Effect of blood transfusions on cognitive development in very low birth weight infants
Journal of perinatology : official journal of the California Perinatal Association. 2021
OBJECTIVE Preterm infants frequently receive red cell transfusions; however, the effect of transfusions on cognition is unclear. We evaluated the relationship between transfusions and cognitive outcomes in preterm infants enrolled in a randomized trial of erythropoiesis stimulating agents (ESAs). STUDY DESIGN Preterm infants were randomized to ESAs or placebo during initial hospitalization, and transfusions recorded. Children were evaluated using standard developmental tests of cognition at 18-22 months (56 ESA, 24 placebo) and 3.5-4 years (39 ESA, 14 placebo). RESULTS Cognitive scores at 18-22 months were inversely correlated with transfusion volume (p = 0.02). Among those receiving ≥1 transfusion, cognitive scores were significantly higher in the ESA-treated group (p = 0.003). At 3.5-4 years, transfusions were not correlated with cognitive scores. CONCLUSIONS In the placebo group, transfused children had lower cognitive scores than did non-transfused children at 18-22 months. In the ESA group, cognitive scores did not differ by transfusion status, suggesting ESAs might provide neuroprotection.
Effects of stored autotransfusion on electrolytes and postoperative complications in patients undergoing elective orthopedic surgery
American journal of translational research. 2021;13(6):7200-7206
OBJECTIVE To ivestigate the effect of stored autotransfusion on the electrolytes and postoperative complications in patients undergoing elective orthopedic surgery. METHODS A total of 76 cases of patients undergoing elective orthopedic surgery were randomly divided into an observation group (38 cases, taking stored autotransfusion) and a control group (38 cases, taking allogeneic blood transfusion) according to a random number table method. The intraoperative-related indexes (intraoperative blood loss, autologous or allogeneic blood transfusion volume, urine volume, and length of hospital stay), electrolyte levels before and 48 hours after the operation, routine blood and coagulation function were compared between the two groups, and the postoperative complications related to blood transfusion were recorded. RESULTS The length of hospital stay of the observation group was significantly lower than that of the control group (P<0.05). The concentrations of K(+) and Na(+) in the control group 48 h after the operation were higher than those before the operation and than those in the observation group, while the concentration of Ca(2+) was lower than that before the operation and that in the observation group (all P<0.05). The levels of Hb, RBC, and HCT in the control group 48 h after the operation were lower than those before the operation and those in the observation group (all P<0.05). The levels of WBC in the two groups 48 h after the operation were significantly higher, but those in the observation group were lower than those in the control group (all P<0.05). There were no significant changes in Pt, APTT, D-D, and FIB levels between the two groups. There were no significant changes in Pt, APTT, D-D, and FIB levels 48 hours after the operation compared with those before the operation (P>0.05). The incidence of postoperative complications caused by blood transfusion in the observation group was lower than that in the control group (P<0.05). CONCLUSION Storage autotransfusion can effectively balance the electrolyte level and reduce the incidence of complications in patients undergoing elective orthopedic surgery. This is worthy of clinical application.
A double-blind, controlled, crossover trial of amlodipine on iron overload status in transfusion dependent β-thalassemia patients
International journal of clinical practice. 2021;75(8):e14337
BACKGROUND AND AIM This study examined whether administration of amlodipine could improve myocardial iron loading status in patients with transfusion dependent β-thalassemia (TDT), through a placebo-controlled, crossover study. METHODS Amlodipine (5 mg, daily) or placebo were prescribed to all patients (n = 19) for 6 months, and after a 2-week washout period, patients were crossed over to the other group. The efficacy of amlodipine on iron loading was assessed by measuring myocardial T2*-weighted magnetic resonance imaging (MRI T2*, millisecond [ms]) and serum ferritin (ng/mL). RESULTS Seventeen patients completed the study. The mean ± standard deviation [SD] of myocardial MRI T2* at baseline was 9.83 ± 2.67 ms Myocardial MRI T2* value rose to 11.44 ± 4.14 ms post amlodipine treatment in all patients. After placebo, myocardial MRI T2* value reached 10.29 ± 4.01 ms After controlling the baseline measures, Hedges's g for ferritin and myocardial MRI T2* outcomes were estimated 3.84 (95% confidence interval [CI] 2.68 to 4.97) and -1.80 (95% CI -2.58 to -0.10), respectively. CONCLUSION Amlodipine might improve myocardial MRI T2* and serum ferritin level compared to placebo. However, larger clinical studies are needed to confirm the results.
