Radiation Exposure in Extracorporeal Life Support.

Extracorporeal membrane oxygenation (ECMO) exposes patients to multiple radiologic studies. We hypothesized ECMO patients endure radiation exposure in excess of the International Commission of Radiological Protection (ICRP) recommendations of cumulative effective dose (CED, >20 mSv and 5-year cumulative limit of CED >100 mSv). We conducted a retrospective observational study in an academic medical center between January 2016 and December 2018 involving adult admissions (N = 306) on ECMO. Ionizing radiation was calculated from reference values to determine CED. Approximately 9.4% (N = 29) patients accrued CED >50 mSv and 4.5% (N = 14) accrued CED >100 mSv during ECMO. Over the entire hospitalization, 28% (N = 85) accrued >50 mSv and 14.7% (N = 45) accrued CED >100 mSv. Median CED during ECMO was 2.3 mSv (IQR, -0.82 to 8.1 mSv), and the entire hospitalization was 17.4 mSv (IQR, -4.5 to 56.6 mSv). Thirteen percent of the median CED accrued during hospitalization could be attributed to ECMO. Longer hospitalization was associated with a higher CED (50 days [IQR, -25 to 76 days] in CED >50 vs. 19 days [IQR, -10 to 32 days] in CED <50). Computer tomography (CT) scans and interventional radiology (IR) procedures contributed to 43.8% and 44.86%, respectively, of CED accrued on ECMO and 52.2% and 37.1% of CED accumulated during the whole hospitalization. Guidelines aimed at mitigating radiation exposure are urgently needed.

Successful treatment of pulmonary mucormycosis (Lichtheimia spp.) in a post-partum patient with COVID-19 ARDS requiring extra-corporeal membrane oxygenation using salvage therapy.

Case Summary: A 31-year-old female presented to a regional hospital at 27 weeks pregnant and was found to have COVID-19 ARDS. She underwent intubation and caesarian section for worsening hypoxia and non-reassuring fetal heart tones. Hypoxemia was refractory to proning requiring ECMO and transfer to a tertiary care center. Admission chest radiography showed a new right lower lobe cavitating lesion with computed tomography scan revealing a large multi-loculated cavity in the right lung and extensive bilateral ground-glass opacities. The patient was started on amphotericin and posaconazole, with final respiratory cultures growing Lichtheimia spp. Source control was discussed via possible open thoracostomy, but medical management alone was continued. Total ECMO support was 3 weeks. At the time of discharge to acute rehab, 1 month of amphotericin and posaconazole had been completed, with continuation of posaconazole. At last update, she had been discharged from rehab and was back home with her infant. Conclusion: Pulmonary mucormycosis, even in the non-ECLS population, carries a high mortality. Treatment in pulmonary disease with surgery improves mortality but is not always feasible. Salvage therapy with extended course antifungal medications may be an option for those not amendable.

Association of Pain With Atrial Fibrillation and Delirium After Cardiac Surgery: A DECADE Sub-Study.

OBJECTIVE: The authors aimed to evaluate the effects of postoperative pain on the incidence of atrial fibrillation and delirium in patients having surgery with cardiopulmonary bypass (CPB). DESIGN: Post hoc analysis of the (An investigator-initiated, multicentre, double-blind trial (ClinicalTrials NCT02004613) (DECADE)), a randomized, placebo-controlled trial. SETTING: Tertiary, academic hospital. PARTICIPANTS: Six hundred five adults from the DECADE enrolled at Cleveland Clinic Main Campus, who had had surgery with CPB. INTERVENTIONS: Dexmedetomidine versus placebo started before surgical incision and postoperatively was maintained until 24 hours. MEASUREMENTS: Primary outcomes were atrial fibrillation, diagnosed by clinicians in the intensive care unit (ICU), presence of delirium assessed with the Confusion Assessment Method for the ICU, data on pain scores, and opioid consumption, occurring between ICU admission and the earlier of postoperative day five or hospital discharge. RESULTS: Postoperative pain levels were similar among patients with or without atrial fibrillation. Two hundred six (34%) patients had atrial fibrillation and ninety-two (15%) had delirium before hospital discharge within the first five postoperative days. The risk of atrial fibrillation was not significantly different between groups (hazard ratio: 1.09; 97.5% confidence interval [CI]: 0.99, 1.20, p = 0.039); there were no associations between postoperative pain and the risk of postoperative delirium (hazard ratio: 0.96; 97.5% CI: 0.84-1.11; p = 0.57). Postoperative opioid consumption was neither significantly associated with postoperative atrial fibrillation nor delirium. CONCLUSIONS: Atrial fibrillation and delirium was not associated with pain after cardiac surgery. Opioid use was not associated with atrial fibrillation and delirium. Because both atrial fibrillation and delirium have a multifactorial nature, further studies should be focused on other plausible mechanisms.

A case of vaping-induced acute respiratory distress syndrome requiring extracorporeal life support.

