energy reserves and bolsters the endogenous glutathione antioxidant system. Pyruvate enhancement of cardiac function may result from one or more of the following mechanisms: increased cytosolic ATP phosphorylation potential and Gibbs free energy of ATP hydrolysis, enhanced sarcoplasmic reticular calcium ion uptake and release, decreased cytosolic inorganic phosphate concentration, oxyradical scavenging via direct neutralization of peroxides and/or enhancement of the intracellular glutathione/NADPH antioxidant system, and/or closure of mitochondrial permeability transition pores. This review aims to summarize evidence for each of these mechanisms and to consider the potential utility of pyruvate as a therapeutic intervention for clinical management of cardiac insufficiency.
Rat peritoneal mesothelial cells in culture have the capability of generating hydrogen peroxide. Exposure of these cells to glucose-enriched, lactated-buffered fluids for peritoneal dialysis significantly increases the production of H(2)O(2). Increased liberation of oxygen radicals also involves the risk of damaging the peritoneal membrane. Pyruvate being a natural oxidant scavenger abundantly present in mammalian cells, we hypothesized that its protective effects facing H(2)O(2) can eventually be of relevance for the mesothelial monolayer of patients on long-term peritoneal dialysis. So far, we designed an experimental study in which rat peritoneal mesothelial cells in culture were exposed to 2 mM H(2)O(2). Cell damage was estimated in terms of decreased capability of the mitochondrial dehydrogenases to reduce MTT. Addition of 2 mM sodium pyruvate to the medium prevented the negative effect of hydrogen peroxide. The MTT/protein values for the control group were 0.00357 +/- 0.00075. The ratio after exposure to 2 mM H(2)O(2) was 0. 00217 +/- 0.00028, whereas that detected in cells incubated in H(2)O(2) plus pyruvate was 0.00325 +/- 0.0082 (p < 0.05). These results indicate that pyruvate protected rat peritoneal mesothelial cells in culture against oxidant injury. These data are one more piece of evidence pointing at pyruvate as a potentially useful buffer for peritoneal dialysis solutions.
The control system for an implantable rotary blood pump is not clearly defined. A detection system is considered to be necessary for pump flow monitoring and abnormal conditions such as back flow or a sucking phenomenon where the septum or left ventricle wall is sucked into the cannula, etc. The ultrasound flowmeter is durable and reliable but the control system should not be totally dependent on the flowmeter. If the flowmeter breaks, the rotary blood pumps have no control mechanism. Therefore, the authors suggest controlling the pumps by an intrinsic parameter. One left ventricular assist device (LVAD) calf model was studied where the flow rate and waveform of the pump flow proved to identify the sucking phenomenon. Thus, the pump flow rate was calculated from the required power, motor speed, and heart rate. The value of the coefficient of determination (R2) between the measured and estimated pump flow rate was 0.796. To estimate this abnormal phenomenon, 2 methods were evaluated. One method was the total pressure head in which the pump flow rate and motor speed were estimated. During normal conditions the total pressure head is 79.5 +/- 7.0 mm Hg whereas in the abnormal condition, it is 180.0 +/- 2.8 mm Hg. There was a statistical difference (p < 0.01). Another method is using a current waveform. There is an association between the current and pump flow waves. The current was differentiated and squared to calculate the power of the differentiated current. The normal range of this value was 0.025 +/- 0.029; the abnormal condition was 11.25 +/- 15.13. There was a statistical difference (p < 0.01). The predicted flow estimation method and a sucking detection method were available from intrinsic parameters of the pump and need no sensors. These 2 methods are simple, yet effective and reliable control methods for a rotary blood pump.
In this study, the effects on varying cardiac function during a left ventricular (LV) bypass from the apex to the descending aorta using a centrifugal blood pump were evaluated by analyzing the left ventricular pressure and the motor current of the centrifugal pump in a mock circulatory loop. Failing heart models (preload 15 mm Hg, afterload 40 mm Hg) and normal heart models (preload 5 mm Hg, afterload 100 mm Hg) were simulated by adjusting the contractility of the latex rubber left ventricle. In Study 1, the bypass flow rate, left ventricular pressure, aortic pressure, and motor current levels were measured in each model as the centrifugal pump rpm were increased from 1,000 to 1,500 to 2,000. In Study 2, the pump rpm were fixed at 1,300, 1,500, and 1,700, and at each rpm, the left ventricular peak pressure was increased from 40 to 140 mm Hg by steps of 20 mm Hg. The same measurements as in Study 1 were performed. In Study 1, the bypass flow rate and mean aortic pressure both increased with the increase in pump rpm while the mean left ventricular pressure decreased. In Study 2, a fairly good correlation between the left ventricular pressure and the motor current of the centrifugal pump was obtained. These results suggest that cardiac function as indicated by left ventricular pressure may be estimated from a motor current analysis of the centrifugal blood pump during left heart bypass.