Recent insight on improving the iron chelation efficacy of deferasirox by adjuvant therapy in transfusion dependent beta thalassemia children with sluggish response
Expert opinion on drug metabolism & toxicology. 2020
Background: Deferasirox is the first line of treatment in iron overload. In spite of the many studies concerning the efficacy of deferasirox, some patients remain unresponsive to deferasirox.Methods: One hundred and sixty patients were enrolled in stratified randomized controlled study. Patients were randomly divided into four regimens, group I (n=40) received 30 mg/kg deferasirox, group II (n=40) received 20 mg omeprazole and 30 mg/kg deferasirox, group III (n=40) received 400 mg vitamin E and 30 mg/kg deferasirox and group IV (n=40) received 420 mg silymarin and 30 mg/kg deferasirox. Blood specimens were collected from each patient for up to 24 h, and then plasma deferasirox concentrations were inspected.Results: Silymarin, Vitamin E and omeprazole significantly increased the peak plasma concentration of deferasirox (P<0.001) by 27.9, 14.9 and 2.4 fold respectively as compared to deferasirox alone. The bioavailability of deferasirox was improved up to 3.03, 3.57 and 4.98-fold, respectively, following administration of omeprazole, vitamin E and silymarin compared to deferasirox alone.Conclusion: Silymarin, vitamin E and omeprazole represent promising adjuvant therapy to improve the chelation efficacy of deferasirox that might also be further applied to enhance the pharmacokinetics of deferasirox to overcome the lack of response.
Transfusion dependent beta thalassemia children with sluggish response (n=160).
Group I 30 mg/kg deferasirox. (n=40).
Group II 20 mg omeprazole and 30 mg/kg deferasirox (n=40); group III 400 mg vitamin E and 30 mg/kg deferasirox (n=40); group IV 420 mg silymarin and 30 mg/kg deferasirox (n=40).
Silymarin, Vitamin E and omeprazole significantly increased the peak plasma concentration of deferasirox by 27.9, 14.9 and 2.4 fold respectively as compared to deferasirox alone. The bioavailability of deferasirox was improved up to 3.03, 3.57 and 4.98-fold, respectively, following administration of omeprazole, vitamin E and silymarin compared to deferasirox alone.
Randomized controlled trial of effect of N-acetylcysteine as an antioxidant on iron overload in children with thalassemia major
Clinical and experimental pediatrics. 2020
BACKGROUND β-Thalassemias are characterized by the presence of mutations in the globin gene that result in the absence or reduced synthesis of β-globin chains of the hemoglobin tetramer. Several studies have reported increased oxidative stress in β-thalassemia major (β-TM) patients. N-acetylcysteine (NAC), a derivative of L-cysteine amino acid, is commonly used as a mucolytic drug. Numerous studies have reported efficient antioxidant activity of NAC. PURPOSE To evaluate the effects of NAC on oxidative stress status and hemoglobin levels in children with β-TM. METHODS This study was conducted between June and December 2019. One hundred β-TM patients were divided into two groups: 50 received NAC 10 mg/kg orally for 3 months (treatment group), while the other 50 received no treatment (non-treatment group). Total oxidant status (TOS), total antioxidant capacity (TAC), oxidative stress index (OSI), and hemoglobin (Hb) and ferritin levels were measured and compared between groups. RESULTS At the end of the study period, Hb and TAC levels were significantly higher in the treatment group than in the non-treatment group (P < .001 and .01, respectively). On the other hand, serum ferritin levels, TOS, and OSI were significantly lower (P = .004, .01, and .001, respectively) in the treatment group. CONCLUSION NAC can effectively reduce the oxidative status and increase the pre-transfusion Hb levels in children with β-TM. Furthermore, NAC could reduce iron overload in these patients.
