Descriptive characteristics and in-hospital mortality of critically bleeding patients requiring massive transfusion: results from the Australian and New Zealand Massive Transfusion Registry.

BACKGROUND AND OBJECTIVES: Critically bleeding patients requiring massive transfusion (MT) are clinically challenging, and limited data exist to support management decisions. This study describes patient characteristics, transfusion support and clinical outcomes from the Australian and New Zealand (NZ) Massive Transfusion Registry (ANZ-MTR). MATERIALS AND METHODS: Retrospective, cohort study of all adult patients receiving MT (≥5 units red blood cells [RBC] in 4 h) at participating ANZ-MTR hospitals, 2011-2015. Mortality information was collected from the Australian National Death Index and NZ Ministry of Health. Associations between patient characteristics and outcomes were modelled using logistic regression. RESULTS: A total of 3560 MT cases were identified. For in-hospital deaths, cardiothoracic surgery was the most frequent bleeding context (24·5%) followed by trauma (18·3%). Age (OR = 1·03; 95% CI: 1·02-1·04), more comorbidities (OR = 1·14; 95% CI: 1·09-1·21), larger volume of RBC in first 24 h from MT onset (OR = 1·04; 95% CI: 1·02-1·06), higher platelet to RBC ratio at 4 h (OR = 2·76; 95% CI: 1·14-6·65) and higher activated partial thromboplastin time (OR = 1·02; 95% CI: 1·01-1·03) were associated with in-hospital mortality. CONCLUSION: Patients with more comorbidities, older age, traumatic or surgical bleeding or requiring more blood components had higher in-hospital mortality. These findings provide a basis to evaluate and monitor practice relating to optimal use of blood products, variation in transfusion practices and patient outcomes, and also enable benchmarking of hospital performance for management of MT in specific patient groups.

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 red cell transfusion in the elective surgical setting: an improvement collaborative with evaluation.

BACKGROUND & OBJECTIVES: Significant research conducted in New South Wales (NSW) hospitals' indicated that about 30% of red cell transfusions in stable adult patients was inappropriate. Of the total Australian government blood product budget in 2009-2010 (i.e. $878·8 million dollars) was spent on fresh blood products and plasma collection. The Clinical Excellence Commission (CEC) launched a systematic intervention called Blood Watch (BW) aiming to reduce inappropriate red cell transfusions in all NSW hospitals. An evaluation of BW was undertaken to measure the effectiveness of the programme and to estimate the associated potential cost-saving. MATERIALS & METHODS: Through the deterministic linkage of the four population-based administrative databases, three outcome indicators and four process indicators were developed. The analyses were of five elective surgical groups as they were the focus of the interventions. Three-level logistic regression and three-level linear regression were used to explore the time trend of the study process and outcome indicators. Modelling of the possible avoided red cell transfusions was also undertaken using a quadratic regression technique. RESULTS: Overall, there was a 27·4% reduction of the blood usage after the introduction of the BW programme and the reductions were consistent across five elective surgical groups. Such a reduction was associated with annual cost-savings of over $8·5 million. CONCLUSIONS: The BW programme which was based on collaborative improvement methods and implemented at scale led to significant reduction of blood usage, consistently across five elective surgical groups and significant cost-saving.

What factors contribute to hospital variation in obstetric transfusion rates?

BACKGROUND AND OBJECTIVES: To explore variation in red blood cell transfusion rates between hospitals, and the extent to which this can be explained. A secondary objective was to assess whether hospital transfusion rates are associated with maternal morbidity. MATERIALS AND METHODS: Linked hospital discharge and birth data were used to identify births (n = 279 145) in hospitals with at least 10 deliveries per annum between 2008 and 2010 in New South Wales, Australia. To investigate transfusion rates, a series of random-effects multilevel logistic regression models were fitted, progressively adjusting for maternal, obstetric and hospital factors. Correlations between hospital transfusion and maternal, neonatal morbidity and readmission rates were assessed. RESULTS: Overall, the transfusion rate was 1.4% (hospital range 0.6-2.9) across 89 hospitals. Adjusting for maternal casemix reduced the variation between hospitals by 26%. Adjustment for obstetric interventions further reduced variation by 8% and a further 39% after adjustment for hospital type (range 1.1-2.0%). At a hospital level, high transfusion rates were moderately correlated with maternal morbidity (0.59, P = 0.01), but not with low Apgar scores (0.39, P = 0.08), or readmission rates (0.18, P = 0.29). CONCLUSION: Both casemix and practice differences contributed to the variation in transfusion rates between hospitals. The relationship between outcomes and transfusion rates was variable; however, low transfusion rates were not associated with worse outcomes.