We originated a novel control strategy for a continuous flow left ventricular assist device (LVAD). We examined our method by acute animal experiments to change the left ventricular (LV) contractility or LV end-diastolic pressure (LVEDP). To estimate the pump pulsatility without any specific sensor, we calculated the index of current amplitude (ICA) from motor current waveform. The ICA had a peak point (t-i point) that corresponded closely with the turning point from partial to total assistance, and a trough (s-i point) that corresponded with the beginning point of ventricular collapse. The pump flow at the t-i point (Qt-i) had no component of flow regurgitation. In the evaluation of the effects of preload LVEDP, afterload (mAoP), and contractility (max LV dp/dt), we found that preload was the only parameter that significantly influenced Qt-i. We concluded that our method could well control continuous flow LVAD by preventing reversed flow and ventricular collapse.
A left ventricular assist device (LVAD) is an effective method to rescue severe heart failure. Although some require a biventricular assist, the control method for the biventricular assist device (BVAD) with a rotary pump is rarely shown. The objective of this study was to investigate the strategy for controlling BVAD with rotary pumps by in vivo studies. Using 5 piglets, we set a BVAD through a left thoracotomy and made global ischemia for 30 min by clamping the base of the ascending aorta. After unclamping, the analysis of pumping performance acted for 6 h reperfusion. We set the target flow of the LVAD and set the right ventricular assist device (RVAD) speed limit as less than when the atrial collapse occurs. To detect the ventricular collapse without any specific sensor, we calculated the index of current amplitude from motor current waveform and simultaneous mean current value. In all cases, over 6 h of observation was performed, and the RVAD was weaned almost automatically.
This article describes a technique offering indirect measurements of pump pressure differential and flow with certain accuracy independent of changes in blood viscosity. This technique is based on noninvasive measurements of the motor current and rotation speed using the physical model equations of the centrifugal pump system. Blood viscosity included in the coefficients of the dynamic equations is first estimated, and then substitution of the estimated viscosity into the steady equations of the model provides pump flow and pressure differential. In vitro tests using a Capiox pump showed a sufficient linear correlation between actual values and their estimates for pressure differential and pump flow. An in vivo test using a 45 kg sheep showed that the proposed algorithm needs robustness for the convergence of estimates of viscosity. An overall evaluation, however, of the developed algorithm/model showed indications of success in terms of efficient computation and modeling.
Rotary blood pumps can be used for long-term left ventricular assist devices. These pumps have several advantages over the conventional pulsatile pumps including smaller size, higher efficiency, and simple design and construction. However, one of the difficulties associated with the rotary blood pump is the proper control method to maintain an optimum flow rate in different physiological conditions. The rotary blood pump can be controlled by two methods. The first is to utilize the measured pump flow rate from its servo signal. The second is to detect and avoid abnormal pumping conditions such as; back flow and sudden increase in the pressure head. This abnormal situation typically occurs from excessive suction of blood when there is a functional or mechanical occlusion in the inflow cannula. The ultrasound flow meter is durable and reliable but it is difficult to continually monitor the blood flow rate of an implantable pump. Therefore, another method is needed instead of the continuous flow monitoring. One chronic calf having an LVAD was subjected for the development of this control system. This calf survived more than 6 months. Voltage, current, motor speed, heart rate and the pump flow rate were recorded and stored at 30-min intervals in a computer. Utilizing these parameters, attempts were made (1) to achieve indirect flow assessments and (2) to reveal abnormal operating parameters of the centrifugal pump (1). Indirect flow measurement, the predicted pump flow rate was calculated from these pump derived parameters (required power, motor speed and heart rate). The value of the coefficient of determination (R) between the measured and estimated pump flow rate was 0.796. (2) Abnormal operating indicator, there was an association between the required current and pump flow waves. The current was differentiated, and then calculated to the power of the differentiated current. The normal range of this value was 0.02+/-0.54. In abnormal conditions, this abnormal operating indicator increased 500 times. The predicted flow estimation method and abnormal operating indicator were available from intrinsic operating parameters of the pump and need no sensors. These two methods were simple, yet they are possibly effective and reliable servo control methods for a rotary blood pump.
Glucose degradation products (GDPs) are cytotoxic in vitro and potentially toxic in vivo during peritoneal dialysis (PD). We are presenting the results of a two-year randomized clinical trial of a new PD fluid, produced in a two-compartment bag and designed to minimize heat-induced glucose degradation while producing a near neutral pH. The effects of the new fluid over two years of treatment on membrane transport characteristics, ultrafiltration (UF) capacity, and effluent markers of peritoneal membrane integrity were investigated and compared with those obtained during treatment with a standard solution.
