Patient blood management knowledge and practice among clinicians from seven European university hospitals: a multicentre survey.

BACKGROUND AND OBJECTIVES: The aim of this survey was to evaluate the knowledge about Patient Blood Management (PBM) principles and practices amongst clinicians working in seven European hospitals participating in a European Blood Alliance (EBA) project. MATERIALS AND METHODS: A web-based questionnaire was sent to 4952 clinicians working in medical, surgery and anaesthesiology disciplines. The responses were analysed, and the overall results as well as a comparison between hospitals are presented. RESULTS: A total of 788 responses (16%) were obtained. About 24% of respondents were not aware of a correlation between preoperative anaemia (POA) and perioperative morbidity and mortality. For 22%, treatment of POA was unlikely to favourably influence morbidity and mortality even before surgery with expected blood loss. More than half of clinicians did not routinely treat POA. 29%, when asked which is the best way to treat deficiency anaemia preoperatively, answered that they did not have sufficient knowledge and 5% chose to 'do nothing'. Amongst those who treated POA, 38% proposed red cell transfusion prior to surgery as treatment. Restrictive haemoglobin triggers for red blood cell transfusion, single unit policy and reduction of number and volumes of blood samples for diagnostic purposes were only marginally implemented. CONCLUSION: Overall, the responses indicated poor knowledge about PBM. Processes to diagnose and treat POA were not generally and homogeneously implemented. This survey should provide further impetus to implement programmes to improve knowledge and practice of PBM.

The revision of the European blood directives: A major challenge for transfusion medicine.

AIM: Using both patient-focused and donor-focused perspectives, to review the current EU blood directives, in order to derive proposals, in principle, for what should evolve during the revision process of these directives. METHODS: Review of the EU blood directives in the light of scientific literature, related reports from the Directorate General Health and Consumers (DG SANTÉ), and from the Council of Europe (CoE). RESULTS: The analyses led us to present the main following proposals: developing voluntary unpaid donations: the directives should consider taking into consideration ethically acceptable forms of compensation consistent with altruistic donation (including plasma donations for fractionation); current expertise: more extensive utilization of the expertise of blood establishments and their consultants should be considered; donor selection: an evidence-based approach for basing donor deferral criteria on sound scientific evidence should be promoted; donor reactions: measures to prevent donor reactions and to make donations safer for the donors should also be included; quality control: The quality control requirements should relate to the Council of Europe Blood Guide specifications: these should become minimum standards (as is the case with monographs of the European Pharmacopeia), facilitating regular update of blood component lists and related specifications and compliance with the specifications; haemovigilance: because of reporting difficulties (e.g. lack of number of blood products transfused), the effectiveness of haemovigilance has so far been limited. This should lead appropriate bodies to investigate alternative or complementary ways to help improve patient safety, taking into consideration, in principle, patient blood management and the appropriate use of blood products. Furthermore, donor vigilance, which is still absent from the current directive should be included in a revised directive. CONCLUSIONS: These proposals for revising the current EU blood directives (if taken into account and given appropriate regulatory formulation) should help to optimize patient safety and donor care, progress the compliance with the ethical principles for donors and improve the efficiency of the healthcare systems dedicated to transfusion medicine.

Collection, processing and testing of bone, corneas, umbilical cord blood and haematopoietic stem cells by European Blood Alliance members.

BACKGROUND AND OBJECTIVES: A questionnaire study was carried out in collaboration with the European Blood Alliance (EBA) Tissues and Cells (T&C) working group. The aim was to assess the level of involvement and commonality of processes on the procurement, testing and storage of bone, corneas, umbilical cord blood (UCB) and haematopoietic stem cells (HSC) in order to identify different practices and to explore whether recommendations can be made for harmonization. MATERIALS AND METHODS: An online questionnaire was used for data collection in 2011, and 43 replies were received covering 71 product answers from 13 countries. RESULTS AND CONCLUSIONS: Estimated percentages of tissue and cell banking covered by EBA member blood banks as a proportion of all collections of each individual country varied markedly. There were also major differences in the amounts of products collected and discarded and in proportions tissues provided for grafting. However, discarding of certain collections also reflects the practice of increasing the likelihood of the very best units being used for transplantation. Harmonization of possible practices should focus on matching supply with demand and on identifying the most efficient operators. This could allow for the development of practices for minimizing unnecessary collections.

Association of CFU-Mk with total colony-forming units in thawed cord blood units.