N-acetylcysteine Restored Heart Rate Variability and Prevented Serious Adverse Events in Transfusion-dependent Thalassemia Patients: a Double-blind Single Center Randomized Controlled Trial
Int J Med Sci. 2020;17(9):1147-1155
Regular blood transfusions in transfusion-dependent thalassemia (TDT) patients can lead to iron overload, causing oxidative stress and sympathovagal imbalance, resulting in increased cardiac complications. We hypothesized that administrating of N-acetylcysteine (NAC) prevents serious adverse events including cardiac complications in TDT patients by reducing systemic oxidative stress and balancing cardiac sympathovagal control. This study was double-blind, randomized control trial, investigating in 59 Thai TDT patients. After randomization, the participants were divided into two groups. The control group received standard care of TDT patient plus placebo, whereas the intervention group received 600 mg of NAC orally for six months. Serum 8-isoprostane, TNF-alpha, IL-10, 24-hour ECG monitoring, echocardiograms and the incidence of thalassemia-related complications were collected. At baseline, no significant difference in any parameters between the control and the intervention groups. At the end of intervention, the incidence of serious adverse events (i.e. infection, worsening thalassemia) was significantly higher in the control group when compared with the intervention group (24.1% vs. 3.3%, p=0.019) (Chi-square test; absolute risk reduction=20.8%, number needed to treat=4.8). The control group also had significantly lower time-dependent HRV parameters, compared with the intervention group (p=0.025 and 0.030, independent t-test). Treatment with NAC restored HRV and reduced serious adverse event in TDT patients, however, no difference in cardiac complications could be demonstrated. NAC could prevent serious adverse events in TDT patients. The proposed mechanism might be the balancing of sympathovagal control.
Clinical Usefulness of Furosemide to Prevent Volume Overload Among Children and Young Adults with Transfusion-Dependent Thalassemia: A Randomized, Open-Label, Crossover Study
Journal of blood medicine. 2020;11:503-513
PURPOSE Red blood cell transfusion is a key element of treatment among patients with transfusion-dependent thalassemia (TDT). Volume overload and HCC syndrome (hypertension, convulsion, and intracranial hemorrhage) are fatal complications related to transfusion. Furosemide has been widely used to prevent hypertension secondary to volume overload with unclear supportive evidence. This study aimed to evaluate the efficacy of furosemide to prevent volume overload among children and young adults diagnosed with TDT. METHODS Patients diagnosed with TDT were enrolled and randomized to receive either furosemide pretransfusion or no furosemide pretransfusion. After 3 weeks to 4 months of wash-out periods, those patients underwent the alternate regimens as per crossover design of the study. Clinical and laboratory parameters including blood pressure and NT-proBNP levels were measured before and after each transfusion. The difference of those parameters between two randomized groups and their potential associated factors were analyzed. RESULTS In all, 30 patients undergoing 60 red blood cell transfusions were enrolled in the study. All were randomized and crossover was designed as receiving and not receiving furosemide pretransfusion. No transfusion reactions, symptoms of volume overload and HCC syndrome were observed. No statistically significant correlation was found between pretransfusion furosemide and the difference between pre- and posttransfusion systolic blood pressure (2 mmHg systolic blood pressure difference in pretransfusion furosemide and 1.5 mmHg in no pretransfusion furosemide; p-value = 0.721), as well as between pretransfusion furosemide and the difference between pre- and posttransfusion NT-proBNP levels (-3.8 pg/mL NT-proBNP level difference in pretransfusion furosemide and -2.4 pg/mL in no pretransfusion furosemide; p-value = 0.490). No significant correlation was also observed even in selected patients with high NT-proBNP levels (p-value = 0.262). Associated factors affecting the difference between pre- and posttransfusion NT-proBNP levels were analyzed, and none of those were affected concerning the difference in the levels. CONCLUSION Furosemide has been included in standard transfusion guidelines in many institutions. Our study provided important evidence of the unnecessary use of the drug in preventing volume overload particularly in pediatric and young adult patients with TDT. THAI CLINICAL TRIALS REGISTRY TCTR NUMBER TCTR20180209001. Registered 6 February 2018, https://www.clinicaltrials.in.th/.
