Immunoglobulin replacement vs prophylactic antibiotics for hypogammaglobulinemia secondary to hematological malignancy.

ABSTRACT: Immunoglobulin replacement and prophylactic antibiotics are commonly used to prevent infections in patients with secondary hypogammaglobulinemia due to hematological malignancies but have never been directly compared. In this randomized controlled feasibility trial conducted in 7 hospitals in Australia and New Zealand, we enrolled patients with secondary hypogammaglobulinemia with either a history of recurrent/severe infection or an immunoglobulin G level <4 g/L. Participants were randomized in a 1:2 ratio to immunoglobulin (0.4 g/kg per 4 weeks IV) or daily antibiotics (trimethoprim-sulfamethoxazole 160 mg/800 mg or, if contraindicated, 100 mg doxycycline) for 12 months. Participants allocated to antibiotics were allowed to crossover after grade ≥3 infections. The primary outcome was proportion of patients alive on the assigned treatment 12 months after randomization. Between August 2017 and April 2019, 63 patients were randomized: 42 to antibiotics and 21 to immunoglobulin. Proportion of participants alive on allocated treatment at 12 months was 76% in the immunoglobulin and 71% in the antibiotic arm (Fisher exact test P=.77; odds ratio, 0.78; 95% CI, 0.22-2.52). The lower quartile for time to first major infection (median, not reached) was 11.1 months for the immunoglobulin and 9.7 months for the antibiotic arm (log-rank test, P=.65). Three participants in the immunoglobulin and 2 in the antibiotic arm had grade ≥3 treatment-related adverse events. A similar proportion of participants remained on antibiotic prophylaxis at 12 months to those on immunoglobulin, with similar rates of major infections. Our findings support the feasibility of progressing to a phase 3 trial. Trial registration #ACTRN12616001723471.

Economic evaluation: immunoglobulin vs prophylactic antibiotics in hypogammaglobulinemia and hematological malignancies.

Patients with hematological malignancies are at high risk of developing hypogammaglobulinemia (HGG) and infections. Immunoglobulin (Ig) is one recommended option to prevent these infections, but it is expensive and its cost-effectiveness compared with other prevention strategies remains unknown. We conducted a trial-based economic evaluation from the Australian healthcare system perspective to estimate the 12-month cost-effectiveness of prophylactic Ig versus prophylactic antibiotics in 63 adults with HGG and hematological malignancies participating in the RATIONAL feasibility trial. Two analyses were conducted: 1) Cost-utility analysis (CUA) to assess the incremental cost per quality-adjusted life-year (QALY) gained; 2) Cost-effectiveness analysis (CEA) to assess the incremental cost per serious infection prevented (grade greater or equal to 3) and per any infection (any grade) prevented. Over 12 months, the total cost per patient was significantly higher in the Ig group than in the antibiotic group (mean difference AU$29,140, p<0.001). Most patients received intravenous Ig (IVIg), which was the main cost driver, only two patients in the intervention arm received subcutaneous Ig (SCIg). There were non-significant differences in health outcomes. Results showed Ig was more costly than antibiotics and associated with fewer QALYs. The incremental cost-effectiveness ratio (ICER) of Ig versus antibiotics was AU$111,262 per serious infection prevented, but Ig was more costly and associated with more infections when all infections were included. On average and for this patient population, Ig prophylaxis may not be cost-effective compared to prophylactic antibiotics. Further research is needed to confirm these findings in a larger population and considering longer-term outcomes. The trial was registered on the Australian and New Zealand Clinical Trials Registry (ACTRN12616001723471).

Protracted fibrinolysis resistance following cardiac surgery with cardiopulmonary bypass: A prospective observational study of clinical associations and patient outcomes.

