Sarah E. Haskell

Neonatal macrosomia is an independent risk factor for adult metabolic syndrome.

Background: Weight in infancy correlates with risk of type 2 diabetes, hypertension, and obesity in adulthood. Clinical observations have been confounded by obesity-prone genotypes and obesity-linked lifestyles. Objectives: To define the effects of isolated neonatal macrosomia in isogenic animals, we compared macrosomic and control C57Bl6 mice co-fostered by healthy dams receiving standard laboratory feed. Methods: Naturally occurring neonatal macrosomia was identified by a gender-specific weanling weight above the 90th percentile for the colony. Macrosomic and control mice were phenotyped in adulthood by exercise wheel, tail cuff and intraperitoneal insulin or glucose challenge. Results: Compared to control males, adult males with a history of neonatal macrosomia had significantly increased body weight, reduced voluntary activity, insulin resistance, fasting hyperinsulinemia, and impaired glucose tolerance. In contrast, adult females with neonatal macrosomia had no significant alteration in body weight or endocrine phenotypes, but did have higher blood pressures and lower heart rates than control females. After these baseline studies, all mice were switched to a hypercaloric, high fat diet (5 kcal/g, 45% of energy as fat). Twenty weeks later, male mice had impaired glucose tolerance and insulin resistance, independent of their weanling weight classification. While on high fat feeds, macrosomic males maintained a significantly higher body weight than control males. Conclusions: We conclude that (1) in our murine model, neonatal macrosomia is an independent risk factor of adult metabolic syndrome, and (2) neonatal macrosomia accentuates the sexually dimorphic predisposition of C57Bl6 male mice towards glucose intolerance and C57Bl6 female mice towards hypertension.

Community public access sites: Compliance with American Heart Association recommendations

BACKGROUND Public access defibrillation (PAD) programs are a major goal of the American Heart Association (AHA) to ensure that automated external defibrillators and trained lay rescuers are available in public areas where sudden cardiac arrest (SCA) is likely to occur. The Johnson County Early Defibrillation Task Force (JCEDTF) is a volunteer organization which distributed AEDs throughout Johnson County, Iowa. JCEDTF was responsible for initial training but ongoing support was the responsibility of each site. OBJECTIVE The purpose of this study was to evaluate compliance of community PAD sites to recommendations for site maintenance as proposed by the American Heart Association (AHA). METHODS Thirty-two surveys were distributed to community PAD sites that received assistance from JCEDTF. PAD sites were categorized into business, educational, or community sites. A twenty-five point scoring system to assess PDA programs was developed based on AHA recommendations. On-site evaluations were conducted to verify survey results and assess barriers to an effective PAD site. Differences among the three categories were measured with ANOVA. RESULTS No site was able to comply with all the AHA guidelines for a PAD site. The mean score among all sites was 57% of possible points with no significant differences among the three categories. Business sites were more compliant with ongoing training compared to educational and community sites (p<0.022). CONCLUSIONS Community PAD sites in Johnson County currently do not comply with the recommendations for effective PAD sites. After initial training and establishment of community PAD sites, better methods for assuring ongoing training and maintenance are needed for sites to be effective.

Perinatal outcomes of pregnancies complicated by maternal depression with or without selective serotonin reuptake inhibitor therapy.

Background: Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed psychotropics for major depressive disorder during pregnancy and are used in up to 6.2% of pregnancies. Objective: To compare the perinatal outcomes of pregnancies complicated by maternal depression with or without SSRI therapy versus nondepressed pregnancies. Methods: International Classification of Diseases (ICD)-9 codes for depression were identified among women who delivered at the University of Iowa from April 2009 to March 2011. Data were extracted from linked maternal-neonatal records for all charts with an ICD-9 code for depression and an equal number of women without ICD-9 codes for depression. Results: Of the 3,695 women who delivered between 2009 and 2011, 238 had an ICD-9 code for depression. Sixteen women had depression listed in their records but did not have an ICD-9 code for depression. Their data were combined with those of the women with ICD-9 codes for depression, and it was found that 126 women (50%) in this combined depression cohort received an SSRI. Women with depression had increased alcohol and tobacco use, BMI and premature delivery rates (p < 0.01). Maternal depression was associated with an increased frequency of neonatal intensive care unit (NICU) admission (p < 0.001). In addition to depression, maternal SSRI use, obesity and smoking were univariate predictors of NICU admission. Conclusions: Among women with depression, the use of an SSRI was not associated with significant differences in any of the measured maternal or neonatal parameters, but further studies are needed to evaluate the specific effects of SSRI exposure in early or late gestation. Despite SSRI utilization, women with depression continue to have increased risks during pregnancy.

