Vox Sanguinis International Forum on the use of prehospital blood products and pharmaceuticals in the treatment of patients with traumatic haemorrhage.

While specific practices and transported blood products vary around the world, most of the respondents in this International Forum transported at least one blood product for the transfusion to bleeding patients en route to the hospital. The most commonly carried product was RBCs, while the use of whole blood will likely increase given the recent reports of its successful use in the civilian setting, and because of the change in the AABB's Standards regulating its use. It will be interesting to see if plasma use in the prehospital setting becomes more widely used given today's enhanced appreciated of the coagulopathy of trauma and plasma's beneficial effect in reversing it, and if blood products are transported to the scene of injury by more vehicles, that is, not just predominantly in helicopters. It was not surprising that TXA is being widely administered as close to the time of injury as possible given its potential benefit in these patients. This International Forum highlights the importance of focusing attention on prehospital transfusion management with a need to further high­quality research in this area to guide optimal resuscitation strategies.

[Anemia and iron deficiency in the elderly. Prevalence, diagnostics and new therapeutic options]. / Anämie und Eisenmangel in der Geriatrie. Prävalenz, Diagnostik und neue Therapieoptionen.

The prevalence of anemia in geriatric patients is high. With some variation in different patient cohorts, prevalence of anemia can reach 40%. Anemia is not an age-related disease on its own, but is a symptom with multifactorial genesis and high risk potential. It directly influences mortality, morbidity, and the rate of hospitalization, particularly in older patients suffering from chronic heart failure or chronic kidney disease. The high prevalence of anemia in chronic kidney disease is explained by a combination of erythropoietin and iron deficiency. This review summarizes the recommendations of the iron symposium at the 2010 German Geriatric Society Meeting in Potsdam, Germany. It intends to provide current information on prevalence, diagnostic work-up, and therapeutic options for anemia in the rapidly growing group of elderly patients.

Efficacy of cinacalcet administered with the first meal after dialysis: the SENSOR Study.

BACKGROUND: Cinacalcet, a novel calcimimetic, simultaneously lowers parathyroid hormone (PTH), phosphorus (P), calcium (Ca) and Ca x P in patients who are on dialysis with secondary hyperparathyroidism (sHPT) associated with CKD. Previous studies have required cinacalcet to be administered during the dialysis session and at the same time on non-dialysis days. The aim of the SENSOR study was to demonstrate that cinacalcet given in a more clinically practical manner with the first major meal after dialysis is noninferior to cinacalcet given with food during the dialysis session. METHODS: In this open-label study dialysis patients with poorly controlled sHPT (intact PTH (iPTH) (3) 300 pg/ml) were randomized to receive cinacalcet either daily with their post-dialysis meal (n = 337) or with food during the dialysis session (n = 336). The primary endpoint was the proportions of patients with mean iPTH pound 300 pg/ml ( pound 31.8 pmol/l) at Weeks 11 and 13 of a 21-week treatment period. Secondary endpoints included the proportion of patients with Ca x P < 55 mg2/dl2 (< 4.44 mmol2/l2) at Weeks 11 and 13 and patients who discontinued the study due to nausea or vomiting. RESULTS: Comparable proportions of patients in the cinacalcet "during dialysis" and "post-dialysis meal" groups had a mean iPTH pound 300 pg/ml (54 vs. 57%, respectively, 95% confidence interval (CI) difference -4, +10%) and Ca x P < 55 mg2/dl2 (78 vs. 73%, respectively, 95% CI difference -11, +2%) at Weeks 11 and 13. The groups were also comparable at Week 21. Cinacalcet was well tolerated, with < 3% of patients in both groups discontinuing due to nausea or vomiting. A combined post-hoc analysis of both groups showed the incidence of nausea and vomiting was lower if cinacalcet was administered during the evening. CONCLUSIONS: Administering cinacalcet with the first main meal after dialysis was as effective as administration with food during the dialysis session. Cinacalcet was well tolerated. The incidence of gastrointestinal adverse events appeared to be lower when cinacalcet was administered in the evening.

[Current recommendations for the treatment of iron deficiency anemia]. / Recommandations actuelles pour le traitement de l'anémie ferriprive.