BACKGROUND: Surgery on cardiopulmonary bypass (CPB) elicits a pleiomorphic systemic host response which, when severe, requires prolonged intensive care support. Given the substantial cross-talk between inflammation, coagulation, and fibrinolysis, the aim of this hypothesis-generating observational study was to document the kinetics of fibrinolysis recovery post-CPB using ClotPro® point-of-care viscoelastometry. Tissue plasminogen activator-induced clot lysis time (TPA LT, s) was correlated with surgical risk, disease severity, organ dysfunction and intensive care length of stay (ICU LOS). RESULTS: In 52 patients following CPB, TPA LT measured on the first post-operative day (D1) correlated with surgical risk (EuroScore II, Spearman's rho .39, p < .01), time on CPB (rho = .35, p = .04), disease severity (APACHE II, rho = .52, p < .001) and organ dysfunction (SOFA, rho = .51, p < .001) scores, duration of invasive ventilation (rho = .46, p < .01), and renal function (eGFR, rho = -.65, p < .001). In a generalized linear regression model containing TPA LT, CPB run time and markers of organ function, only TPA LT was independently associated with the ICU LOS (odds ratio 1.03 [95% CI 1.01-1.05], p = .01). In a latent variables analysis, the association between TPA LT and the ICU LOS was not mediated by renal function and thus, by inference, variation in the clearance of intraoperative tranexamic acid. CONCLUSIONS: This observational hypothesis-generating study in patients undergoing cardiac surgery with cardiopulmonary bypass demonstrated an association between the severity of fibrinolysis resistance, measured on the first post-operative day, and the need for extended postoperative ICU level support. Further examination of the role of persistent fibrinolysis resistance on the clinical outcomes in this patient cohort is warranted through large-scale, well-designed clinical studies.

Costs and consequences of over-investigation of minor transfusion reactions.

BACKGROUND: Adverse transfusion events create a direct cost burden on the healthcare system through increased morbidity, mortality, extra investigations for diagnosis, patient treatment and increased use of hospital resources. Understanding the costs and impact minor transfusion reactions have on the healthcare system presents an opportunity for potential cost savings and improved clinical practice. AIMS: To determine the cost associated with investigating minor transfusion reactions, to identify opportunities to improve the management of blood transfusion reactions and potential cost savings through the application of current national guidelines. METHODS: A retrospective review of all suspected transfusion reactions reported to the laboratory over a 6-year period was performed. Reports were assessed for appropriateness of clinical management and associated investigations. Cost of inappropriate investigations and associated blood product discard was calculated using current national tariffs. RESULTS: Of the 274 reports, febrile non-haemolytic transfusion reactions were the most common reactions, with 96 (35%) cases. One hundred forty-eight patients were unnecessarily investigated for suspected transfusion reactions totalling AU$ 32 427.00. The initial total value of partially discarded blood products was AU$ 55 656.00. CONCLUSION: The study demonstrated that unnecessary investigation of minor transfusion reactions adds a significant financial burden to the healthcare system.

Effects of Exercise Rehabilitation on Physical Function in Adults With Hematological Cancer Receiving Active Treatment: A Systematic Review and Meta-Analysis.

OBJECTIVE: Evaluate the efficacy of exercise rehabilitation at improving physical function during active treatment for adults diagnosed with a hematological malignancy. DATA SOURCE: Systematic review with a multilevel meta-analysis of randomized trails was conducted. Four electronic databases, MEDLINE (EBSCOhost), CINAHL, Scopus, and CENTRAL, were searched using key words and medical subject headings. Articles were screened and assessed against the predetermined eligibility criteria. Data extracted were appraised using the Cochrane risk of bias tool for randomized trials and the GRADE guidelines. A meta-analysis examined four key clinical objectives. CONCLUSION: Twelve studies representing a total of 812 participants were included. Analysis of 36 dependent effect sizes from nine studies revealed structured and prescribed exercise interventions improved physical function (SMD = 0.39; 95% CI 0.21-0.57) compared to usual care or an active control. Exercise interventions with a multimodal design consisting of both aerobic and resistance exercise had a statistically significant effect on physical function (P < .001). Exercise intensity also had a statistically significant effect on physical function when prescribed at a moderate (P = .003) and vigorous (P < .001) intensity during active treatment in patients with leukemia or lymphoma. IMPLICATIONS FOR NURSING PRACTICE: This review suggests individuals diagnosed with leukemia or lymphoma can optimize physical function during and immediately post-treatment by attending exercise rehabilitation 3-5 times per weeks performing moderate-vigorous aerobic and resistance exercise. While further research is needed to identify optimal prescription guidelines throughout the treatment continuum, this review underscores the importance for hematology nurses to support patient referrals to exercise oncology professionals to gain positive improvements in physical function.

Point-of-care diagnosis and monitoring of fibrinolysis resistance in the critically ill: results from a feasibility study.

