Effect of Poloxamer 188 vs Placebo on Painful Vaso-Occlusive Episodes in Children and Adults With Sickle Cell Disease: A Randomized Clinical Trial.

Importance: Although effective agents are available to prevent painful vaso-occlusive episodes of sickle cell disease (SCD), there are no disease-modifying therapies for ongoing painful vaso-occlusive episodes; treatment remains supportive. A previous phase 3 trial of poloxamer 188 reported shortened duration of painful vaso-occlusive episodes in SCD, particularly in children and participants treated with hydroxyurea. Objective: To reassess the efficacy of poloxamer 188 for vaso-occlusive episodes. Design, Setting, and Participants: Phase 3, randomized, double-blind, placebo-controlled, multicenter, international trial conducted from May 2013 to February 2016 that included 66 hospitals in 12 countries and 60 cities; 388 individuals with SCD (hemoglobin SS, SC, S-ß0 thalassemia, or S-ß+ thalassemia disease) aged 4 to 65 years with acute moderate to severe pain typical of painful vaso-occlusive episodes requiring hospitalization were included. Interventions: A 1-hour 100-mg/kg loading dose of poloxamer 188 intravenously followed by a 12-hour to 48-hour 30-mg/kg/h continuous infusion (n = 194) or placebo (n = 194). Main Outcomes and Measures: Time in hours from randomization to the last dose of parenteral opioids among all participants and among those younger than 16 years as a separate subgroup. Results: Of 437 participants assessed for eligibility, 388 were randomized (mean age, 15.2 years; 176 [45.4%] female), the primary outcome was available for 384 (99.0%), 15-day follow-up contacts were available for 357 (92.0%), and 30-day follow-up contacts were available for 368 (94.8%). There was no significant difference between the groups for the mean time to last dose of parenteral opioids (81.8 h for the poloxamer 188 group vs 77.8 h for the placebo group; difference, 4.0 h [95% CI, -7.8 to 15.7]; geometric mean ratio, 1.2 [95% CI, 1.0-1.5]; P = .09). Based on a significant interaction of age and treatment (P = .01), there was a treatment difference in time from randomization to last administration of parenteral opioids for participants younger than 16 years (88.7 h in the poloxamer 188 group vs 71.9 h in the placebo group; difference, 16.8 h [95% CI, 1.7-32.0]; geometric mean ratio, 1.4 [95% CI, 1.1-1.8]; P = .008). Adverse events that were more common in the poloxamer 188 group than the placebo group included hyperbilirubinemia (12.7% vs 5.2%); those more common in the placebo group included hypoxia (12.0% vs 5.3%). Conclusions and Relevance: Among children and adults with SCD, poloxamer 188 did not significantly shorten time to last dose of parenteral opioids during vaso-occlusive episodes. These findings do not support the use of poloxamer 188 for vaso-occlusive episodes. Trial Registration: ClinicalTrials.gov Identifier: NCT01737814.

Transfusion medicine: A research agenda for the coming years.

The important scientific and clinical advances of the last century in transfusion medicine include methods for avoiding hemolytic transfusion reactions and preventing transmission of viral infectious diseases. The next great clinical advances will require improving the efficacy and safety of transfusions, as well as acknowledgement of the now proven serious complications of transfusion, including nosocomial infection, thrombosis, inflammation and multi-organ failure. Possible strategies include (1) universal leukoreduction to mitigate transfusion immunomodulation effects and improve storage conditions, (2) minimizing transfusion of ABO incompatible antibodies and cellular/soluble antigens, (3) substituting use of safer solutions for normal saline during apheresis, component infusion and washing (4) new techniques to improve the efficacy and safety of blood components, including improved storage solutions/conditions, supernatant removal by washing, and rejuvenation and (5) maximizing the risk to benefit ratio of transfusions by employing more restrictive and physiologic indications for transfusion (including patient blood management) and improving clinical decision making through novel laboratory and bedside tests such as thromboelastography.

Indications for red cell transfusions in pediatric patients.