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.

Postoperative risk stratification in oral squamous cell carcinoma.

Postoperative prognostic stratification using the Union for International Cancer Control (UICC) TNM 8th edition staging rules (UICC 8) may identify additional groups of patients who could benefit from adjuvant radiotherapy. Currently, selection for such treatment is not based on all known prognostic factors, and their relative importance may vary depending on the overall risk category. The objective of this study therefore was to evaluate these possibilities. We retrospectively studied 644 patients who had surgery with curative intent for oral squamous cell carcinoma (OSCC) between March 2006 and February 2017. The outcomes of interest were disease-specific survival (DSS) and locoregional recurrence (LRR). Patients were re-staged according to the UICC 8 staging rules. Putative clinical and pathological prognostic variables were evaluated and hazard ratios estimated. Regression analysis was done to identify independent prognostic factors, and iterative analyses identified clinically-relevant risk categories with a minimum of residual prognostic variables. The significance of recognised pathological prognostic factors differed according to the overall risk category. An intermediate risk group comprising patients with pN1 disease as well those with pT3 disease solely on the basis of a depth of invasion (DOI) of more than 10 mm, was identified. A trial to evaluate the benefit or otherwise of adjuvant radiotherapy in this group is now required. Individual prognostic risk factors should be considered within the context of the overall risk category in patients with OSCC.

Memory performance of chemical workers exposed to polybrominated biphenyls.

Twenty-five chemical workers who manufactured polybrominated biphenyls (PBB's) were given objective tests of learning and memory. Although this group had high concentrations of PBB's in adipose tissue, mean scores on all memory tests were normal. The PBB concentration was not correlated with memory performance; the most contaminated workers showed no evidence of memory dysfunction.

Recombinant activated factor VII in critical bleeding: experience from the Australian and New Zealand Haemostasis Register.

BACKGROUND: There has been increasing off-label use of recombinant activated factor VII (rFVIIa/NovoSeven; Novo Nordisk, Bagsvaerd, Denmark) for patients with critical bleeding. Given the lack of high-level evidence, the clinical indications, observed response and adverse events are important to capture. METHODS: The Haemostasis Registry collects retrospective and contemporaneous data on all use of rFVIIa at participating institutions for non-haemophiliac patients with critical bleeding (i.e. off-label use). RESULTS: As of October 2006, 694 cases had been reported into the register from 37 hospitals across Australia and New Zealand. These comprise an array of therapeutic categories, including salvage use in: perioperative cardiothoracic surgery (44%), trauma (16%), medical bleeding (9%), obstetric bleeding (4%) and other types of critical bleeding (28%). Patients received a median (interquartile range) dose of 91 mug/kg (75-103) and 83% of patients received a single dose of rFVIIa. The documented response rate to a single dose of rFVIIa was 69%. The 28-day survival was 68%, but varied with clinical category. The rate of adverse events probably or possibly linked to the use of rFVIIa was 6%, with most of the thromboembolic adverse events occurring in the cardiac surgery group. CONCLUSION: The Haemostasis Registry cannot replace well-designed prospective randomized controlled trials, but in their absence this registry provides a basis for understanding current clinical experience of rFVIIa. Registries continue to be vital in monitoring off-label uses of medications.

Clinicians as gatekeepers: what is the best route to optimal blood use?