A two-group parallel design with 80 continuous ambulatory peritoneal dialysis patients was used. The patients were randomly assigned to either the new fluid (N = 40) or to a conventional one (N = 40), and were stratified with respect to age, diabetes, and time on PD. Peritoneal transport characteristics were assessed by the Personal Dialysis Capacity (PDCtrade mark) test at 1, 6, 12, 18, and 24 months after inclusion and by weighing the overnight bag daily. Infusion pain and handling were evaluated using a questionnaire. Peritoneal mesothelial and interstitial integrity were evaluated by analyzing overnight effluent dialysate concentrations of CA 125, hyaluronan (HA), procollagen-1-C-terminal peptide (PICP), and procollagen-3-N-terminal peptide (PIIINP) at 1, 6, 12, 18, and 24 months.
The handling of the new two-compartment bag was considered easy, and there were no indications of increased discomfort with the new system. Furthermore, no changes in peritoneal fluid or solute transport characteristics were observed during the study period for either fluid, and neither were there any differences with regard to peritonitis incidence. However, significantly higher dialysate CA 125 (73 +/- 41 vs. 25 +/- 18 U/mL), PICP (387 +/- 163 vs. 244 +/- 81 ng/mL), and PIIINP (50 +/- 24 vs. 29 +/- 13 ng/mL) and significantly lower concentrations of HA (395 +/- 185 vs. 530 +/- 298 ng/mL) were observed in the overnight effluent during treatment with the new fluid.
We conclude that the new fluid with a higher pH and less GDPs is safe and easy to use and has no negative effects on either the frequency of peritonitis or peritoneal transport characteristics as compared with conventional ones. Our results indicate that the new solution causes less mesothelial and interstitial damage than conventional ones; that is, it may be considered more biocompatible than a number of conventional PD solutions currently in use.
Peritoneal solute transport increases with time on treatment in a proportion of peritoneal dialysis (PD) patients, contributing to ultrafiltration failure. Continuous exposure of the peritoneum to hypertonic glucose solutions results in morphologic damage that may have a causative role in changes in peritoneal function. The purpose of this analysis was to establish whether increased exposure to glucose preceded changes in solute transport in a selected group of long-term PD patients. Peritoneal solute transport, residual renal function, peritonitis rate, and peritoneal exposure to glucose were recorded prospectively in a cohort of 303 patients at a single dialysis center. A subgroup of individuals, treated continuously for 5 yr, were identified and defined retrospectively as having either stable or increasing transport status. Of the 22 patients who were treated continuously for 5 yr, 13 had stable solute transport (solute transport at start, 0.67 [+/-0.1]; at 5 yr, 0.67 [+/-0.1]), whereas 9 had a sustained increase (solute transport at start, 0.56 [+/-0.08]; at 5 yr, 0.77 [+/-0.09]). Compared with the stable patients, those with increasing transport had earlier loss in residual renal function and were exposed to significantly more hypertonic glucose during the first 2 yr of treatment that preceded the increase in solute transport. This was associated with greater achieved ultrafiltration compensating for the reduced urinary volumes in these patients. Further increases in glucose exposure were observed as solute transport continued to rise. Peritonitis, including severity of infection and causative organism, was similar in both groups. In this selected group of long-term survivors on PD, an increase in solute transport with time was preceded by increased peritoneal exposure to hypertonic glucose. This is supportive evidence that hypertonic glucose may play a causative role in alterations in peritoneal membrane function.
The index of motor current amplitude (ICA) has feasibility in continuous-flow ventricular assist device control. It can demonstrate the safe range of pump speed, which exists between the starting point of total assistance (t-point) and the starting point of sucking (s-point). The objective of this study was to investigate how the ICA characteristic curve changes with each condition of contractility, preload, and afterload changes. We changed preload, afterload, and contractility of closed-mock circulation and plotted the change of the ICA value against pump speed. Then the shift of ICA characteristic curve against the change of each condition was considered. When preload increased, ICA characteristic curves showed the expansion of a safe range. When afterload increased, ICA characteristic curves were shifted to the high rotation side, slightly narrowing a safe range. When contractility increased, ICA characteristic curves showed the shift of a convex above to narrowing of a safe range. As these shift patterns were observed even when the driving conditions of a circuit changed, reproducibility was checked. Understanding the feature of a shift pattern of ICA characteristic curves correctly, a possibility that change of the heart function could be predicted by change of ICA value and a possibility for a flexible control method based on ICA, according to hemodynamic state, were suggested.