Evaluation of clinical coding data to determine causes of critical bleeding in patients receiving massive transfusion: a bi-national, multicentre, cross-sectional study.

OBJECTIVES: To evaluate the use of routinely collected data to determine the cause(s) of critical bleeding in patients who receive massive transfusion (MT). BACKGROUND: Routinely collected data are increasingly being used to describe and evaluate transfusion practice. MATERIALS/METHODS: Chart reviews were undertaken on 10 randomly selected MT patients at 48 hospitals across Australia and New Zealand to determine the cause(s) of critical bleeding. Diagnosis-related group (DRG) and International Classification of Diseases (ICD) codes were extracted separately and used to assign each patient a cause of critical bleeding. These were compared against chart review using percentage agreement and kappa statistics. RESULTS: A total of 427 MT patients were included with complete ICD and DRG data for 427 (100%) and 396 (93%), respectively. Good overall agreement was found between chart review and ICD codes (78·3%; κ = 0·74, 95% CI 0·70-0·79) and only fair overall agreement with DRG (51%; κ = 0·45, 95% CI 0·40-0·50). Both ICD and DRG were sensitive and accurate for classifying obstetric haemorrhage patients (98% sensitivity and κ > 0·94). However, compared with the ICD algorithm, DRGs were less sensitive and accurate in classifying bleeding as a result of gastrointestinal haemorrhage (74% vs 8%; κ = 0·75 vs 0·1), trauma (92% vs 62%; κ = 0·78 vs 0·67), cardiac (80% vs 57%; κ = 0·79 vs 0·60) and vascular surgery (64% vs 56%; κ = 0·69 vs 0·65). CONCLUSION: Algorithms using ICD codes can determine the cause of critical bleeding in patients requiring MT with good to excellent agreement with clinical history. DRG are less suitable to determine critical bleeding causes.

Improving outcomes for hospital patients with critical bleeding requiring massive transfusion: the Australian and New Zealand Massive Transfusion Registry study methodology.

BACKGROUND: The Australian and New Zealand (ANZ) Massive Transfusion (MT) Registry (MTR) has been established to improve the quality of care of patients with critical bleeding (CB) requiring MT (≥ 5 units red blood cells (RBC) over 4 h). The MTR is providing data to: (1) improve the evidence base for transfusion practice by systematically collecting data on transfusion practice and clinical outcomes; (2) monitor variations in practice and provide an opportunity for benchmarking, and feedback on practice/blood product use; (3) inform blood supply planning, inventory management and development of future clinical trials; and (4) measure and enhance translation of evidence into policy and patient blood management guidelines. The MTR commenced in 2011. At each participating site, all eligible patients aged ≥18 years with CB from any clinical context receiving MT are included using a waived consent model. Patient information and clinical coding, transfusion history, and laboratory test results are extracted for each patient's hospital admission at the episode level. RESULTS: Thirty-two hospitals have enrolled and 3566 MT patients have been identified across Australia and New Zealand between 2011 and 2015. The majority of CB contexts are surgical, followed by trauma and gastrointestinal haemorrhage. Validation studies have verified that the definition of MT used in the registry correctly identifies 94 % of CB events, and that the median time of transfusion for the majority of fresh products is the 'product event issue time' from the hospital blood bank plus 20 min. Data linkage between the MTR and mortality databases in Australia and New Zealand will allow comparisons of risk-adjusted mortality estimates across different bleeding contexts, and between countries. Data extracts will be examined to determine if there are differences in patient outcomes according to transfusion practice. The ratios of blood components (e.g. FFP:RBC) used in different types of critical bleeding will also be investigated. CONCLUSIONS: The MTR is generating data with the potential to have an impact on management and policy decision-making in CB and MT and provide benchmarking and monitoring tools for immediate application.

Diagnosis and management of thrombotic thrombocytopenic purpura (TTP) in Australia: findings from the first 5 years of the Australian TTP/thrombotic microangiopathy registry.