BACKGROUND AND OBJECTIVES: Cord blood unit (CBU) total colony-forming unit (CFU) count both pre-cryo and post-thaw has been shown to be associated with platelet (PLT) engraftment. Pre-cryo CBUs show good growth of megakaryocytic CFUs (CFU-Mk); however, CFU-Mk have rarely been studied in post-thaw CBUs. MATERIALS AND METHODS: Nucleated cells (NCs) from post-thaw CB were cultured in a collagen-based assay designed to support growth of CFU-Mk. To ensure accurate counting two independent investigators evaluated four culture chambers per sample for CFU-Mk growth. Post-thaw CFU and other cellular characteristics of the CBUs were enumerated independently and compared to CFU-Mk. RESULTS: The post-thaw CBU total CFU count varied from 0·47 to 4·20×10(6) colonies (median, 0·99×10(6)) and total CFU-Mk count from 0·11 to 0·70×10(6) colonies (median, 0·21×10(6)). Total CFU-Mk count was closely associated with total CFU count (Spearman's Rho=0·86, P=0·0072), haemoglobinized CFU (Rho=0·86, P=0·0072) and CFU-granulocyte/macrophage (CFU-GM; Rho=0·81; P=0·0154). Total CFU-Mk count also correlated with the post-thaw total CD34+ cell count (median, 2·55×10(6); range, 1·40-12·5×10(6); Rho=0·83; P=0·0154). CONCLUSION: CFU-Mk growth was associated with total CFU, haemoglobinized CFU, CFU-GM and CD34+ cells in thawed CBUs. This study confirms the preservation of CFU-Mk potential after CB cryopreservation.

Association of cord blood platelet count and volume with hemoglobin in healthy term infants.

OBJECTIVE: The aim of this study was to investigate relationships of cord blood cells in healthy term infants both from vaginal and Cesarean sections. STUDY DESIGN: The study sample comprised 167 consecutive cord blood collections accepted for processing in an accredited cord blood bank. The effect of varying anticoagulant-to-blood ratio was excluded by standardizing the cell concentrations to reflect the values in native blood. Statistical analysis included descriptive statistics, simple linear regression analysis, Mann-Whitney U-test, cumulative frequency plots and Smirnov two-sample test. RESULT: As expected, hemoglobin correlated with red blood cell concentration. Interestingly, mean platelet volume was associated with hemoglobin, red blood cell concentration and hematocrit. The platelet count was inversely associated with the parameters. CONCLUSION: The observed associations of cord blood hemoglobin with mean platelet volume and platelet count reflect the physiology of fetal hematopoiesis at term.

Prothrombin activation fragment 1 + 2 as a marker of coagulation activation in cord blood collection for banking.

There have been efforts to increase the quality of cord blood (CB) collections aimed at banking and transplantation. Yet, the effect of CB collection techniques on haemostatic activation is scarcely studied, despite the unique nature of the neonatal haemostatic system. The aim of this study was to explore coagulation system and platelet (PLT) activation during CB collection at a national CB bank. At three time points over a 9-year period (in 1998, 2000 and 2006), CB collections were assessed to evaluate the collection process during bank setup and changes in procedures. Thrombin generation and PLT activation were assessed with prothrombin activation fragment 1 + 2 (F1 + 2) and PLT factor 4 (PF4), respectively. The median F1 + 2 level was 2.8 nmol L(-1) in 1998 (n = 11), 0.7 nmol L(-1) in 2000 (n = 10) and 0.7 nmol L(-1) in 2006 (n = 6), the decrease being statistically significant (1998 vs 2000, P < 0.001; 1998 vs 2006, P = 0.01). The median PF4 level was 117 IU mL(-1) in 1998 and 104 IU mL(-1) in 2000. PF4 was not measured in 2006. The level of F1 + 2 correlated with that of PF4 (n = 21; Spearman's Rho = 0.59, P = 0.006). Haemostatic activation, assessed as a part of CB bank process control, decreased from the first to the subsequent sample series. F1 + 2 may be a candidate for quality control in CB banking; however, further studies are needed to optimise the analyses and to assess the effect of haemostatic activation on CB quality.

Effect of time interval between food and drug ingestion on the absorption of oxybutynin from a controlled-release tablet.