Iron deficiency is a frequent complication in chronically ill patients and in pregnant women. Iron status can now be characterised precisely and relatively easily by determining serum ferritin, transferritin saturation and if necessary hypochromic erythrocytes and the haemoglobin content of erythrocytes (CHr). Oral iron replacement is usually restricted by limited absorption and low tolerability. Intravenous iron therapy is possible in such cases and can be combined with rHuEPO (e.g. EPREX/ epoetin alfa) in severe cases. Iron saccharate (VENOFER) is commercially available in Switzerland and this permits high dose iron replacement without any danger of anaphylaxis or acute iron toxicity.

[Diagnosis and treatment of disordered acid-base balance]. / Diagnostik und Therapie von Störungen des Säure-Basen-Haushalts. Warum Patienten sauer werden.

Differential diagnosis in disordered acid-base homeostasis is usually possible by measuring the pH, pCO2, pO2 and bicarbonate concentration, and enables differentiation between respiratory alkalosis and acidosis, and metabolic alkalosis and acidosis. Compensatory counter-regulation (respiratory or renal) can make correct assessment of the primary disorder problematic. Treatment of the underlying disease, in particular the provision of adequate oxygenation in respiratory disorders is of the essence. In chronic forms of metabolic acidosis, for example in chronic renal insufficiency and elderly patients, bicarbonate substitution should be initiated in order to prevent the negative effects on various organ systems. Sodium bicarbonate formulations that can be assimilated from the small bowel are especially tolerable and suitable.

[Management of patients with chronic renal failure]. / Die Früherkennung einer Niereninsuffizienz lohnt sich immer. Handeln Sie, bevor das Kreatinin ansteigt.

Terminal renal failure has an incidence of approximately 60 persons per million population, and is on the increase. Victims suffer from an appreciably compromised quality of life and life expectancy. The financial burden on the health service imposed by the need for renal replacement therapy (dialysis or renal transplantation) is considerable. To achieve a therapeutic impact, the underlying kidney disease, as well as the factors driving progression and injury need to be identified as early as possible. Of particular importance in this connection is the rigorous management of arterial hypertension with the use of ACE inhibitors, dietetic measures and normalization of hemoglobin levels.

Parathyroid hormone increases thiol proteinase activity by activation of protein kinase C in cultured kidney tubule cells (OK).

Chronic exposure (24 h) to parathyroid hormone (PTH) increases the intracellular proteolytic activity in cultured opossum kidney cells 2-fold at physiological PTH concentrations (10(-12) mol/l). This increase can be blocked by E-64, an inhibitor of thiol proteinases. The phorbol ester TPA mimicks the effect of PTH, whereas the calcium ionophore A23187 reduces the intracellular proteinase activity. Forskolin and dibutyrylic cAMP do not elevate proteinase activity. The protein kinase C inhibitor staurosporine is equally effective in blocking the TPA- and PTH-induced proteinase activity increase. These data indicate that PTH increases the intracellular thiol proteinase activity by an activation of protein kinase C and not by the cAMP dependent way.

Effect of beta 2-microglobulin on immunoglobulin production.

Chronic renal failure patients display high serum levels of beta 2-microglobulin (beta 2-M) and a pronounced defect in immunoglobulin production. In this light, the present study was conducted to investigate whether beta 2-M might influence the rate of antibody synthesis. Peripheral blood mononuclear cells (PBMC) from healthy subjects were cultured in the presence of beta 2-M (80 mg/l) for 7 days. Immunoglobulin concentrations were measured by ELISA-techniques in culture supernatants. Basal IgM levels were 390 +/- 10 ng/ml and increased to 940 +/- 216 ng/ml in the presence of beta 2-M. After PWM stimulation, IgM concentrations were 2654 +/- 614 ng/ml without and 3750 +/- 914 ng/ml with beta 2-M. IgG and IgA production by PBMCs was not influenced by beta 2-M in the culture medium. Likewise, the generation of beta 2-M by PBMCs was unchanged in the presence of exogenous beta 2-M in the medium. In terms of clinical relevance, serum beta 2-M levels of 28 uremic patients were correlated with capacity of their PBMCs for immunoglobulin production in vitro. However, there was no apparent correlation between beta 2-M serum levels and immunoglobulin synthesis in vitro. Taken together, beta 2-M seems to have a stimulatory effect on IgM synthesis in vitro. Whether this has some clinical meaning in patients with chronic renal failure remains to be investigated.