BACKGROUND: Thrombotic thrombocytopenic purpura (TTP) is a rare, life-threatening thrombotic microangiopathy (TMA). In 2009, the Australian TTP/TMA registry was established to collect data on patients presenting with TTP/TMA throughout Australia. AIM: To summarise information on the diagnosis and management of patients with TTP collected in the first 5 years (2009-2014) of the Australian TTP registry. METHODS: Registry data from June 2009 to October 2014 were reviewed. RESULTS: Fifty-seven patients were identified with TTP (defined as ADAMTS13 activity <10%), accounting for 72 clinical episodes. ADAMTS13 inhibitor testing was performed in nine out of 57 patients (16%), reflecting the limited availability of accredited testing facilities. Sixty-seven out of 72 episodes were treated with therapeutic plasma exchange (PEx) using cryodepleted plasma (40% of episodes), fresh frozen plasma (36%) or a mixture (22%). Median exposure to plasma products was 55.9 L. PEx was commenced ≥2 days from stated diagnosis in 15% of episodes. Adverse reactions to PEx were common with documented allergic reactions (including life threatening) in 21% of episodes. Adjunctive immunosuppression was documented in 76% of episodes (corticosteroid 71% and rituximab 39%). Platelet transfusion was administered in 15% of episodes. CONCLUSIONS: Data from the Australian TTP/TMA registry suggest a heterogenous approach to the diagnosis and management of TTP in Australia over the assessed period. These observations highlight areas for improvement and standardisation of practice, including comprehensive diagnostic testing, more immediate access to PEx and a more uniform approach to adjunctive immunosuppression and supportive care.

Elucidating the clinical characteristics of patients captured using different definitions of massive transfusion.

BACKGROUND AND OBJECTIVES: The type and clinical characteristics of patients identified with commonly used definitions of massive transfusion (MT) are largely unknown. The objective of this study was to define the clinical characteristics of patients meeting different definitions of MT for the purpose of patient recruitment in observational studies. MATERIALS AND METHODS: Data were extracted on all patients who received red blood cell (RBC) transfusions in 2010 at three tertiary Australian hospitals. MT patients were identified according to three definitions: ≥10 units RBC in 24 h (10/24 h), ≥6 units RBC in 6 h (6/6 h) and ≥5 units RBC in 4 h (5/4 h). Clinical coding data were used to assign bleeding context. Data on in-hospital mortality were also extracted. RESULTS: Five hundred and forty-two patients met at least one MT definition, with 236 (44%) included by all definitions. The most inclusive definition was 5/4 h (508 patients, 94%) followed by 6/6 h (455 patients, 84%) and 10/24 h (251 patients, 46%). Importantly, 40-55% of most types of critical bleeding events and 82% of all obstetric haemorrhage cases were excluded by the 10/24 h definition. Patients who met both the 5/4 h and 10/24 h definitions were transfused more RBCs (19 vs. 8 median total RBC units; P < 0·001), had longer ventilation time (120 vs. 55 h; P < 0·001), median ICU (149 vs. 99 h; P < 0·001) and hospital length of stay (23 vs. 18 h; P = 0·006) and had a higher in-hospital mortality rate (23·3% vs. 16·4%; P = 0·050). CONCLUSION: The 5/4 h MT definition was the most inclusive, but combination with the 10/24 h definition appeared to identify a clinically important patient cohort.

Investigation of outcomes following recombinant activated FVII use for refractory bleeding during abdominal aortic aneurysm repair.

OBJECTIVE: To evaluate the outcomes following recombinant activated factor VII (rFVIIa) use during abdominal aortic aneurysms (AAA) repair. DESIGN: AAA patients were selected from the Australian and New Zealand Haemostasis Registry (ANZHR) who received off-licence rFVIIa to control critical bleeding. METHODS: Patient characteristics and outcomes were compared between responders (bleeding stopped/attenuated) and non-responders (bleeding continued) to rFVIIa, stratified by aneurysm status (ruptured (r-AAA) vs. non-ruptured (nr-AAA)). Patients were also scored using POSSUM (Physiological and Operative Severity Score for the enUmeration of Mortality and morbidity) and Hardman Index mortality predictive models. RESULTS: In total, 77 AAA patients were included in the analysis. Approximately 73% (n = 56) of them had ruptured aneurysms and about 50% (n = 35/70 with known data) responded positively to rFVIIa. Eleven incidents of thromboembolic adverse events were reported in 9 patients (6 r-AAA and 3 nr-AAA). Responders in both ruptured and non-ruptured groups had significantly lower 28-day mortality than non-responders (r-AAA: 40% (10/25) vs. 92% (24/26); P < 0.001; nr-AAA: 30% (3/10) vs. 67% (6/9); P < 0.01). Mortality predictive models did not show any difference between overall observed and expected mortality in ANZHR patients. CONCLUSION: Patients who responded to rFVIIa had a lower mortality than those who did not respond to the treatment.

Transfusion practice and guidelines in Australian and New Zealand intensive care units.