Red cell transfusions are amongst the most common therapeutic procedures in seriously ill children, particularly in the inpatient setting. This is despite the fact that there is no evidence base for most clinical settings, with the exception of patients with hemoglobinopathies, particularly thalassemia and sickle cell anemia. Obviously exsanguinating hemorrhage and life threatening anemia are urgent indications for which no other therapeutic approach is currently available. Most transfusions are, however, given prophylactically to prevent the complications of hypoxia or hemodynamic stability, based upon expert opinion and a faith in the oxygen carrying capacity and beneficial hemodynamic properties of transfused red cells. The question confronting current day pediatric practice is to what extent transfused red cells prevent adverse events, other than in thalassemia and sickle cell anemia, as opposed to causing them. Do transfusions of red cells prevent organ failure, stroke, etc. or not? There is epidemiologic evidence in the adult randomized trial literature that liberal red cell transfusion likely causes more such adverse events than it prevents. The relevance of such studies to children, particularly neonates, is uncertain. Randomized trials in critically ill neonates have yielded little to no evidence that liberal red cell transfusion is beneficial, but the data are not definitive. In critically ill older children the data suggest there is no benefit to liberal red cell transfusion, but the indications for red cell transfusion are uncertain. Most practitioners would agree that combining laboratory data such hemoglobin/hematocrit with clinical indications for transfusions (evidence of end organ hypoxia such as tachycardia, shortness of breath, etc.) is the only viable strategy at present, until more definitive randomized trial data are available.

0.9% NaCl (Normal Saline) - Perhaps not so normal after all?

Crystalloid infusion is widely employed in patient care for volume replacement and resuscitation. In the United States the crystalloid of choice is often normal saline. Surgeons and anesthesiologists have long preferred buffered solutions such as Ringer's Lactate and Plasma-Lyte A. Normal saline is the solution most widely employed in medical and pediatric care, as well as in hematology and transfusion medicine. However, there is growing concern that normal saline is more toxic than balanced, buffered crystalloids such as Plasma-Lyte and Lactated Ringer's. Normal saline is the only solution recommended for red cell washing, administration and salvage in the USA, but Plasma-Lyte A is also FDA approved for these purposes. Lactated Ringer's has been traditionally avoided in these applications due to concerns over clotting, but existing research suggests this is not likely a problem. In animal models and clinical studies in various settings, normal saline can cause metabolic acidosis, vascular and renal function changes, as well as abdominal pain in comparison with balanced crystalloids. The one extant randomized trial suggests that in very small volumes (2 l or less) normal saline is not more toxic than other crystalloids. Recent evidence suggests that normal saline causes substantially more in vitro hemolysis than Plasma-Lyte A and similar solutions during short term storage (24 hours) after washing or intraoperative salvage. There are now abundant data to raise concerns as to whether normal saline is the safest replacement solution in infusion therapy, red cell washing and salvage, apheresis and similar uses. In the USA, Plasma-Lyte A is also FDA approved for use with blood components and is likely a safer solution for these purposes. Its only disadvantage is a higher cost. Additional studies of the safety of normal saline for virtually all current clinical uses are needed. It seems likely that normal saline will eventually be abandoned in favor of safer, more physiologic crystalloid solutions in the coming years.

Management of Sickle Cell Disease in Children.

Sickle cell disease (SCD) is a heterogeneous inherited disorder of hemoglobin that causes chronic hemolytic anemia, vaso-occlusion, and endothelial dysfunction. These physiologic derangements often lead to multiorgan damage in infancy and throughout childhood. The most common types of SCD are homozygous hemoglobin S (HbSS disease), hemoglobin SC disease, and sickle ß thalassemia. HbSS disease and sickle ß(0) thalassemia often are referred to as sickle cell anemia because they have similar severity. Screening and preventive measures, including infection prophylaxis and vaccination, have significantly improved outcomes for children with SCD. Evidence-based therapies, such as hydroxyurea and transfusion, play an important role in preventing progression of select complications. Many chronic complications develop insidiously and require multidisciplinary care for effective treatment. Primary care physicians, as well as physicians in many other disciplines, may care for these patients and should be familiar with the potential acute and chronic complications of this disease. This review addresses healthcare maintenance guidelines, common complications, and recommendations for management of pediatric patients with SCD.

A Case-Based Approach to Transition of Care for Patients With Sickle Cell Disease.

Young adults with sickle cell disease must navigate a difficult road to independence once they age out of pediatric care. The anxiety surrounding transition, the challenges of medical complications, and chronic psychosocial stressors are obstacles to a seamless transition to adult medical care. The two cases presented here demonstrate that a team-based, multidisciplinary approach can facilitate a successful transition.

WT1 expression at diagnosis does not predict survival in pediatric AML: a report from the Children's Oncology Group.

WT1 is a transcription factor that is aberrantly overexpressed in acute and chronic leukemias. Overexpression of WT1 in pediatric acute myeloid leukemia has been reported, but the prognostic significance is unclear because sample sizes in these studies have been relatively small. WT1 expression was measured by quantitative RT-PCR in samples obtained at diagnosis from 155 pediatric AML patients treated on a cooperative group protocol. Neither overall survival nor event-free survival was correlated with WT1 expression.