Evaluation of the efficacy and safety of deferiprone compared with deferasirox in paediatric patients with transfusion-dependent haemoglobinopathies (DEEP-2): a multicentre, randomised, open-label, non-inferiority, phase 3 trial
Lancet Haematol. 2020;7(6):e469-e478
BACKGROUND Transfusion-dependent haemoglobinopathies require lifelong iron chelation therapy with one of the three iron chelators (deferiprone, deferasirox, or deferoxamine). Deferasirox and deferiprone are the only two oral chelators used in adult patients with transfusion-dependent haemoglobinopathies. To our knowledge, there are no randomised clinical trials comparing deferiprone, a less expensive iron chelator, with deferasirox in paediatric patients. We aimed to show the non-inferiority of deferiprone versus deferasirox. METHODS DEEP-2 was a phase 3, multicentre, randomised trial in paediatric patients (aged 1 month to 18 years) with transfusion-dependent haemoglobinopathies. The study was done in 21 research hospitals and universities in Italy, Egypt, Greece, Albania, Cyprus, Tunisia, and the UK. Participants were receiving at least 150 mL/kg per year of red blood cells for the past 2 years at the time of enrolment, and were receiving deferoxamine (<100 mg/kg per day) or deferasirox (<40 mg/kg per day; deferasirox is not registered for use in children aged <2 years so only deferoxamine was being used in these patients). Any previous chelation treatment was permitted with a 7-day washout period. Patients were randomly assigned 1:1 to receive orally administered daily deferiprone (75-100 mg/kg per day) or daily deferasirox (20-40 mg/kg per day) administered as dispersible tablets, both with dose adjustment for 12 months, stratified by age (<10 years and ≥10 years) and balanced by country. The primary efficacy endpoint was based on predefined success criteria for changes in serum ferritin concentration (all patients) and cardiac MRI T2-star (T2*; patients aged >10 years) to show non-inferiority of deferiprone versus deferasirox in the per-protocol population, defined as all randomly assigned patients who received the study drugs and had available data for both variables at baseline and after 1 year of treatment, without major protocol violations. Non-inferiority was based on the two-sided 95% CI of the difference in the proportion of patients with treatment success between the two groups and was shown if the lower limit of the two-sided 95% CI was greater than -12.5%. Safety was assessed in all patients who received at least one dose of study drug. This study is registered with EudraCT, 2012-000353-31, and ClinicalTrials.gov, NCT01825512. FINDINGS 435 patients were enrolled between March 17, 2014, and June 16, 2016, 393 of whom were randomly assigned to a treatment group (194 to the deferiprone group; 199 to the deferasirox group). 352 (90%) of 390 patients had beta-thalassaemia major, 27 (7%) had sickle cell disease, five (1%) had thalassodrepanocytosis, and six (2%) had other haemoglobinopathies. Median follow-up was 379 days (IQR 294-392) for deferiprone and 381 days (350-392) for deferasirox. Non-inferiority of deferiprone versus deferasirox was established (treatment success in 69 [55.2%] of 125 patients assigned deferiprone with primary composite efficacy endpoint data available at baseline and 1 year vs 80 [54.8%] of 146 assigned deferasirox, difference 0.4%; 95% CI -11.9 to 12.6). No significant difference between the groups was shown in the occurrence of serious and drug-related adverse events. Three (2%) cases of reversible agranulocytosis occurred in the 193 patients in the safety analysis in the deferiprone group and two (1%) cases of reversible renal and urinary disorders (one case of each) occurred in the 197 patients in the deferasirox group. Compliance was similar between treatment groups: 183 (95%) of 193 patients in the deferiprone group versus 192 (97%) of 197 patients in the deferisirox group. INTERPRETATION In paediatric patients with transfusion-dependent haemoglobinopathies, deferiprone was effective and safe in inducing control of iron overload during 12 months of treatment. Considering the need for availability of more chelation treatments in paediatric populations, deferiprone offers a valuable treatment option for this age group. FUNDING EU Seventh Framework Programme.
Paediatric patients with transfusion-dependent haemoglobinopathies enrolled in the DEEP-2 multicentre randomised trial (n=393).