BACKGROUND: Fibrinolysisis is essential for vascular blood flow maintenance and is triggered by endothelial and platelet release of tissue plasminogen activator (t-PA). In certain critical conditions, e.g. sepsis, acute respiratory failure (ARF) and trauma, the fibrinolytic response is reduced and may lead to widespread thrombosis and multi-organ failure. The mechanisms underpinning fibrinolysis resistance include reduced t-PA expression and/or release, reduced t-PA and/or plasmin effect due to elevated inhibitor levels, increased consumption and/or clearance. This study in critically ill patients with fibrinolysis resistance aimed to evaluate the ability of t-PA and plasminogen supplementation to restore fibrinolysis with assessment using point-of-care ClotPro viscoelastic testing (VET). METHODS: In prospective, observational studies, whole-blood ClotPro VET evaluation was carried out in 105 critically ill patients. In 32 of 58 patients identified as fibrinolysis-resistant (clot lysis time > 300 s on the TPA-test: tissue factor activated coagulation with t-PA accelerated fibrinolysis), consecutive experimental whole-blood VET was carried out with repeat TPA-tests spiked with additional t-PA and/or plasminogen and the effect on lysis time determined. In an interventional study in a patient with ARF and fibrinolysis resistance, the impact of a 24 h intravenous low-dose alteplase infusion on coagulation and fibrinolysis was prospectively monitored using standard ClotPro VET. RESULTS: Distinct response groups emerged in the ex vivo experimental VET, with increased fibrinolysis observed following supplementation with (i) t-PA only or (ii) plasminogen and t-PA. A baseline TPA-test lysis time of > 1000 s was associated with the latter group. In the interventional study, a gradual reduction (25%) in serial TPA-test lysis times was observed during the 24 h low-dose alteplase infusion. CONCLUSIONS: ClotPro viscoelastic testing, the associated TPA-test and the novel experimental assays may be utilised to (i) investigate the potential mechanisms of fibrinolysis resistance, (ii) guide corrective treatment and (iii) monitor in real-time the treatment effect. Such a precision medicine and personalised treatment approach to the management of fibrinolysis resistance has the potential to increase treatment benefit, while minimising adverse events in critically ill patients. TRIAL REGISTRATION: VETtiPAT-ARF, a clinical trial evaluating ClotPro-guided t-PA (alteplase) administration in fibrinolysis-resistant patients with ARF, is ongoing (ClinicalTrials.gov NCT05540834 ; retrospectively registered September 15th 2022).

Achieving haemostasis in thrombocytopenia in remote settings: an in vitro comparison of frozen and lyophilized products.

BACKGROUND: Platelet concentrates have a limited shelf life due to room temperature storage and therefore, are not kept in regional centres where turnover is low. Cryopreserved platelets have been proposed as an alternative to platelet transfusion in austere circumstances and fibrinogen concentrate has improved thromboelastometry parameters in thrombocytopenia. This study compared the ability of stored haemostatic products and platelets to correct thromboelastometry parameters in thrombocytopenia. MATERIALS AND METHODS: Blood from eight patients with severe thrombocytopenia was combined with platelet concentrates, cryoprecipitate, fibrinogen concentrate, factor VIII, factor XIII and cryopreserved platelets in ratios equivalent to transfusion. Tissue factor initiated thromboelastometry (EXTEM) was compared between the products. RESULTS: EXTEM amplitude at 20 minutes (A20) improved by 13.1 mm with platelets (p<0.01). The 5mm increase in A20 seen with cryoprecipitate (p=0.06) was not statistically different from platelets (p=0.19). No improvement in A20 was observed with cryopreserved platelets or factor concentrates. EXTEM clotting times (CT) improved with cryopreserved platelets (19.4 s, p=0.001) and cryoprecipitate (24.1 s, p<0.05), but not fibrinogen, and both were superior to platelets (9.9 s, p<0.05). Clotting concentrates did not improve EXTEM parameters although further studies suggested the improvement in A20 was largely driven by higher fibrinogen concentrations in cryoprecipitate. DISCUSSION: These results suggest that cryopreserved platelets enhance clot initiation but do not contribute to clot strength in thrombocytopenia. When platelets are not available for transfusion, cryoprecipitate may be of value, however this requires further clinical studies.

Interventions to reduce infections in patients with hematological malignancies: a systematic review and meta-analysis.