OBJECTIVE: To describe the relationship between clinical practice and national guidelines for the transfusion of red blood cells (RBCs), fresh frozen plasma (FFP), platelets, and cryoprecipitate in Australian and New Zealand intensive care units (ICUs). SETTING: Forty-seven ICUs over a 5-week period from August to September 2008. DESIGN: Prospective, observational, multicentre, cohort study. PATIENTS: A total of 874 patients receiving any type of blood transfusion. METHODS: All patients who were transfused at least one unit of any blood component were included. Patient-specific and blood-component specific data were gathered. Pre-transfusion haemoglobin, platelet count, international normalised ratio (INR), and fibrinogen levels were compared to national guidelines. RESULTS: Of all 874 patients, 757 received RBCs (86.6%), 231 (26.4%) received platelets, 340 (38.9%) received FFP, and 78 (8.9%) received cryoprecipitate. Bleeding was the reason for administration of RBCs in 46%, FFP in 55%, and platelets in 47% of transfusions. The mean (SD) pre-transfusion haemoglobin was 77.6 (9.5) g/l, while the geometric means (95% CI) for platelet count, INR, and fibrinogen were 67.0 (59.7-75.3) x 10(9)/l, 1.84 (1.76-1.93), and 1.4 (1.1-1.8) g/l, respectively. The proportions of transfusions not adherent to guidelines were 2% for RBC, but 53% for platelets, 29% for FFP, and 88% for cryoprecipitate (RBC vs. other transfusion p < 0.001 for all). CONCLUSIONS: Transfusion practice of RBCs in Australian and New Zealand ICUs is restrictive and is concordant with guidelines. However, the transfusion of other blood components is not.

Mice lacking synapsin III show abnormalities in explicit memory and conditioned fear.

Synapsin III is a neuron-specific phosphoprotein that plays an important role in synaptic transmission and neural development. While synapsin III is abundant in embryonic brain, expression of the protein in adults is reduced and limited primarily to the hippocampus, olfactory bulb and cerebral cortex. Given the specificity of synapsin III to these brain areas and because it plays a role in neurogenesis in the dentate gyrus, we investigated whether it may affect learning and memory processes in mice. To address this point, synapsin III knockout mice were examined in a general behavioral screen, several tests to assess learning and memory function, and conditioned fear. Mutant animals displayed no anomalies in sensory and motor function or in anxiety- and depressive-like behaviors. Although mutants showed minor alterations in the Morris water maze, they were deficient in object recognition 24 h and 10 days after training and in social transmission of food preference at 20 min and 24 h. In addition, mutants displayed abnormal responses in contextual and cued fear conditioning when tested 1 or 24 h after conditioning. The synapsin III knockout mice also showed aberrant responses in fear-potentiated startle. As synapsin III protein is decreased in schizophrenic brain and because the mutant mice do not harbor obvious anatomical deficits or neurological disorders, these mutants may represent a unique neurodevelopmental model for dissecting the molecular pathways that are related to certain aspects of schizophrenia and related disorders.

Clinical guidelines and off-license recombinant activated factor VII: content, use, and association with patient outcomes.

BACKGROUND: Recombinant activated factor VII (rFVIIa) is increasingly being used off-license for treating critical bleeding. Guidelines may therefore be useful for improving processes and outcomes. Little is known regarding guidelines for off-license rFVIIa or their association with patient outcomes. OBJECTIVES: To investigate the availability of hospital guidelines for off-license rFVIIa use and the association between these guidelines and mortality. METHODS: Data were extracted from the Haemostasis Registry, which collects all cases of off-license rFVIIa use in participating institutions in Australia and New Zealand. Contributing hospitals were requested to supply a copy of the institutional guideline relating to off-license rFVIIa administration. The characteristics of patients treated in accordance with all elements of the guidelines were compared with those of patients for who one or more guideline elements had been violated. The relationship between guideline-directed treatment and 28-day mortality was investigated using stepwise logistic regression. RESULTS: Two thousand five hundred and fifty-one patients in 75 hospitals were available for analysis. Of these hospitals, 58 provided a guideline for analysis. Patients complying with all guideline elements (n = 530) did not differ from patients receiving care that violated guidelines (n = 1035) regarding age, size of dose, or gender. Guideline-directed treatment was not found to have an association with 28-day mortality following logistic regression. CONCLUSIONS: Few patients are treated in accordance with the criteria of rFVIIa guidelines, despite their availability in the majority of hospitals. Moreover, 28-day mortality does not appear to be associated with the use of guidelines in this patient group. Refinement of guidelines relating to the off-license use of rFVIIa is therefore required.

