IMPORTANCE Thrombocytopenia and intraventricular hemorrhage (IVH) are common among very-low-birth-weight (VLBW) infants. Survey results suggest that US neonatologists frequently administer platelet transfusions to VLBW infants with mild to moderate thrombocytopenia. OBJECTIVES To characterize platelet transfusion practices in US neonatal intensive care units (NICUs), to determine whether severity of illness influences platelet transfusion decisions, and to examine the association between platelet count (PCT) and the risk for IVH in the first 7 days of life. DESIGN, SETTING, AND PARTICIPANTS This multicenter, retrospective cohort study included 972 VLBW infants treated in 6 US NICUs, with admission dates from January 1, 2006, to December 31, 2007. Data were collected from all infants until NICU discharge or death (last day of data collected, December 4, 2008). Data were entered into the central database, cleaned, and analyzed from May 1, 2009, to February 11, 2016. INTERVENTION Platelet transfusion. MAIN OUTCOMES AND MEASURES Number of platelet transfusions and incidence of IVH. RESULTS Among the 972 VLBW infants (520 [53.5%] male; mean [SD] gestational age, 28.2 [2.9] weeks), 231 received 1002 platelet transfusions (mean [SD], 4.3 [6.0] per infant; range, 1–63 per infant). The pretransfusion PCT was at least 50 000/μL for 653 of 998 transfusions (65.4%) with this information. Two hundred eighty-one transfusions (28.0%) were given during the first 7 days of life. During that period, platelet transfusions were given on 35 of 53 days (66.0%) when the patient had a PCT less than 50 000/μL and on 203 of 436 days (46.6%) when the patient had a PCT of 50 000/μL to 99 000/μL. At least 1 marker of severe illness was present on 198 of 212 patient-days (93.4%) with thrombocytopenia (PCT, <100 000/μL) when a platelet transfusion was given compared with 113 of 190 patient-days (59.5%) with thrombocytopenia when no platelet transfusion was given. Thrombocytopenia was a risk factor for intraventricular hemorrhage during the first 7 days of life (hazard ratio, 2.17; 95% CI, 1.53–3.08; P < .001). However, no correlation was found between severity of thrombocytopenia and risk for IVH. After controlling for significant clinical factors and thrombocytopenia, platelet transfusions did not have a significant effect on the incidence of IVH (hazard ratio, 0.92; 95% CI, 0.49–1.73; P = .80). CONCLUSIONS AND RELEVANCE A large proportion of platelet transfusions were given to VLBW infants with PCT greater than 50 000/μL. Severity of illness influenced transfusion decisions. However, the severity of thrombocytopenia did not correlate with the risk for IVH, and platelet transfusions did not reduce this risk.

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The most common cause of persistent hypoglycemia in the neonatal period is hyperinsulinism. Severe, refractory hypoglycemia resulting from hyperinsulinism can lead to significant brain injury and permanent cognitive disability. Diazoxide is the first-line and only US Food and Drug Administration–approved, pharmacologic treatment for refractory hyperinsulinism. In recent years, the use of diazoxide in neonates with persistent hyperinsulinemic hypoglycemia has increased in the United States. Known adverse effects of diazoxide include fluid retention, hypertrichosis, neutropenia, thrombocytopenia, and more recently, pulmonary hypertension. It is currently unknown if diazoxide exposure is associated with an increased risk of necrotizing enterocolitis (NEC) in neonates. We reviewed the cases of 24 patients in a level IV NICU at Massachusetts General Hospital who received diazoxide over 12 years (April 2006–April 2018). All 24 patients received enteral diazoxide for refractory hyperinsulinemic hypoglycemia. A total of 5 patients developed NEC after initiation of diazoxide based on clinical and radiographic findings, corresponding to 20% of infants exposed to diazoxide. This is above our baseline incidence of NEC (1% for all inborn infants and 6% for all inborn very low birth weight infants). More research and monitoring are necessary to characterize the potential risk of NEC associated with the use of diazoxide in the neonatal period.