Neonatal SSRI Exposure Programs a Hypermetabolic State in Adult Mice

Background. Selective serotonin reuptake inhibitor (SSRI) therapy complicates up to 10% of pregnancies. During therapy, SSRIs exert pleiotropic antidepressant, anorexigenic, and neurotrophic effects. Intrauterine SSRI exposure has been modeled by neonatal administration to developmentally immature rodents, and it has paradoxically elicited features of adult depression. We hypothesized neonatal SSRI exposure likewise programs a rebound hypermetabolic state in adult mice. Methods. C57BL/6 pups were randomized to saline or sertraline (5 mg/kg/d) from P1–P14. Because estrogen increases tryptophan hydroxylase 2 (TPH2) expression, a subset of female mice underwent sham surgery or bilateral ovariectomy (OVX). Metabolic rate was determined by indirect calorimetry. Results. In both male and female mice, neonatal SSRI exposure increased adult caloric intake and metabolic rate. SSRI-exposed female mice had significantly decreased adult weight with a relative increase in brain weight and melatonin excretion, independent of ovarian status. Cerebral cortex TPH2 expression was increased in SSRI-exposed male mice but decreased in OVX SSRI-exposed female mice. Conclusions. SSRI exposure during a critical neurodevelopmental window increases adult caloric intake and metabolic rate. Ovarian status modulated central TPH2 expression, but not adult energy balance, suggesting programmed neural connectivity or enhanced melatonin production may play a more important role in the post-SSRI hypermetabolic syndrome.

Defibrillation in children

Defibrillation is the only effective treatment for ventricular fibrillation (VF). Optimal methods for defibrillation in children are derived and extrapolated from adult data. VF occurs as the initial rhythm in 8-20% of pediatric cardiac arrests. This has fostered a new interest in determining the optimal technique for pediatric defibrillation. This review will provide a brief background of the history of defibrillation and a review of the current literature on pediatric defibrillation. The literature search was performed through PubMed, using the MeSH headings of cardiopulmonary resuscitation, defibrillation and electric countershock. The authors’ personal bibliographic files were also searched. Only published articles were chosen. The recommended energy dose has been 2 J/kg for 30 years, but recent reports may indicate that higher dosages may be more effective and safe. In 2005, the European Resuscitation Council recommended 4 J/kg as the initial dose, without escalation for subsequent shocks. Automated external defibrillators are increasingly used for pediatric cardiac arrest, and available reports indicate high success rates. Additional research on pediatric defibrillation is critical in order to be able to provide an equivalent standard of care for children in cardiac arrest and improve outcomes.

Impact of neonatal sertraline exposure on the post-myocardial infarction outcomes of adult male mice.

Abstract: Neonatal exposure to a selective serotonin reuptake inhibitor (SSRI) leads to decreased left ventricular volumes and sympathetic activation in adult mice. We hypothesized this neonatal SSRI exposure–induced small left heart syndrome would increase post–myocardial infarction (MI) morbidity and mortality. C57BL/6 mice received saline or sertraline (5 mg/kg intraperitoneally) on postnatal days 1–14. At 5 months, male mice underwent coronary artery ligation and were monitored by radiotelemetry until death or 4 weeks after ligation. After ligation, SSRI-exposed mice had increased heart rates (SSRI, 516 ± 13 bpm; control, 470 ± 15 bpm; P < 0.05). SSRI-exposed mice had significant reductions in left ventricular systolic volumes both before and after coronary ligation (SSRI: baseline = 20 ± 3 &mgr;L, post-MI = 37 ± 10 &mgr;L; control: baseline = 30 ± 3 &mgr;L, post-MI = 65 ± 23 &mgr;L). Post-MI echocardiography showed significantly decreased ejection fraction in control mice (baseline = 60% ± 4%, post-MI = 41% ± 2%, P < 0.01) but not the SSRI-exposed mice (baseline = 65% ± 3%, post-MI = 53% ± 7%). Neonatal SSRI exposure did not significantly alter post-MI survival. We conclude that the preexisting SSRI-induced small left heart syndrome may provide protection from post-MI ventricular dilation.