Pharmacokinetics of 1M gadobutrol in patients with chronic renal failure.

RATIONALE AND OBJECTIVES: To investigate the pharmacokinetics of 1M gadobutrol as a new neutral MR contrast agent in patients with impaired renal function. METHODS: Twenty-one patients with impaired renal function and any indication for a contrast-enhanced MRI were enrolled into this prospective study and classified in two subgroups according to their creatinine clearance (group 1, 30-80 mL/ min; group 2, 30 mL/min or less, not requiring dialysis). Eleven patients were assigned to the lower dose of 0.1 mmol Gd/kg and 10 patients to the higher dose of 0.3 mmol Gd/kg. To calculate pharmacokinetic parameters, urine and venous blood samples were drawn at baseline and up to 72 hours for group 1 and 120 hours for group 2 after administration of gadobutrol. RESULTS: The predominant extracellular distribution of gadobutrol at steady state did not change according to the degree of renal impairment. The mean elimination half-life of gadobutrol increased to 7.4 +/- 2.6 hours (0.1 mmol/kg) and 5.4 +/- 1.5 hour (0.3 mmol/kg) in group 1 and to 17.9 +/- 6.2 hours (0.1 mmol/kg) and 20.4 +/- 16.9 hours (0.3 mmol/kg) in group 2, compared with 1.5 hours in healthy volunteers. The relation between serum (tbeta) and urine (t(elim)) elimination half-lives, as well as total serum and renal clearance, indicated renal elimination as the main pathway of elimination. The recovery of gadobutrol in the urine of group 1 was complete within 72 hours for both dosage levels. Patients with severe renal impairment showed a mean recovery of 80.1% (0.1 mmol/kg) and 85.3% (0.3 mmol/kg) within the observation period of 120 hours. CONCLUSIONS: The half-life of gadobutrol is prolonged in patients with impaired renal function, but elimination by means of the kidneys is the predominant route.

Hypochromic red blood cells and reticulocytes.

The management of recombinant human erythropoietin (rHuEPO) treatment in hemodialysis patients requires close monitoring of iron status, because the pharmacologically stimulated erythropoiesis is particularly dependent on a continuous supply of iron. Parameters commonly measured to assess iron status are serum ferritin and the transferrin saturation. Both are indirect measures of iron availability for hemoglobin synthesis and frequently do not permit an assessment of the adequacy of iron supply to the erythron. Using flow cytometry, cell volume and hemoglobin concentration can be measured in individual red blood cells and reticulocytes. Based on these techniques, two parameters have proved to be particularly useful in identifying iron-deficient erythropoiesis. (a) The percentage of hypochromic erythrocytes (defined as red blood cells with a hemoglobin concentration of less than 28 g/dl) has been shown to detect insufficient marrow iron supply with a fairly good accuracy. (b) More recently, determination of the content of hemoglobin in reticulocytes (CHr) has been suggested by a number of authors to be even more sensitive in detecting iron-deficient erythropoiesis. For those who have access to an H*3 hematology analyzer, both indices can be determined at the time of a routine blood count at a minimal incremental cost.

Reduced protein catabolism by the antiglucocorticoid RU 38486 in acutely uremic rats.