Thrombocytopenia affects 20-35% of infants admitted to Neonatal Intensive Care Units. The incidence of thrombocytopenia is inversely proportional to gestational age, and approaches 70% among the most preterm neonates (birth weight <1,000 grams). Preterm infants also have the highest incidence of bleeding of any age group, with 25-31% developing intracranial hemorrhage. Currently, platelet (plt) transfusions are the only therapeutic option for thrombocytopenic neonates. In the last 5 years, two thrombopoietin (TPO) mimetics, romiplostim (ROM) and eltrombopag, received FDA approval for the treatment of adults with ITP. Based on the severity and duration of thrombocytopenia, 10% of thrombocytopenic neonates could benefit from TPO-mimetic therapy. Our prior in vitro studies demonstrated that human neonatal megakaryocyte (MK) progenitors are significantly more sensitive to TPO than adult progenitors (Pastos et al., Blood, 2006; Liu et al., Blood, 2011). This study was designed to compare the in vivo responses of newborn vs. adult mice to ROM. Based on prior observations, we hypothesized that newborn pups would be more sensitive to TPO-mimetics than adult mice. As a first step, healthy adult C57BL/6 mice were given a single subcutaneous (SC) injection of 0.1% BSA (control) or ROM at a dose of 10, 30, 100, or 300 ng/g body weight. Newborn mice on post-natal day 1 (P1) received a single SC injection of either 0.1% BSA or ROM at a dose of 30 or 300 ng/g. Plt count and immature plt fraction (IPF) were measured on the day of injection and every other day for 14 days. The baseline plt count in adult mice was 1,184±204 x103/µL. Adult mice treated with ROM (n=3-4 per group) exhibited a dose-dependent increase in plt count and IPF, which peaked on day 5 in those receiving lower ROM doses (10 and 30 ng/g), and on day 7 in those receiving higher ROM doses (100 and 300 ng/g). On day 7, adult mice treated with ROM 300 ng/g had a 4.2-fold increase in plt count compared to BSA controls (6,733±511 vs. 1,600±216 x103/µL, respectively; p<0.0001). Newborn mice (P1) had significantly lower baseline plt counts (624±130 x103/µL; p<0.0001) compared to adults, and similarly responded to ROM injection with a dose-dependent increase in plt count that peaked on day 5. However, plt counts on post-natal day 5 (P5) were 1,020±198 x103/µL for newborn mice treated with ROM 30 ng/g and 1,355±137 x103/µL for newborn mice treated with ROM 300 ng/g (n=17 per group), representing less than a 2-fold increase over BSA treated pups (701±119 x103/µL). To evaluate the effect of ROM on megakaryopoiesis, a subset of adult and newborn mice treated with 0.1% BSA or ROM 300 ng/g (n=3-4 per group) were euthanized on day 5 after injection. Liver, spleen, and bone marrow (BM) MKs were immunohistochemically stained for von Willebrand factor and quantified as described (Hu Z et al., Neonatology, 2010). Overall, ROM-treated adult mice had significantly increased numbers of MKs compared to controls in BM (2.3-fold increase; p=0.0002) and spleen (3.9-fold increase; p=0.006). ROM-treated newborn mice exhibited non-significant increases in MK numbers in BM (2.2-fold increase; p=0.19), spleen (1.6-fold increase; p=0.35), and liver (1.4-fold increase; p=0.31). Because newborn C57BL/6 mice transition from fetal liver to adult BM hematopoiesis during the first 10 to 14 days of life and the BM is not well formed until P10, we injected newborn mice at P5 (instead of P1) and evaluated the response to ROM. Similar to the younger group, P5 mice treated with ROM 300 ng/g reached peak platelet counts at P11, but the plt count was only 1.4-fold higher than BSA control animals (1,340±440 vs. 927±151 x103/µL, respectively; p=0.19). In conclusion, this study indicated that newborn mice are less responsive to ROM than adult mice. This was a surprising finding, given that human neonatal MK progenitors have been consistently shown to be more sensitive to TPO than adult MK progenitors. The reasons underlying the modest in vivo response of neonates are unclear, but might be related to the transition in hematopoietic sites that occurs during this period in murine development (corresponding to the second trimester of human gestation), high baseline thrombopoietic demands associated with rapid growth, potential pharmacokinetic factors, or developmental differences in the splenic or BM microenvironments of newborn and adult mice. Disclosures: No relevant conflicts of interest to declare.