Maintaining the supply of allogeneic blood has always been a challenge and its optimal use difficult to ensure and monitor. Increasingly, economic pressures and public perceptions have been driving decision making in delivery of sufficient and safe blood components of high quality. On the other hand, many of the assumed benefits of allogenic blood component therapy are being questioned, and the potential hazards of transfusion have been underestimated. Indeed, recent evidence suggests that in many clinical settings there are significant under-recognised hazards of transfusion in which benefit is difficult to confirm. This paper questions the current paradigm, in which there is excessive focus on the supply side of the blood transfusion chain rather than the clinical problem facing patients and clinicians. Blood transfusion should no longer be the default therapeutic decision when evidence for efficacy is lacking and there is clinical uncertainty. The appropriateness of transfusion practices will only improve, not by expecting clinicians to be gatekeepers of the blood supply, but with better patient blood management based on a sound understanding of pathophysiology and better evidence for transfusion efficacy. Evidence-based transfusion medicine should view a patient's own blood as a valuable and unique natural resource that should be conserved and managed appropriately. Altruistically donated allogeneic blood transfusion should only be used as therapy when there is evidence for potential benefit, there are no alternatives, a quality product is available and the risks are appropriately considered and balanced against the benefits.

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.

Fulminant lupus pneumonitis with acute renal failure and RBC aplasia. Successful management with plasmapheresis and immunosuppression.

Acute interstitial pneumonitis is a well-recognized, although rare, complication of systemic lupus erythematosus (SLE) that has been associated with a poor prognosis. Fulminant lupus pneumonitis, acute renal failure, and RBC hypoplasia occurred in a 14-year-old girl. The patient's condition was managed with large-volume plasmapharesis, dialysis, and immunosuppressive therapy. Her respiratory, renal, and hematologic changes all resolved, and response was maintained with cyclophosphamide and prednisolone therapy. Although serologic evidence of SLE persisted, clinically, the patient was well four years after the initial appearance of SLE. There are several acute pulmonary manifestations of SLE, and plasmapheresis may be useful in the management of some of these conditions.

The effects of plasma exchange on cholesterol metabolism.

Four patients heterozygous for familial hypercholesterolaemia were treated by repeated plasma exchange with or without lipid-lowering drugs. Repeated plasma exchange without drug therapy in 3 patients was associated with a significant 18--28% decrement in plasma cholesterol level, comparing control with plateau values observed 3 weeks after exchange. Further decrements in plateau values followed the addition of lipid-lowering drugs used in combination, clofibrate--nicotinic acid or clofibrate--nicotinic acid--cholestyramine (range of total decrement 39--50%). Plasma exchange was associated with an increased excretion of endogenous faecal steroids, but this increase was completely abolished by the subsequent administration of clofibrate--nicotinic acid. This therapy prevented any increase in bile acid excretion with concomitant use of cholestyramine resin. Plasma exchange with drug therapy was associated with a sustained rise in plasma cholesterol specific radioactivity. In a fourth patient, clofibrate--nicotinic acid was administered prior to plasma exchange and led to a 24% fall in plasma cholesterol. Subsequent plasma exchange in this patient produced no sustained change in plasma cholesterol plateau level. In two patients, withdrawal of drugs allowed plasma cholesterol to return to pre-exchange control levels. These observations suggest that plasma exchange probably produced an increase in endogenous cholesterol synthesis and a mobilisation of tissue cholesterol. In relation to plateau cholesterol values 3 weeks after an exchange, the data suggested that the reduction in plasma cholesterol level with plasma exchange and drug therapy could have been achieved by intensive drug therapy alone.

Lymphoproliferative disease with IgM lambda monoclonal protein and autoimmune hemolytic anemia. A report of four cases and a review of the literature.

Four patients with lymphoproliferative disease with immunoglobulin M lambda (IgMlambda) monoclonal proteins and severe autoimmune hemolytic anemia are described. These patients had many features in common that may warrant their recognition as a specific entity within the lymphoproliferative spectrum. In each case, a wide thermal range low titer cold agglutinin was present. The association of cold autoimmune hemolytic anemia with IgMlambda monoclonal protein and lymphoproliferative disease is unusual. The literature on IgM monoclonal proteins associated with lymphoproliferative disease is reviewed with emphasis on the presence of direct antiglobulin test positive autoimmune hemolytic anemia.

Iron deficiency. Misunderstood, misdiagnosed and mistreated.