INTRODUCTION: An upsurge of e-cigarette, or vaping, product use-associated lung injury has been reported in the United States. The potential role of extracorporeal life support in e-cigarette, or vaping, product use-associated lung injury merits consideration. CASE REPORT: We present a case of vaping-induced severe acute respiratory distress syndrome that was salvaged with extracorporeal life support and had excellent recovery. DISCUSSION: The mechanistic reasons for the sudden outbreak of e-cigarette, or vaping, product use-associated lung injury are under active investigation. A predominantly diffuse, bilateral pattern of lung injury has been reported, with some cases meeting the criteria for severe acute respiratory distress syndrome. To date, 68 deaths from e-cigarette, or vaping, product use-associated lung injury have been confirmed by the centers of disease control. However, resolution of lung injury has been reported in most cases, thereby justifying candidacy for extracorporeal life support, if required. CONCLUSION: Extracorporeal life support can be successfully utilized as a bridge to recovery in vaping-induced severe acute respiratory distress syndrome.

Effectiveness, safety, and Economic Comparison of Two Inhaled Epoprostentol Products (Flolan and Veletri) in Cardiothoracic Surgery Patients.

BACKGROUND: No previous studies exist examining two inhaled epoprosternol formulations (Flolan compared with Veletri) in a homogenous cardiothoracic surgery patient population. OBJECTIVE: To compare the impact of inhaled Flolan and inhaled Veletri on the effectiveness, safety, or cost in cardiothoracic surgery patients. MATERIALS AND METHODS: This was a retrospective, noninferiority study comparing inhaled Flolan and inhaled Veletri in cardiothoracic surgery patients. Participants included were ≥18 years old, admitted to the cardiothoracic intensive care unit, and received inhaled Flolan or inhaled Veletri therapy for ≥1 hour. RESULTS: A total of 244 patients were included in the primary outcome analysis (122 patients per group). The primary outcome, change in the partial pressure of arterial oxygen to fraction of inspired oxygen (PaO2/FiO2) ratio 1 hour after administration of inhaled Flolan or inhaled Veletri, did not cross the lower limit of the noninferiority margin (95% CI = -14.8 to 65.4). Significant differences in secondary outcomes included duration of mechanical ventilation (4.4 vs 2.6 days; P < 0.01), number of tracheostomies (24 vs 9; P = 0.01), number of patients initiated on dialysis (25 vs 12; P = 0.02), and cost per median duration of therapy ($257 vs $183; P = 0.02) in the inhaled Flolan and inhaled Veletri groups, with the average duration of therapy being 1.6 and 1.3 days, respectively. CONCLUSIONS AND RELEVANCE: Inhaled Veletri was demonstrated to be non-inferior to inhaled Flolan when comparing change in PaO2/FiO2 ratio 1 hour post -therapy initiation,and inhaled Veletri was an acceptable alternative to inhaled Flolan in a cardiothoracic surgery patient population.

Psychosocial interventions for disruptive behaviour problems in children in low- and middle-income countries: a systematic review and meta-analysis.

BACKGROUND: Most of the evidence for psychosocial interventions for disruptive behaviour problems comes from Western, high-income countries. The transferability of this evidence to culturally diverse, low-resource settings with few mental health specialists is unknown. METHODS: We conducted a systematic review with random-effects meta-analysis of randomized controlled trials examining the effects of psychosocial interventions on reducing behaviour problems among children (under 18) living in low- and middle-income countries (LMIC). RESULTS: Twenty-six randomized controlled trials (representing 28 psychosocial interventions), evaluating 4,441 subjects, met selection criteria. Fifteen (54%) prevention interventions targeted general or at-risk populations, whereas 13 (46%) treatment interventions targeted children selected for elevated behaviour problems. Most interventions were delivered in group settings (96%) and half (50%) were administered by non-specialist providers. The overall effect (standardized mean difference, SMD) of prevention studies was -0.25 (95% confidence interval (CI): -0.41 to -0.09; I2 : 78%) and of treatment studies was -0.56 (95% CI: -0.51 to -0.24; I2 : 74%). Subgroup analyses demonstrated effectiveness for child-focused (SMD: -0.35; 95% CI: -0.57 to -0.14) and behavioural parenting interventions (SMD: -0.43; 95% CI: -0.66 to -0.20), and that interventions were effective across age ranges. CONCLUSIONS: Our meta-analysis supports the use of psychosocial interventions as a feasible and effective way to reduce disruptive behaviour problems among children in LMIC. Our study provides strong evidence for child-focused and behavioural parenting interventions, interventions across age ranges and interventions delivered in groups. Additional research is needed on training and supervision of non-specialists and on implementation of effective interventions in LMIC settings.

Regulation of Blood Pressure, Appetite, and Glucose by Leptin After Inactivation of Insulin Receptor Substrate 2 Signaling in the Entire Brain or in Proopiomelanocortin Neurons.