Thrombocytopenia is frequent among sick neonates. While most cases are transient, some neonates experience prolonged and severe thrombocytopenia. These infants often pose diagnostic and therapeutic challenges, and may receive large numbers of platelet transfusions. Romiplostim (ROM) is a thrombopoietin (TPO)-receptor-agonist approved for treatment of adults with chronic immune thrombocytopenia (ITP). The immature platelet fraction (IPF) is a novel measure of newly produced platelets, which could aid with the diagnostic evaluation of thrombocytopenic neonates. This study had the following two objectives: (1) compare the response of newborn and adult mice to escalating doses of ROM in vivo and (2) assess the correlation between IPF and megakaryocyte (MK) mass in newborn and adult treated and untreated mice. In the first set of studies, newborn (day 1) and adult mice received a single subcutaneous (SC) dose of ROM ranging from 0 to 300 ng/g, and platelet counts were followed every other day for 14 days. Both sets of mice responded with dose-dependent platelet and IPF increases, peaking on days 5-7 post-treatment, but neonates had a blunted response (2.1-fold compared to 4.2-fold maximal increase in platelet counts, respectively). On day 5 post-treatment with 300 ng/g ROM, MKs in the bone marrow (BM) and spleen of adult mice were significantly increased in numbers and size (p < 0.0001 for both) compared to controls. MKs in the spleen and BM (but not liver) of treated neonates also increased in number, but not in size. The immature platelet count (IPC, calculated as IPF x platelet count) was highly correlated with the MK number and size in neonatal and adult BM and spleen, but not neonatal liver. The lack of response of neonatal liver MKs was not due to a cell-intrinsic reduced responsiveness to TPO, since neonatal liver progenitors were more sensitive to murine TPO (mTPO) in vitro than adult BM progenitor. In vivo treatment of newborn mice with high mTPO doses or with higher doses of ROM (900 ng/g) resulted in peak platelet counts approaching 3-fold of controls. Taken together, our data indicate that newborn mice are less responsive to ROM than adult mice in vivo, due to a combination of likely pharmacokinetic differences and developmental differences in the response of MKs to thrombopoietic stimulation, evidenced by neonatal MKs increasing in numbers but not in size. PK/PD studies in human infants treated with ROM are warranted.

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Objectives: There is abundant literature on simulation use in individual pediatric residency programs but limited overall data on simulation in US pediatric residency programs. This study sought to determine how US pediatric residency programs use simulation for teaching and assessment and the challenges programs face in their use of simulation. Methods:The Association of Pediatric Program Director's Healthcare Simulation in Pediatrics Learning Community members developed a 15multipart question survey on the use of simulation in US pediatric residency programs using best practices in survey design. The survey was distributed electronically to US pediatric residency program directors. Qualitative questions were analyzed by content analysis and quantitative questions using descriptive statistics. Results:The survey response rate was 21%; respondents were disproportionately from large academic medical centers. Qualitative analysis found that respondents use simulation to teach pediatric residents in the areas of urgent/emergent situations, procedures, and communication, and common challenges to simulation implementation are time, physical resources, expertise, competing priorities, logistics, and buy-in. Quantitative analysis demonstrated that, although respondents are largely confident that their simulation programs improve resident preparedness and competence, few objectively evaluate their simulation programs.Conclusions: Pediatric residency programs use simulation for similar purposes and face similar challenges. By collaborating, the resources of the national pediatric simulation community can be leveraged to collect evidence for best practices for simulation use in pediatric residency training.

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