Protein breakdown in acute uremia is enhanced, as evidenced by an increment in amino acid release from skeletal muscle and an increased amino acid uptake and urea and glucose production by the liver. To study whether this metabolic pattern is mediated by glucocorticoids, we investigated the effect of the antiglucocorticoid RU 38486 on both muscle protein breakdown and urea and glucose production of isolated hepatocytes in acutely uremic rats. Animals were rendered uremic by bilateral nephrectomy (BNX). Forty-eight hours after BNX, the rats had markedly elevated serum levels of urea nitrogen, creatinine, potassium, and phosphorus. In uremic rats receiving RU 38486 comparable levels of serum creatinine were found, but the serum levels of urea nitrogen (221 +/- 4 vs. 259 +/- 5 mg/dl) and phosphorus (6.5 +/- 0.3 vs. 8.5 +/- 0.4 mmol/liter) were significantly decreased as compared to uremic animals without RU 38486. In comparison to sham operated rats, urea-N appearance (net urea production) was increased by 56% 48 hours after BNX. This increment was almost completely reversed in uremic animals receiving the antiglucocorticoid. In untreated uremic rats, plasma levels of Nt-methylhistidine were 10.3 +/- 0.9 micrograms/dl, whereas the administration of RU 38486 caused a significant decline in the levels of this amino acid (7.6 +/- 0.5 micrograms/dl). Hepatic glucose production in BNX rats was significantly increased from alanine (+174%), glutamine (+158%), and serine (+87%) as compared to sham-operated controls. Concomitantly, hepatic urea formation from amino acid substrates was also enhanced in BNX animals. With the administration of RU 38486 to acutely uremic rats, both hepatic glucose and urea production were normalized.(ABSTRACT TRUNCATED AT 250 WORDS)

Urinary excretion of cathepsin B and cystatins as parameters of tubular damage.

The urinary excretion of the lysosomal hydrolases cathepsin B and beta-N-acetylglucosaminidase (beta-NAG) was compared with the tubular activities of these enzymes in remnant kidneys 16 weeks after subtotal nephrectomy (5/6 NX) or unilateral nephrectomy (UNX), as well as in kidneys from diabetic rats. In addition, the urinary excretion of the low-molecular weight protein cystatins, inhibitors of lysosomal cathepsins, was also followed in these animals. The urinary excretion of cathepsin B and beta-NAG was significantly enhanced in all three models of renal disease. The highest excretion rates for these enzymes were found in diabetic animals (cathepsin B: 4-fold; beta-NAG: more than a 10-fold increase over respective controls). In terms of tubular enzyme activities, tissue activities of both hydrolases were reduced in the remnant kidney after 5/6 NX, while in UNX and diabetes only cathepsin B activity was decreased. The urinary excretion of cystatins was enhanced in all three animal models, particularly in 5/6 nephrectomized rats, where a 40-fold increment over control animals was observed. Taken together, these findings indicate that there was severe tubular damage in the remnant kidney after 5/6 NX (reduced tubular enzyme activities, enzymuria and severely compromised tubular protein reabsorption). Furthermore, considerable enzymuria and disturbed protein reabsorption in early diabetes suggest tubular dysfunction before signs of glomerular damage become evident.

Amperometric creatinine biosensor for hemodialysis patients.

BACKGROUND: Creatinine is an important clinical laboratory parameter for the evaluation of kidney function. It is essential to determine its concentration in serum of patients suffering from renal insufficiency. During hemodialysis treatment, the measurement of creatinine in the effluent dialysate or ultrafiltrate may give additional information on the efficiency of the extracorporal procedure. Therefore, enzyme sensors with co-immobilized creatinine amidohydrolase, creatine amidinohydrolase and sarcosine oxidase have been used to determine creatinine. METHODS: Enzymatically generated hydrogen peroxide has amperometrically been detected at a platinum-working electrode. To exclude electroactive compounds of the sample matrix, which might interfere with the electrochemical measurement, the sensors have additionally been modified by a Nafion membrane. RESULTS: Such sensors showed a linear detection range of 0.06-1.7 mg/dl for creatinine. Diluting the sample with measuring buffer, it has also been possible to measure pathological creatinine concentrations up to 11 mg/dl. A good correlation between creatinine concentrations in serum, dialysate and ultrafiltrate determined by the presented enzyme sensors and those obtained by both, conventional colorimetric Jaffé and enzymatic measurements have been achieved. CONCLUSION: Further developments will aim at the integration of this measuring principle into the concept to low-cost disposable planar sensors.

Cadmium and renal hypertension.