The effect of time interval between food and drug ingestion on the bioavailability of oxybutynin was investigated in a randomized, three-phase cross-over study in 31 healthy volunteers. The serum concentrations of oxybutynin and the metabolite, N-desethyloxybutynin were measured up to 48 hr after ingestion of a controlled-release 10 mg oxybutynin tablet either in fasting state, 2 hr after breakfast or 1 hr before. The Cmax of both oxybutynin (P < 0.0001) and N-desethyloxybutynin (P < 0.0001) and the AUC0-1 of N-desethyloxybutynin (P < 0.05) were significantly larger when oxybutynin was ingested 2 hr after breakfast, than during the fasting, but the AUC0-1 of oxybutynin remained unchanged. Breakfast ingested 1 hr after oxybutynin did not affect the pharmacokinetic parameters of oxybutynin or N-desethyloxybutynin. The saliva secretion rate decreased slightly more (P < 0.05), when oxybutynin was administered 2 hr after breakfast than during fasting. The effect of food ingestion on the serum concentrations of oxybutynin and N-desethyloxybutynin is expected to have minor clinical significance only. However, ingestion of the controlled-release tablet 1 hr before meal increases the likelihood of obtaining constant drug levels with lower peak concentrations during the dosage interval, and thus ingestion of the controlled-release tablet 0.5-1 hr before food may well improve tolerability and compliance in patients who suffer from adverse reactions.

Itraconazole moderately increases serum concentrations of oxybutynin but does not affect those of the active metabolite.

OBJECTIVE: Oxybutynin has low oral bioavailability due to an extensive presystemic metabolism. It has been suggested that the biotransformation of oxybutynin is dependent on CYP3A. Because itraconazole, a widely used mycotic, is a potent inhibitor of CYP3A4, we wanted to study a possible interaction between oxybutynin and itraconazole. METHODS: In this double-blind, randomized, two-phase cross-over study, ten healthy volunteers received either 200 mg itraconazole or placebo for 4 days. On day 4, each volunteer ingested a single dose of 5 mg oxybutynin. Serum concentrations of oxybutynin, its active metabolite N-desethyloxybutynin, and itraconazole were monitored over 24 h. RESULTS: Itraconazole significantly increased both the area under the serum drug concentration-time curve (AUC0-t) and the peak concentration of oxybutynin twofold. The AUC0-t and the peak concentration of N-desethyloxybutynin were not significantly affected by itraconazole. Itraconazole did not change the peak time or the elimination half-life of either oxybutynin or N-desethyloxybutynin. The occurrence of adverse events after oxybutynin administration was not increased by itraconazole. CONCLUSIONS: Itraconazole moderately increases serum concentrations of oxybutynin, probably by inhibiting the CYP3A-mediated metabolism. However, the concentrations of N-desethyloxybutynin were practically unchanged. Since about 90% of the antimuscarinic activity of oxybutynin is attributable to N-desethyloxybutynin, any interaction of oxybutynin with CYP3A4 inhibiting drugs has only minor clinical significance.

Bioavailability of two clodronate formulations.

Sodium clodronate is effective in the management of osteolytic lesions, hypercalcaemia and bone pain associated with skeletal metastasis. Clinical and biochemical data underpin a licensed total daily dose of 1600-3200 mg.

Effect of food on the bioavailability of oxybutynin from a controlled release tablet.

OBJECTIVE: The effect of food on the bioavailability of oxybutynin was assessed in a randomised cross-over study in 23 healthy volunteers. A single oral 10 mg dose of a controlled release oxybutynin tablet was administered after a high fat breakfast and to fasting subjects. The AUC, Cmax, tmax, t1/2 and MRT of oxybutynin and its active metabolite N-desethyloxybutynin were determined. RESULTS: Breakfast did not change the AUC of oxybutynin but increased the AUC of N-desethyloxybutynin by about 20%. The Cmax of oxybutynin and N-desethyloxybutynin were two-fold higher when the drug was administered after breakfast compared to the fasting state. CONCLUSION: Breakfast significantly reduced the MRT of oxybutynin and N-desethyloxybutynin.

The effect of erythromycin on the pharmacokinetics and pharmacodynamics of zopiclone.

1. The effect of erythromycin on the pharmacokinetics and pharmacodynamics of oral zopiclone, a non-benzodiazepine hypnotic, was investigated in a double-blind, cross-over study. 2. Ten healthy volunteers were given placebo or 500 mg erythromycin orally three times a day for 6 days followed by an oral dose of 7.5 mg zopiclone. 3. Erythromycin increased plasma zopiclone concentration by 4-fold at 0.5 h (P < 0.05) and by 2-fold at 1 h (P < 0.05). There were increases of 3- and 2-fold in the AUC(0,1 h) and AUC(0,2 h) values (P < 0.05). The total AUC of zopiclone increased by 80% (P < 0.05) but the peak concentration by only 40% (P < 0.05). The peak time of zopiclone concentration was reduced from 2 to 1 h (P < 0.001). 4. Significant pharmacodynamic differences between the treatments were observed from 0.5 h to 2 h with respect to saccadic latency and digit symbol substitution tests. 5. The interaction between erythromycin and zopiclone resulted mainly in accelerated absorption which may lead to a faster hypnotic effect in patients.