Uncontrolled bleeding in surgical patients: the role of recombinant activated factor VIIa.

Recombinant activated factor VII (rFVIIa), developed and effective in managing inhibitors in haemophilia patients, is being widely used off-label as a "panhaemostatic agent" with ongoing controversy as to its benefits and risks in terms of controlling critical haemorrhage and improving patient outcomes. Current insights into haemostatic mechanisms have resulted in a better understanding of the central role of FVII/FVIIa and tissue factor in the localization and initiation of haemostasis. There is a plethora of case reports and series published on the use of rFVIIa in critical life-threatening haemorrhage and in perioperative settings associated with significant blood loss or the potential for catastrophic haemorrhage. Additionally, the literature is replete with reviews for the use of rFVIIa in various clinical settings, but there is a dearth of good evidence from randomized controlled trials for efficacy. Safety, especially from the thrombogenicity perspective, has been a major issue, but turns out to be less of a concern with thrombotic potential needing to be weighed against the anticipated benefits. Although there is some clinical trial and observational data supporting efficacy it has been difficult to recommend clear clinical practice guidelines, especially as clinical outcome data in terms of morbidity and mortality is limited. Some of the best evidence relates to reduction in allogeneic blood transfusion requirements. This in itself is important and probably clinically relevant in view of the accumulating evidence that allogeneic blood transfusion is an independent risk factor for poorer clinical outcome. It is unlikely that there will be adequate randomized clinical trials to better answer the question of efficacy, thus making data from registries of greater importance. Indeed, the process of establishing efficacy, safety and regulation of a therapeutic that is increasingly used off-label is not without significant difficulties.

Antifibrinolytics in cardiac surgical patients receiving aspirin: a systematic review and meta-analysis.

While conventional practice is to discontinue aspirin prior to elective cardiac surgery there is evidence that its continuation may be associated with improved perioperative outcomes. However, uncertainty exists regarding the efficacy of antifibrinolytic agents in the presence of aspirin. We performed a systematic review and meta-analysis of the literature to address the question of the effects of antifibrinolytic agents in cardiac surgery patients maintained on aspirin in terms of both efficacy and adverse events. We conducted an extensive search for randomized controlled trials of antifibrinolytic use in adult patients undergoing coronary artery bypass grafting +/- valve surgery, where aspirin therapy was maintained or initiated through the preoperative period. Data from 17 trials (n=1620) confirmed the efficacy of antifibrinolytic therapy to reduce both chest-tube drainage (weighted mean difference 374 ml, 95% CI 275-473 ml; P<0.00001) and blood transfusion requirements (odds ratio 0.37, 95% CI 0.27-0.49; P<0.00001) in cardiac surgical patients receiving aspirin. We found no difference in the rates of adverse events between groups but observed a trend towards a reduced risk for the composite outcome of thrombotic complications (odds ratio 0.49, 95% CI 0.21-1.13; P=0.09). Antifibrinolytic agents are effective for reducing both chest-tube drainage and transfusion requirements in cardiac surgical patients receiving aspirin. We found no difference between antifibrinolytic and placebo in terms of adverse events but the population was predominantly low-risk. Further studies are required to determine the optimal balance between antiplatelet and antifibrinolytic effects in cardiac surgery.

Intracranial meningioma and ionizing radiation in medical and occupational settings.

In a population-based case-control study of 200 cases and 400 controls in western Washington State, the authors assessed associations between meningioma and ionizing radiation in medical and occupational settings. No significant associations were observed for diagnostic studies or occupational settings, but associations were observed for radiation therapy to head or neck (odds ratio 3.7, 95% CI 1.5 to 9.5), especially for neoplastic conditions. Only four patients (2%) had meningiomas that followed high-dose cranial radiation.

History of head trauma and risk of intracranial meningioma: population-based case-control study.

A population-based case-control study in western Washington state was performed to assess the relation between head trauma and meningioma. Based on 200 case and 400 control subjects, head trauma was associated with an increased risk of meningioma (odds ratio = 1.83; 95% CI = 1.28, 2.62), especially head traumas occurring 10 to 19 years before reference date (odds ratio = 4.33; 95% CI = 2.06, 9.10). A dose-response relationship was present for number, but not severity, of head traumas. Whether the associations observed in this study are causal remains unclear.