Perinatal SSRI exposure permanently alters cerebral serotonin receptor mRNA in mice but does not impact adult behaviors

Abstract Purpose: Associations have been made between maternal selective serotonin reuptake inhibitor (SSRI) use during pregnancy and altered behavior in offspring, including an increased risk of autism. Given the important role serotonin plays in behavior, we hypothesized SSRI exposure in the perinatal period would alter central serotonin receptor expression and program adult behaviors in mice. Methods: Female mice were injected with sertraline or saline throughout pregnancy. Offspring continued to receive injections on postnatal days 1–14, a time period in mice similar to the third trimester in human pregnancy. Adult offspring underwent behavioral testing, and serotonin receptor mRNA levels were quantified. Results: Compared to controls, SSRI exposed mice did not have a reduction in social interactions, spatial learning, or exploratory behavior. As adults, sertraline exposed mice had significantly increased mRNA levels of multiple 5-HT receptors, serotonin transporter (5-HTT), and tryptophan hydroxylase isoform 2 in the cerebral cortex. Conclusion: Although no behavioral phenotype was observed, SSRI exposure in the perinatal period permanently alters cerebral receptor mRNA levels. We speculate these shifts in mRNA expression provide important compensation during SSRI exposure. Further pre-clinical and clinical investigation into additional serotonin-regulated phenotypes is necessary to further assess the long-term implications of perinatal SSRI exposure.

Cardiac Outcomes After Perinatal Sertraline Exposure in Mice

Abstract: Selective serotonin reuptake inhibitors are prescribed to 6%–10% of pregnant women in the United States. Using an intrauterine plus neonatal exposure model to represent exposure throughout human pregnancy, we hypothesized sertraline exposure would impact intracardiac serotonin signaling and lead to small left heart syndrome in the absence of maternal psychopathology. C57BL/6 adult female mice received sertraline (5 mg·kg−1·d−1 IP) or saline throughout pregnancy to time of delivery. Pups maintained exposure on postnatal days 1–14 to encompass the developmental window analogous to human gestation. Sertraline-exposed mice had increased cardiac hydroxyproline content, decreased 5-HT2B receptor mRNA levels, and increased 5-HT2A receptor and serotonin transporter mRNA levels on postnatal day 21 (P < 0.05). These changes were associated with diminished exercise capacity at 6 weeks (P < 0.05) and decreased adult shortening fraction and stroke volume at 5 months. Isolated cardiomyocytes from neonatal sertraline-exposed mice had significantly decreased proliferation, cross-sectional area, and phosphorylation of Akt (P < 0.05 vs. neonatal control mice). Perinatal sertraline exposure alters neonatal cardiac development and produces long-standing changes in adult cardiac function and exercise capacity. Further studies are needed to assess whether similar findings are present in the growing population that has been exposed to selective serotonin reuptake inhibitors during development.

Neonatal Growth Restriction Slows Cardiomyocyte Development and Reduces Adult Heart Size: NEONATAL GROWTH AND ADULT CARDIOMYOCYTE SIZE

Prematurity is associated with reduced cardiac dimensions and an increased risk of cardiovascular disease. While prematurity is typically associated with ex utero neonatal growth restriction (GR), the independent effect of neonatal GR on cardiac development has not been established. We tested the hypothesis that isolated neonatal GR decreases cardiomyocyte growth and proliferation, leading to long‐term alterations in cardiac morphology. C57BL/6 mice were fostered in litters ranging in size from 6 to 12 pups to accentuate normal variation in neonatal growth. Regardless of litter size, GR was defined by a weight below the 10th percentile. On postnatal day 8, Ki67 immunoreactivity, cardiomyocyte nucleation status and cardiomyocyte profile area were assessed. For adult mice, cardiomyocyte area was determined, along with cardiac dimensions by echocardiography and cardiac fibrosis by Massons trichrome stain. On day 8, cardiomyocytes from GR versus control mice were significantly smaller and less likely to be binucleated with evidence of persistent cell cycle activity. As adults, GR mice continued to have smaller cardiomyocytes, as well as decreased left ventricular volumes without signs of fibrosis. Neonatal GR reduces cardiomyocyte size, delays the completion of binucleation, and leads to long‐term alterations in cardiac morphology. Clinical studies are needed to ascertain whether these results translate to preterm infants that must continue to grow and mature in the midst of the increased circulatory demands that accompany their premature transition to an ex utero existence. Anat Rec, 2018.