In our study we investigated 36 patients with renal disease, 22 of whom were hypertensive. In all proteinuria was present (4.30 +/- 5.05 g protein/day) and renal lesions were proved by renal biopsy. Blood cadmium in non-smokers was significantly (P less than 0.05) lower than in smokers. We found a positive correlation between cadmium concentrations in blood and urine (P less than 0.01, r = 0.44) and between cadmium concentration in blood and serum uric acid levels (P less than 0.01, r = 0.44). Proteinuria was weakly correlated with cadmium concentration in urine (P less than 0.05, r = 0.35). Patients with hypertension showed a significantly higher (P less than 0.05) urine cadmium excretion per day (1.60 +/- 1.12 micrograms/day compared with normotensives with disease of the kidney (1.14 +/- 1.47 micrograms/day). Our results indicate that cadmium may be involved in the development of hypertension in patients with renal disease.

Iron metabolism in rhEPO-treated hemodialysis patients.

A number of factors have been shown to limit the response to recombinant human erythropoietin (rhEPO). One major factor appears to be an inadequate iron supply to the bone marrow. Erythropoiesis is dependent upon a continuous supply of iron to the bone marrow. The rate at which iron can be drawn from existing stores may easily limit the rate of delivery for hemoglobin synthesis. This may result in "functional iron deficiency" which is distinct from "absolute iron deficiency" caused by depletion of iron stores. At present there are three main parameters available to clinicians wishing to monitor iron status in their patients: serum ferritin and transferrin saturation (TFS), which are indirect measurements, and the percentage of hypochromic red cells, which directly reflects marrow iron status. Ferritin levels should be measured before starting rhEPO therapy to ensure adequate iron stores (> 200 microg/l), and when patients move from the correction phase to the maintenance phase of therapy (have stores become depleted during the correction phase?). In addition, ferritin levels can give an indication of iron overload following excess parenteral iron administration. The TFS represents a balance between iron supply by the stores and demand by bone marrow. A saturation below 20% probably indicates iron-deficient erythropoiesis. However, this is an indirect measure of marrow iron supply and wide fluctuations have been observed when determined at different time points. The percentage of hypochromic red blood cells is measured by flow cytometry and a hypochromic subpopulation of more than 10% (normal percentage > 2.5%) indicates iron-deficient erythropoiesis. However, not all departments have access to the required equipment. The aim of iron supplementation is to provide sufficient iron for the correction phase and replace iron losses (1,500 - 3,000 mg/year in hemodialysis patients) during the maintenance phase of rhEPO therapy. This amounts to a daily iron need in the range of 5-7 mg, which is well above the normal dietary intake and absorptive capacity of the human intestine. Therefore there is a need for intravenous iron, in particular when the patient ha absolute or functional iron deficiency, is in tolerant of oral iron, or is not complying we with the oral regimen.

Anaphylactoid reactions during hemodialysis.

Taken together, with the wide-spread use of ACE-inhibitors within the dialysis population, a novel type of hypersensitivity reaction has been recognized, which may occur not only during hemodialysis but also during other forms of extracorporeal therapy. From the data available today, it seems that such reactions are triggered by negatively charged biomaterials which are capable to activate factor XII, leading among others to the generation of bradykinin. Normally this kinin is rapidly degraded by the serine proteinase kininase II. Thus, in the absence of ACE inhibitors plasma bradykinin levels increase only moderately during dialysis with AN69 membranes and clinically most patients are free of symptoms. However, once kininase II, which is identical with converting enzyme, is blocked by ACE inhibitors, plasma levels may increase more than 100-fold and patients will suffer from severe anaphylaxis. Based on our present knowledge, the consequences for clinical medicine are straightforward. It is mandatory to avoid the combination of negatively charged membranes or other biomaterials with ACE inhibitor therapy. As there are many different membranes available, this should be no unsurmountable problem in the setting of clinical hemodialysis.

Improved sexual function in hemodialysis patients on recombinant erythropoietin: a possible role for prolactin.