Acquired hypogammaglobulinemia is common in chronic lymphocytic leukemia (CLL), non-Hodgkin lymphoma (NHL), and multiple myeloma (MM). No previous systematic reviews (SRs) have compared different approaches to infection prevention. We sought to assess the efficacy and safety of prophylactic immunoglobulin, antibiotics, and vaccination in these patients. We performed an SR and meta-analysis of randomized controlled trials (RCTs) evaluating the efficacy and safety of prophylactic immunoglobulin, antibiotics, and vaccination in adult patients with hematological malignancies commonly associated with acquired hypogammaglobulinemia, specifically, CLL, NHL, and MM. We searched PubMed (MEDLINE), EMBASE, and Cochrane Registry up to 9 January 2021. Results for dichotomous data were expressed as relative risk (RR) with 95% confidence interval (CI) and pooled in a random-effects model. This review was registered with PROSPERO CRD42017070825. From 10 576 studies screened, there were 21 completed RCTs and 1 ongoing. Of these, 8 evaluated prophylactic immunoglobulin (n = 370; 7 published before 2000), 5 evaluated prophylactic antibiotics (n = 1587), 7 evaluated vaccination (n = 3996), and 1 compared immunoglobulin to antibiotics (n = 60). Prophylactic immunoglobulin reduced the risk of clinically documented infection (CDI) by 28% (n = 2 trials; RR, 0.72; 95% CI, 0.54-0.96), and vaccination reduced the risk by 63% (RR, 0.37; 95% CI, 0.30-0.45). Prophylactic antibiotics did not reduce the risk. No intervention reduced all-cause mortality. Prophylactic immunoglobulin and antibiotics increased the risk of adverse events. Findings should be interpreted with caution, given the high risk of bias in many studies. There is a clear need for high-quality contemporary trials to establish the effectiveness of different approaches to preventing infection.

Superior Hemostatic and Wound-Healing Properties of Gel and Sponge Forms of Nonoxidized Cellulose Nanofibers: In Vitro and In Vivo Studies.

Many materials have been engineered and commercialized as hemostatic agents. However, there is still a gap in the availability of hemostats that offer biocompatibility and biodegradability in combination with effective hemostatic properties. Cellulose nanofibers are investigated as hemostatic materials with most studies focusing on oxidized cellulose-derived hemostats. The recent studies demonstrate that by optimizing the morphological properties of nonoxidized cellulose nanofibers (CNFs) enhanced hemostasis is achieved. Herein, the hemostatic and wound-healing properties of CNFs with optimized morphology using two forms, gel, and sponge is investigated. In vitro thromboelastometry studies demonstrate that CNFs reduce clotting time by 68% (±SE 2%) and 88% (±SE 5%) in gel and sponge forms, respectively. In an in vivo murine liver injury model, CNFs significantly reduce blood loss by 38% (±SE 10%). The pH-neutral CNFs do not damage red blood cells, nor do they impede the proliferation of fibroblast or endothelial cells. Subcutaneously-implanted CNFs show a foreign body reaction resolving with the degradation of CNFs on histological examination and there is no scarring in the skin after 8 weeks. Demonstrating superior hemostatic performance in a variety of forms, as well as biocompatibility and biodegradability, CNFs hold significant potential for use in surgical and first-aid environments.

Cryoprecipitate as an alternative to platelet transfusion in thrombocytopenia.

Platelet transfusions are not always available for bleeding in severe thrombocytopenia, as storage outside of major centers is limited by their short shelf-life. Data are lacking to support alternative available blood products; however, additional fibrinogen has been shown to enhance clot formation in vitro. To test the hypothesis that cryoprecipitate supplementation could improve clot formation in severe thrombocytopenia, eight hematological malignancy patients with platelet counts under 10 × 109/L each had 10 units of apheresis cryoprecipitate transfused prior to planned prophylactic platelet transfusions. The primary endpoint of thromboelastometry amplitude at 20 min increased by a mean of 5.1 mm (p < 0.01) following cryoprecipitate transfusion despite persisting thrombocytopenia. Thromboelastometry clotting times reduced by a mean of 7.8 s (p < 0.05) and alpha angle increased by a mean of 10.6° (p < 0.01). These results are consistent with cryoprecipitate enhancing the strength of the fibrin/platelet meshwork within the forming thrombus. While platelet transfusion remains the standard of care, where platelet supplies are limited, these data provide a rationale for the use of cryoprecipitate to obtain hemostasis in bleeding thrombocytopenic patients.

A review of electronic medical records and safe transfusion practice for guideline development.

BACKGROUND AND OBJECTIVES: Electronic medical records (EMRs) are often composed of multiple interlinking systems, each serving a particular task, including transfusion ordering and administration. Transfusion may not be prioritized when developing or implementing electronic platforms. Uniform guidelines may assist information technology (IT) developers, institutions and healthcare workforces to progress with shared goals. MATERIALS AND METHODS: A narrative review of current clinical guidance, benefits and risks of electronic systems for clinical transfusion practice was combined with feedback from experienced transfusion practitioners. RESULTS: There is opportunity to improve the safety, quality and efficiency of transfusion practice, particularly through decision support and better identification procedures, by incorporating transfusion practice into EMRs. However, these benefits should not be assumed, as poorly designed processes within the electronic systems and the critically important electronic-human process interfaces may increase risk while creating the impression of safety. CONCLUSION: Guidelines should enable healthcare and IT industries to work constructively together so that each implementation provides assurance of safe practice.