Iron deficiency is a common medical problem that may present in a variety of ways to the general practitioner or the specialist. An understanding of iron physiology is relevant to diagnosis and treatment of iron deficiency. Human iron metabolism is a system based on conservation. For this reason, the most common cause of iron deficiency is loss of the normal conservation of iron and this usually means blood loss. The important implication is that the search for the cause of iron deficiency will usually focus on the gastrointestinal tract in males and non-pregnant, non-menstruating females. Iron deficiency is commonly misdiagnosed. The usual error is misinterpretation of the laboratory features of the anaemia of chronic disease. The serum iron is low, but the iron binding capacity is normal and ferritin is normal or high. There are problems and exceptions involved in interpretation of iron indices. Treatment of iron deficiency requires an understanding of iron absorption and the ability of the marrow to respond. In most circumstances, iron deficiency will respond to adequate doses of oral iron; however, there are a few situations when oral iron is unsuitable and parenteral iron is required. An inadequate response to iron may indicate inadequate supply of iron to the bone marrow (e.g. malabsorption, non-compliance) or failure of the marrow to respond (e.g. concomitant folate deficiency). Pregnancy is a special situation in which conservation of iron is overcome by fetal iron requirements and in which application of the knowledge of iron physiology should be applied to prevent and treat iron deficiency.

A fatal case of cold autoimmune hemolytic anemia.

A fatal case of acute low-titer wide-thermal-range cold agglutinin disease is reported. High-dose corticosteroids, cyclophosphamide, and plasmapheresis failed to control hemolysis. This uncommon syndrome is discussed, and current approaches to treatment are reviewed.

In-vitro synthesis of an anti-BI cold agglutinin complicating a case of lymphoma.

A woman of 47 with lymphocytic lymphoma was found to have a high-titer cold autoagglutinin of anit-BI specificity. Her group B erythrocytes autoagglutinated of anti-BI specificity. Her group B erythrocytes autoagglutinated in vitro and the direct antiglobulin reaction was positive, but she had no symptom of cold intolerance, no evidence of hemolysis, and she could receive transfusions of compatible group O erythrocytes. In addition, evidence for synthesis of the autoantibody by the lymphoma cells was obtained by short-term bone-marrow culture.

Effects of microbial activity on aquatic pollutants.

Bacteria and fungi present in estuarine and marine water and sediment accomplish significant degradation of crude oil, refined oils, polychlorinated biphenyls, and organomercurials, with the rate and extent of degradation varying with species, geographic source, temperature, and other biologic and environmental parameters. Our biodegradation studies have been extended to determine if physical weathering and/or microbial degradation of oil by microorganisms present in Chesapeake Bay water and sediment produces potentially carcinogenic substances. Water and sediment from an area in Chesapeake Bay that receives heavy input of oil and from a relatively nonpolluted site have been assayed for mutagenic ability by use of the Ames method, which is a bacterial assay and is highly sensitive. Preliminary findings indicate the presence of mutagenic substances in samples collected from the polluted site. Extracts of oil subjected to microbial degradation under controlled laboratory conditions did not yield detectable mutagenic activity. In situ studies are in progress.

Analysis of low-molecular mass products from biosolubilized coal.

A relatively simple, rapid sample preparation method has been developed for analysis of low-molecular mass compounds present in soluble coal products generated by microbial coal solubilizing agents. Acidification of the sample followed by direct extraction into hexanes is coupled with gas chromatography/mass spectrometry analysis for characterization of the soluble coal products. Characterization of the products can contribute to a more complete understanding of the solubilization processes involved, provide further information as to the structure of coal and identify products of potential commercial value.

Effects of taipan (Oxyuranus scutellatus) venom on erythrocyte morphology and blood viscosity in a human victim in vivo and in vitro.

The case of a snake handler with envenoming due to Australian taipan (Oxyuranus scutellatus) showing marked morphological changes in his red blood cells is presented. The red cells underwent sphero-echinocytic transformation and in subsequent experiments in vitro the effects of taipan venom on red cells were further characterized. Taipan venom induced sphero-echinocytic transformation at nanogram/ml concentrations and led to a marked increase in whole blood viscosity. These changes have not been featured in previous reports of taipan envenomation and are reported to highlight the diagnostic value of blood film examination in cases of suspected envenomation. The significance of the hyperviscosity, and consequent reduction in blood fluidity, is unknown and requires further investigation.