Daily deferiprone (75-100 mg/kg per day) (n=194).
Daily deferasirox (20-40 mg/kg per day) (n=199).
Non-inferiority of deferiprone versus deferasirox was established (treatment success in 55.2% patients assigned deferiprone with primary composite efficacy endpoint data available at baseline and 1 year vs. 54.8% assigned deferasirox). No significant difference between the groups was shown in the occurrence of serious and drug-related adverse events. Compliance was similar between treatment groups: 95% of patients in the deferiprone group versus 97% of patients in the deferasirox group.
Blood transfusion and ischaemic outcomes according to anemia and bleeding in patients with non-ST-segment elevation acute coronary syndromes: Insights from the TAO randomized clinical trial
Int J Cardiol. 2020
BACKGROUND The benefits and risks of blood transfusion in patients with acute myocardial infarction who are anemic or who experience bleeding are debated. We sought to study the association between blood transfusion and ischemic outcomes according to haemoglobin nadir and bleeding status in patients with NST-elevation myocardial infarction (NSTEMI). METHODS The TAO trial randomized patients with NSTEMI and coronary angiogram scheduled within 72h to heparin plus eptifibatide versus otamixaban. After exclusion of patients who underwent coronary artery bypass surgery, patients were categorized according to transfusion status considering transfusion as a time-varying covariate. The primary ischemic outcome was the composite of all-cause death or MI within 180 days of randomization. Subgroup analyses were performed according to pre-transfusion hemoglobin nadir and bleeding status. RESULTS 12,547 patients were enrolled. Among these, blood transfusion was used in 489 (3.9%) patients. Patients who received transfusion had a higher rate of death or MI (29.9% vs. 8.1%, p<0.01). This excess risk persisted after adjustment on GRACE score and nadir of hemoglobin (HR 3.36 95%CI 2.63-4.29 p<0.01). Subgroup analyses showed that blood transfusion was associated with a higher risk in patients without overt bleeding (adjusted HR 6.25 vs. 2.85; p-interaction 0.001) as well as in those with hemoglobin nadir > 9.0 g/dl (HR 4.01; p-interaction<0.0001). CONCLUSION In patients with NSTEMI, blood transfusion was associated with an overall increased risk of ischaemic events. However, this was mainly driven by patients without overt bleeding and those hemoglobin nadir > 9.0g/dl. This suggests possible harm of transfusion in those groups.
Green tea influence on iron overload in thalassemia intermedia patients: a randomized controlled trial
Background: Although iron chelation therapies have been available for many years for thalassemia intermedia patients, iron accumulation remains the major cause of death. Therefore, the need for additional chelation options is in demand. This randomized controlled study aimed to understand the effects of green tea on iron balance in thalassemia intermedia patients. Methods: Using a random selection method, 141 thalassemia intermedia patients were initially screened for inclusion in this trial; only 68 patients included after applying exclusion criteria. Two equal groups were generated (n=34/group): green tea (three cups/day after meals) + usual treatment (deferasirox iron chelator and on demand blood transfusion); and control (only usual treatment). The study lasted for a period of 12 months. Patients failing to comply to the trial methodology were excluded, leaving a final total of 29 patients in the green tea group and 28 patients in the control group. Liver iron concentration, and serum ferritin were assessed at baseline and 12 months, while hemoglobin levels were assessed monthly. Results: At baseline, both groups were matched regarding general demographics. At 12 months, the net drop of liver iron concentration in the green tea group (7.3 mg Fe/g dry weight) was significantly higher than the control group (4.6 mg Fe/g dry weight) (p<0.05). This was also seen with serum ferritin; net reduction in green tea and control groups were 1289 ng/ml and 871 ng/ml, respectively (p<0.05). Hemoglobin levels were slightly higher in the green tea group compared with the control group, but this was not significant. Conclusions: Regular green tea consumption had a significant capability to improve iron deposition in thalassemia intermedia patients who already undergo deferesirox iron chelation therapy. Trial registration: UMIN-CTR Clinical Trials Registry, UMIN000040841 (retrospectively registered June 21, 2020).