As it was reported that correction of anemia in long-term hemodialysis patients by recombinant human erythropoietin (r-HuEPO) is associated with improved sexual function, we conducted the present study to further delineate the mechanism(s) by which this is brought about. Serum prolactin, testosterone, and parathyroid hormone (PTH) levels were followed during 4 months of r-HuEPO therapy. Within 4 months of treatment with r-HuEPO, hematocrit values rose from 23.7 +/- 1.2 to 35.7 +/- 0.2% and hemoglobin increased from 7.3 +/- 0.3 to 11.3 +/- 0.4 g/100 ml. In parallel, serum prolactin values decreased significantly from 66.9 +/- 9.3 to 9.6 +/- 2.6 ng/ml in females and from 39.5 +/- 10.5 to 10.3 +/- 1.0 ng/ml in male dialysis patients. Testosterone concentrations were low in male patients and remained unchanged during r-HuEPO therapy. Baseline PTH values were elevated (1,880 +/- 220 pg/ml) in patients of both sexes and declined to 1,410 +/- 180 pg/ml during treatment with r-HuEPO. However, this difference did not reach statistical significance. Sexual function improved in 4 out of 7 males and 5 out of 9 female patients began to menstruate regularly again. It appears that treatment of anemia in end-stage renal disease by r-HuEPO improves sexual function via normalization of elevated serum prolactin concentrations.

Improvement of dialyzer compatibility by reduction of membrane surface area.

The present study was devised to investigate, whether reduction of membrane surface area would contribute to enhanced dialyzer membrane compatibility. Therefore, 10 hemodialysis patients were dialyzed with three different cuprophan dialyzers, displaying membrane surface areas of 0.9 m2, 1.2 m2, and 1.8 m2. As an index of biocompatibility release of granulocyte elastase and secretion of granulocyte lactoferrin were determined by enzyme-linked immunoassays. With the three cuprophan membranes, marked leukopenia occurred 15 min after the start of hemodialysis, without significant distinction between the different membranes. On the other hand, the release of leukocyte elastase was strictly dependent on the membrane surface area. Thus, at the end of dialysis, plasma levels of elastase were as follows: 0.9 m2: 255 +/- 51; 1.2 m2: 356 +/- 65; 1.8 m2: 471 +/- 56 ng/ml. The magnitude of secretion of leukocytic lactoferrin was also dependent on membrane surface area. Therefore, the increment during dialysis was 300% with the 1.2 m2 membrane compared to 650% using a 1.8 m2 dialyzer. Based upon these data, we concluded that, using measurements of granulocyte degranulation as an index of biocompatibility, reduction of membrane area resulted in a marked improvement of membrane compatibility.

Change of elastase and cathepsin G content in polymorphonuclear leukocytes during hemodialysis.

Previous studies have demonstrated an increment of polymorphonuclear (PMN) elastase plasma levels during hemodialysis, suggesting release of this proteinase during dialysis treatment. In order to gain further evidence that proteinases are liberated from PMN leukocytes during dialysis both plasma levels of PMN elastase and the content of elastase and cathepsin G in neutrophils were determined during 3 hours of hemodialysis with cellulosic membranes (Cuprophan) in 10 patients. In blood smears, obtained at different times during dialysis, neutrophils were classified into 3 groups according to their proteinase content. Thus, group I neutrophils contained low, group II moderate, and group III leukocytes contained high amounts of both proteinases. With regard to their elastase content, prior to the onset of dialysis, 6% of the circulating PMN leukocytes were classified as fraction I, 58% as fraction II, and 36% as fraction III neutrophils. After 15 minutes of dialysis, at the nadir of leukopenia, all fractions of PMN leukocytes were significantly reduced (fraction I: -9%, fraction II: -60%, and fraction III: -83%) as compared to initial values. 30 minutes into hemodialysis, there was a significant increase in fraction I (+ 78%), whereas fraction II (-28%) and fraction III (-70%) remained diminished. At 180 times of hemodialysis the increment of fraction I neutrophils was even more pronounced (+ 187%), fraction II was also increased (+ 16%), and fraction III neutrophils had almost reached initial values. The cathepsin G content of PMN leukocytes displayed a rather similar pattern during dialysis. As to plasma levels of PMN elastase, there was a steady and significant increase from baseline values of 107.3 +/- 11.5 ng/ml up to 388.1 +/- 51.6 ng/ml after 3 hours of hemodialysis.(ABSTRACT TRUNCATED AT 250 WORDS)