Pediatric Out-of-Hospital Cardiac Arrest: Pushing for Progress in Public Response.

Cardiac arrest has been recognized as a public health problem affecting nearly 600 000 people annually, with 2% to 3% being children.1 Significant efforts have been made to educate and engage laypersons to perform cardiopulmonary resuscitation (CPR), beginning with American Heart Association courses in the 1970s. The Chain of Survival was developed to emphasize the need for early recognition and response as well as a systems-oriented approach. But despite concerted efforts, national survival statistics remain static. Nevertheless, survival rates of up to 50% have been achieved in selected communities that emphasize early CPR and adherence to current guidelines.2 Bystander CPR is the first link in the Chain of Survival. A recent meta-analysis3 reported that patients who experience out-of-hospital cardiac arrest (OHCA) and receive bystander CPR have a 4-fold increase in survival rates, confirming the importance of bystander CPR. The rate of bystander CPR in the United States remains low, and survival from adult and pediatric OHCA continues to be less than 10%.4-6 Compressiononly CPR was incorporated into adult guidelines in 2008 to increase bystander CPR. For pediatric arrests, traditional CPR is recommended, and compression-only CPR is preferred to no CPR. While important research continues to optimize resuscitation outcomes, this critical first link in the Chain of Survival needs immediate attention if we are to improve survival for patients with OHCA. In this issue of JAMA Pediatrics, Naim et al7 demonstrated bystander CPR alone was associated with higher rates of overall survival and neurologically favorable status after pediatric OHCA. This is a key study describing the effect of bystander CPR in children younger than 18 years. During the 2-year period, 3900 children with OHCA were evaluated from the Cardiac Arrest Registry to Enhance Survival database. The study included both conventional CPR and compression-only CPR. The prevalence of bystander CPR in this study was 47%, much higher than previous rates reported in the United States5 and slightly below rates reported in Japan.8 In those who received bystander CPR, survival to hospital discharge was 14.3%, and 11.6% had favorable neurologic outcomes. Overall survival to hospital discharge (11.3%) and favorable neurologic status (9.1%) for children with OHCA was also higher compared with other recent pediatric studies.6,9,10 Approximately equal distributions of conventional CPR and compression-only CPR were performed, with children aged 1 to 18 years more likely to receive compression-only CPR. Although bystander CPR was associated with improved outcomes compared with no CPR, important distinctions were noted in this article. Conventional CPR had higher survival rates than compression-only CPR in all analyses. Bystander CPR was more common for white children than other races/ethnicities. The important messages from this study are the improved outcomes of pediatric cardiac arrest with bystander CPR, the greater benefit of standard CPR over compression-only resuscitation, and the racial disparity which exists in many communities. Although bystander CPR has been shown to improve outcomes in adult cardiac arrest, it is important to demonstrate that children also benefit. The etiologies, severity of hypoxia and acidosis, and rhythms differ in the 2 populations, so it is not a given that bystander CPR will have as great a benefit. This article by Naim et al7 demonstrates the benefit of bystander CPR for children, including the benefit of compression-only CPR in children aged 1 to 18 years. Kitamura et al9 previously reported that conventional CPR and compression-only CPR were similarly effective in arrests from cardiac causes, but conventional CPR was preferred for those with noncardiac causes. However, Goto et al8 reported only conventional bystander CPR was associated with a greater likelihood of neurologically intact survival compared with compression-only CPR, irrespective of cardiac arrest etiology. The study by Naim et al7 did not differentiate by probable cause of the arrest, and a shortcoming of the Japanese studies8,9 is that the etiology was assigned at the scene, which may not be correct. Given the accumulated data, the current American Heart Association recommendations can be strongly supported. Bystander CPR should be provided; rescue breaths are preferred but compression-only CPR is still of benefit. The one exception is children younger than 1 year, in whom all studies support conventional CPR. A major problem in bystander CPR is the racial disparity that exists in some populations.1 A recent study examining 1980 children with OHCA reported no difference in rates of bystander CPR associated with race/ethnicity.6 Unfortunately, this study by Naim et al7 and several others still report bystander CPR is less likely to occur in African American or Hispanic populations.1 Given the improvement in outcomes in children with OHCA that received bystander CPR, this is an important public health concern that needs to be addressed. This article affirms that we are making progress. Bystander CPR rates were 47%, and the rate of survival with favorable neurologic outcomes in those who received bystander CPR was greater than 10%. Although one may argue that the Related article Opinion