Dose of midazolam should be reduced during diltiazem and verapamil treatments.

1. The effects of diltiazem and verapamil on the pharmacokinetics and pharmacodynamics of midazolam were investigated in a double-blind randomized cross-over study of three phases. 2. Nine healthy volunteers were given orally diltiazem (60 mg), verapamil (80 mg) or placebo three times daily for 2 days. On the second day they received a 15 mg oral dose of midazolam, after which plasma samples were collected and performance tests carried out for 17 h. 3. The area under the midazolam concentration-time curve was increased from 12 +/- 1 microgram ml-1 min to 45 +/- 5 micrograms ml-1 min by diltiazem (P < 0.001) and to 35 +/- 5 micrograms ml-1 min by verapamil (P < 0.001). The peak midazolam concentration was doubled (P < 0.01) and the elimination half-life of midazolam prolonged (P < 0.05) by both diltiazem and verapamil treatments. 4. These changes in the pharmacokinetics of midazolam were also associated with profound and prolonged sedative effects. 5. If the administration of midazolam cannot be avoided, the dose of midazolam should be reduced during concomitant treatment with diltiazem and verapamil.

A pharmacokinetic interaction between roxithromycin and midazolam.

The interaction between roxithromycin and midazolam was investigated in a double-blind, randomised crossover study of two phases. Ten healthy volunteers were given roxithromycin (300 mg) or placebo once daily for 6 days. On the sixth day they ingested 15 mg midazolam. Plasma samples were collected and psychomotor performance measured for 17 h. Roxithromycin administration significantly increased the area under the plasma midazolam concentration-time curve from 8.3 to 12.2 micrograms.ml-1.min and the elimination half-lives from 1.7 to 2.2 h. In psychomotor performance only minor differences were seen between the treatments in one of the measured psychomotor parameters. Thus, in contrast to the strong interaction between erythromycin and midazolam, the interaction between roxithromycin and midazolam appears less likely to be clinically significant.

Effects of psychotropic drugs on digit substitution: comparison of the computerized symbol-digit substitution and traditional digit-symbol substitution tests.

The digit-symbol substitution test (DSST), performed with paper and pencil or computerized, is widely used to reveal decrements in human attention and cognition. We programmed sets of adjustable tasks (digit-symbol, digit-digit, symbol-digit, symbol-symbol) into a microcomputer and compared the symbol-digit substitution (SDST) and the digit copying test (DDCT) with the traditional DSST in two placebo-controlled double-blind studies of psychotropic drugs with pre-trained young healthy subjects. Performances were measured before drug intake and several times after it; matched, different codes were used at consecutive tests. DSST and SDST substitutions remained at the baseline level after placebo, while the simple DDCT performance improved during the placebo session. The prolonged (3 min) test was not exhaustive because interim counts at 90 s predicted the final performance well. In Trial I, 15 mg diazepam orally reduced DSST and SDST functions in a similar way, but it also impaired simple copying in the DDCT, though to a lesser extent. Ebastine, an H(1)-antihistamine, proved inert alone and failed to increase the effects of diazepam on these variables. In Trial II, 7.5 mg zopiclone, 0.4 mg suriclone and 50 mg chlorpromazine, alone and in combinations, impaired the DSST performance in the manner expected. The drug effects were similar in the SDST, and somewhat less in the DDCT, while the substitution errors were subject related and not altered significantly by any treatment. The simple correlation matrices (Pearson, Spearman), confirmed by analysis of covariance, showed that the results of DSST correlated fairly well with those of SDST after zopiclone, chlorpromazine and their combination, but not after suriclone or its combination with chlorpromazine. The DDCT results correlated with those of the substitution tests when analysing pooled baseline values, but not when analysing the performances after drug intake. Subjective visual analogue variables correlated poorly or not at all with objective performances. Our results suggest that manual dexterity in these computerized tests might contribute significantly to the total impairment of performance in response to different drugs. The DSST and SDST matched each other fairly well in their sensitivity to drug effects, yet this similarity may depend on the drug used.

Ethanol inhibits melatonin secretion in healthy volunteers in a dose-dependent randomized double blind cross-over study.