Chilling invokes different morphologies in two Salmonella enteritidis PT4 strains.

The reduction in chemical preservatives in food processing has resulted in more refrigerated (chilled) products. However, the effect of chilling on Salmonella enteritidis PT4 isolates has received relatively little attention. This study investigates the effect of chilling on two Salm. enteritidis PT4 isolates, denoted E and I. These isolates differ in their tolerance to heat, acidification, survival on surfaces, and behaviour in animal models. E routinely shows greater tolerance and pathogenicity than I. Chilling invokes profound cell elongation and heterogeneity in E which corresponded to a 90% sublethal injury; neither such substantial cell elongation nor significant injury was seen in I. The ability to recover resistance to desoxycholate coincided with a reduction to normal cell size. Incomplete cell division and failure of the septum to form is a likely hypothesis for cell elongation although outer membrane changes could be responsible. Possible links are suggested between cell elongation of the hat- and acid-tolerant strain and pathogenicity.

Mastopathy in insulin-requiring diabetes mellitus.

Diabetic mastopathy is a recently described collection of histopathological features found in dense fibrous breast masses in insulin-requiring diabetics. Fifty-seven breast biopsy specimens showing nonspecific benign disease were examined in a blinded fashion from 21 diabetics (seven insulin-requiring, 14 non-insulin-requiring), 30 age-matched controls and six patients with thyroid disease. Five diabetics had the constellation of extensive keloidal fibrosis, mononuclear perivasculitis, and mononuclear ductitis and/or lobulitis, whereas none of the controls or patients with thyroid disease had all of these features. All five patients with diabetic mastopathy were insulin-requiring (two type I, three type II). Epithelioid fibroblasts in the stroma, a previously described component of this constellation, were present in three of the five cases but do not appear to be essential in making the diagnosis. Four of the five diabetics were hypertensive, and three had secondary diabetic complications. The mean duration of diabetes in the five patients was greater than 13 years. Based on a previous report and the current study, this constellation of histological features appears to be relatively specific for insulin-requiring diabetes mellitus. The single clinical factor common to all patients with diabetic mastopathy in this article and in a previous study was exogenous insulin use.

Results of a double-blind, placebo-controlled clinical trial program of single-dose ceftizoxime versus multiple-dose cefoxitin as prophylaxis for patients undergoing vaginal and abdominal hysterectomy.

In a series of three double-blind, controlled, clinical studies, the efficacy and safety of a single 1 gram dose of ceftizoxime were compared with those of a standard regimen, three 2 gram doses of cefoxitin, for prophylaxis of perioperative infection in women undergoing abdominal or vaginal hysterectomy. Two hundred and twenty-seven patients received ceftizoxime prophylaxis and 234 patients received cefoxitin prophylaxis. Study 1 entered 110 patients in Dallas, Texas and Los Angeles, California. Study 2 entered 242 patients in Canada. Study 3 entered 109 patients in Denver, Colorado. Within studies, the distribution of surgical procedures was comparable between antibiotic groups. The groups were similar for demographic and medical factors at each center and overall. Analyses were performed within and across studies, applying consistent criteria to the selection of evaluable patients and to the definitions of prophylactic success and primary and secondary prophylactic failure. Three hundred and sixteen patients were evaluable, 160 who received ceftizoxime and 156 who received cefoxitin. Overall, complete prophylactic success occurred in 138 of 160 evaluable patients (86.3 percent) receiving ceftizoxime and 128 of 156 evaluable patients (82.1 percent) receiving cefoxitin. Prophylactic success rates differed by study as well as by type of hysterectomy. In studies 1 and 2, prophylactic success rates for ceftizoxime were 95.1 and 87.6 percent, respectively, versus 93.1 and 87.8 percent for cefoxitin. In study 3, success rates were lowest, 70.0 percent for ceftizoxime and 59.5 percent for cefoxitin. Among evaluable patients overall, prophylactic success rates after vaginal hysterectomy were 91.0 percent for those receiving ceftizoxime and 85.1 percent for those receiving cefoxitin. After abdominal hysterectomy, success rates were 78.3 percent for both groups. Febrile morbidity rates and duration of hospitalization were comparable for both groups across all studies and within individual studies. Ceftizoxime and cefoxitin were safe and well tolerated. The results of these controlled studies indicate that single-dose ceftizoxime is as effective and safe as multiple-dose cefoxitin when used as adjunctive chemoprophylaxis in patients at risk of postoperative infection after vaginal or abdominal hysterectomy.