Non-oxidized cellulose nanofibers as a topical hemostat: In vitro thromboelastometry studies of structure vs function.

Hemorrhage remains a significant cause of morbidity and mortality following trauma and during complex surgeries. A variety of nanomaterials, including oxidized cellulose nanofibers (OCNFs), have been studied to overcome the disadvantages of current commercial topical hemostats. However, the relationship between nano-structural characteristics and hemostatic efficacy of non-oxidized cellulose nanofibers (CNFs) has not been elucidated. Herein, we present the first report of the correlation between structure and hemostatic performance of CNFs. In vitro thromboelastometry studies on CNFs, synthesized by ball-milling, showed that there is an optimum balance point between the aspect ratio (AR) and specific surface area (SSA) of nanofibers in terms of their maximum contribution to platelet function and plasma coagulation. The optimized CNFs with high SSA (17 m2/g) and a high AR (166) shortened normal whole blood clotting time by 68 %, outperforming cellulose-based hemostats. Additionally, CNFs reduced clotting time in platelet-deficient blood (by 80 %) and heparinized blood (by 54 %).

Near Infrared Spectroscopy in Anemia Detection and Management: A Systematic Review.

Red cell transfusions are intended to improve oxygen delivery to tissues. Although studies comparing hemoglobin concentration triggers for transfusion have been done, the hemoglobin threshold for clinical benefit remains uncertain. Direct measurement of tissue oxygenation with non-invasive near infrared spectroscopy has been proposed as a more physiological transfusion trigger, but its clinical role remains unclear. This systematic review examined the role of near infrared spectroscopy for detection of anemia and guiding transfusion decisions. Abstracts were identified up until May 2019 through searches of PubMed, EMBASE and The Web of Science. There were 69 studies meeting the inclusion criteria, most (n = 65) of which were observational studies. Tissue oxygen saturation had been measured in a wide range of clinical settings, with neonatal intensive care (n = 26) and trauma (n = 7) being most common. Correlations with hemoglobin concentration and tissue oxygenation were noted and there were correlations between changes in red cell mass and changes in tissue oxygenation through blood loss or transfusion. The value of tissue oxygenation for predicting transfusion was determined in only four studies, all using muscle oxygen saturation in the adult trauma setting. The overall sensitivity was low at 34% (27%-42%) and while it had better specificity at 78% (74%-82%), differing and retrospective approaches create a high level of uncertainty with respect to these conclusions. There were four prospective randomized studies involving 540 patients, in cardiac and neurological surgery and in neonates that compared near infrared spectroscopy to guide transfusion decisions with standard practice. These showed a reduction in the number of red cells transfused per patient (OR: 0.44 [0.09-0.79]), but not the number of patients who received transfusion (OR: 0.71 [0.46-1.10]), and no change in clinical outcomes. Measuring tissue oxygen saturation has potential to help guide transfusion; however, there is a lack of data upon which to recommend widespread implementation into clinical practice. Standardization of measurements is required and greater research into levels at which tissue oxygenation may lead to adverse clinical outcomes would help in the design of future clinical trials.

Perceptions on consumer information in transfusion. A qualitative study of consumers and prescribers.

BACKGROUND AND OBJECTIVES: Fresh blood product transfusion requires patient education for fully informed consent, and written consumer information is frequently used. Few studies have examined consumer preferences regarding written and verbal transfusion information provided. As a qualitative study, this research was designed to explore participant understanding and by analysing and integrating themes, generate a model to understand how transfusion information should be developed and used in practice. MATERIALS AND METHODS: Semi-structured interviews were conducted with healthcare consumers of transfusion information from various hospital clinical departments. Transcripts were coded to qualitatively compare nature/extent of content and opinions regarding transfusion information through thematic analysis. RESULTS: Analysis identified themes relating to healthcare engagement, purpose of information, mode of delivery and content delivered. Differences were identified between perceived purpose of information provided to consumers between 13 transfusion prescribers and consumers. Prescribers viewed information as a tool for obtaining informed consent, whereas consumers desired reassurance and knowledge. Consumers described both the specialized nature and volume of information as limiting their ability to question professionals on whom they were dependent. Information provided should be tailored to consumers and utilize simple, succinct explanations. CONCLUSION: Both groups were satisfied with written information adjunctive to verbal information. These findings will be used to redesign transfusion information and may be employed at the bedside when discussing transfusion. They may have implications for consumer information in other settings.