To elucidate the effects of alcohol on pineal rhythmicity, ethanol was administered in the evening in amounts usually consumed during social ingestion to nine healthy volunteers in a double blind, cross-over study. Plasma concentrations of melatonin, catecholamines (norepinephrine and epinephrine), and ethanol were measured by RIA, high pressure liquid chromatography, and gas chromatography before and for 12 h after the administration of 0, 0.5, and 1 g ethanol/kg wt. Plasma melatonin and catecholamines displayed expected diurnal rhythms, with peak values at 0300-0400 h for melatonin and trough values at 0100-0400 h for catecholamines. Intake of ethanol between 1900-1945 h inhibited the nocturnal melatonin secretion dose-dependently during the first half of the night, with no changes in urinary excretion of melatonin. The inhibition was 41% (P < 0.05) from the control at midnight for both ethanol doses, 33% (P < 0.05) at 0100 h, and 18% (P < 0.05) at 0200 h for the higher dose. In addition, the higher dose of ethanol increased plasma norepinephrine levels at 2000 and 2200 h (P < 0.01) until 0400 h (P < 0.05). Taking into account the involvement of melatonin in the regulation of sleep and diurnal rhythms, we suggest that ethanol-induced suppression of nocturnal melatonin secretion and an increase in noradrenergic activity may be closely associated with disturbances in sleep and performance.

A potentially hazardous interaction between erythromycin and midazolam.

Interaction between erythromycin and midazolam was investigated in two double-blind, randomized, crossover studies. In the first study, 12 healthy volunteers were given 500 mg erythromycin three times a day or placebo for 1 week. On the sixth day, the subjects ingested 15 mg midazolam. In the second study, midazolam (0.05 mg/kg) was given intravenously to six of the same subjects, after similar pretreatments. Plasma samples were collected, and psychomotor performance was measured. Erythromycin increased the area under the midazolam concentration-time curve after oral intake more than four times (p < 0.001) and reduced clearance of intravenously administered midazolam by 54% (p < 0.05). In psychomotor tests (e.g., saccadic eye movements), the interaction between erythromycin and orally administered midazolam was statistically significant (p < 0.05) from 15 minutes to 6 hours. Metabolism of both erythromycin and midazolam by the same cytochrome P450IIIA isozyme may explain the observed pharmacokinetic interaction. Prescription of midazolam for patients receiving erythromycin should be avoided or the dose of midazolam should be reduced by 50% to 75%.

Diazepam effects on the performance of healthy subjects are not enhanced by treatment with the antihistamine ebastine.

1. We have given 12 healthy subjects the H1-antihistamine ebastine (20 mg) or placebo in a randomized double-blind and crossover study for 1 week each. The subjects were tested for drug effects on day 6 of each period, and for interactions of ebastine with oral 15 mg diazepam (DZ) on day 7. On both days, the testing runs were at baseline and 1.5, 3, 4.5 and 6 h after intake. 2. The performance was evaluated both objectively (digit symbol substitution, flicker fusion, Maddox wing, simulated driving, body balance) and subjectively (visual analogue scales, questionnaires). Venous blood was sampled daily during the maintenance and during each testing round for the assay of plasma carebastine (the active metabolite of ebastine) by high pressure liquid chromatography and plasma diazepam by radioreceptor assay. Three-way ANOVA, paired t-test, Wilcoxon rank sign test and Fisher's fourfold table test were used for data analysis. 3. Plasma carebastine reached steady levels from day 3 onwards. The mean concentrations in the morning were 82 micrograms l-1 on day 6 and 85 micrograms l-1 on day 7. The rise (+ 150%) in plasma carebastine after an extra 20 mg ebastine was not modified by DZ. Ebastine did not affect performance objectively or subjectively, yet borderline drowsiness was recorded during the first 3 h. On day 7, plasma DZ concentrations peaked (mean 480 micrograms l-1) at 1.5 h after the intake. DZ produced impaired performance in various objective tests, and drowsiness, weakness, clumsiness, mental slowness and poor performance were reported on visual analogue scales.(ABSTRACT TRUNCATED AT 250 WORDS)

A survey of sudden death associated with the use of antipsychotic or antidepressant drugs: 49 cases in Finland.

Phenothiazines have repeatedly been found to be associated with cases of sudden death, but the issue of causality has remained controversial. A survey of medicolegal autopsies performed in Finland over a 3-year period revealed that sudden unexpected deaths of 31 women (mean age 44 years, range 25-69) and 18 men (mean age 40 years, range 26-62) were associated with either the use of antipsychotic or antidepressant drugs. Therapeutic use of phenothiazines was documented in all but 3 of these 49 cases and thioridazine was involved in over half of them. Thus, whereas thioridazine was the only antipsychotic drug associated with 15 cases, only 5 cases were associated with any of the other antipsychotic or antidepressant drugs. The differences between the subgroups of psychotropic drugs remained clear after adjustment according to the respective data on drug use in the population. Although there are several uncontrolled confounding factors, the overrepresentation of phenothiazines, especially thioridazine, among psychiatric patients who died suddenly is striking and, taken together with their well-established arrhythmogenic effects, warrants further attention.