Insulin receptor substrate 2 (IRS2) is one of the 3 major leptin receptor signaling pathways, but its role in mediating the chronic effects of leptin on blood pressure, food intake, and glucose regulation is unclear. We tested whether genetic inactivation of IRS2 in the entire brain (IRS2/Nestin-cre mice) or specifically in proopiomelanocortin (POMC) neurons (IRS2/POMC-cre mice) attenuates the chronic cardiovascular, metabolic, and antidiabetic effects of leptin. Mice were instrumented with telemetry probes for measurement of blood pressure and heart rate and with venous catheters for intravenous infusions. After a 5-day control period, mice received leptin infusion (2 µg/kg per minute) for 7 days. Compared with control IRS2(flox/flox) mice, IRS2/POMC-cre mice had similar body weight and food intake (33±1 versus 35±1 g and 3.6±0.5 versus 3.8±0.2 g per day) but higher mean arterial pressure (MAP) and heart rate (110±2 versus 102±2 mm Hg and 641±9 versus 616±5 bpm). IRS2/Nestin-cre mice were heavier (38±2 g), slightly hyperphagic (4.5±1.0 g per day), and had higher MAP and heart rate (108±2 mm Hg and 659±9 bpm) compared with control mice. Leptin infusion gradually increased MAP despite decreasing food intake by 31% in IRS2(flox/flox) and in Nestin-cre control mice. In contrast, leptin infusion did not change MAP in IRS2/Nestin-cre or IRS2/POMC-cre mice. The anorexic and antidiabetic effects of leptin, however, were similar in all 3 groups. These results indicate that IRS2 signaling in the central nervous system, and particularly in POMC neurons, is essential for the chronic actions of leptin to raise MAP but not for its anorexic or antidiabetic effects.

Psychosocial interventions for disruptive behavioural problems in children living in low- and middle-income countries: study protocol of a systematic review.

INTRODUCTION: Disruptive behaviour disorders (DBDs) are among the most common forms of child psychopathology and have serious long-term academic, social, and mental health consequences worldwide. Psychosocial treatments are the first line of evidence-based treatments for DBDs, yet their effectiveness often varies according to patient sociodemographic characteristics, practice setting, and implementation procedures. While a large majority of the world's children live in low- and middle-income countries (LMIC), most studies have evaluated psychosocial treatments for DBDs in high-income Anglo countries. METHODS AND ANALYSIS: The primary objective of this systematic review is to assess the effects of psychosocial treatments for DBDs in children and adolescents (under age 18) diagnosed with oppositional defiant disorder, conduct disorder, or other disruptive behavioural problems living in LMIC. The secondary objectives are to: (1) describe the range and types of psychosocial treatments used to address DBDs in LMIC and (2) identify key dissemination and implementation factors (adaptation processes, training/supervision processes, and financial costs). All controlled trials comparing psychosocial treatments versus waiting list, no treatment, or treatment as usual in children living in LMIC will be included. Studies will be identified using the methods outlined in the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines without restrictions on language, publication type, status, or date of publication. The primary outcome measures will be disruptive behavioural problems (eg, oppositionality, defiance, aggression or deceit). Secondary outcomes will be positive mental health outcomes (eg, prosocial behaviour), function impairment, institutionalisation (or hospitalisation), academic outcomes and caregiver outcomes. ETHICS AND DISSEMINATION: This study uses data from published studies; therefore ethical review is not required. Findings will be presented in a published manuscript. TRIAL REGISTRATION NUMBER: PROSPERO CRD42014015334.

Screening for Mutations in ABCC8 and KCNJ11 Genes in Saudi Persistent Hyperinsulinemic Hypoglycemia of Infancy (PHHI) Patients.

The autosomal recessive form of persistent hyperinsulinemic hypoglycemia of infancy (PHHI) is associated with mutations in either ABCC8 or KCNJ11 genes. In the present study, we describe the clinical features and results of genetic analysis of 13 Saudi Arabian patients with PHHI. Clinically, most patients presented with infantile seizures and/or developmental delay, with a subset of patients who were also found to have abnormal brain imaging and electrophysiological studies. Interestingly no coding pathogenic mutations were identified in these two genes by direct sequencing. However, two splice variants were identified in ABCC8 gene in two patients, and a large deletion of exons 1-22 of the ABCC8 gene was identified in three patients. Our data shows that large deletions in ABCC8 gene are the common genetic mechanism in the Saudi population.

Homozygosity analysis in subjects with autistic spectrum disorder.

Autistic spectrum disorder (ASD) is a complex neurodevelopmental disorder that results in social and communication impairments, as well as repetitive and stereotyped patterns. Genetically, ASD has been described as a multifactorial genetic disorder. The aim of the present study was to investigate possible susceptibility loci of ASD, utilizing the highly consanguineous and inbred nature of numerous families within the population of Saudi Arabia. A total of 13 multiplex families and 27 affected individuals were recruited and analyzed using Affymetrix GeneChip(®) Mapping 250K and 6.0 arrays as well as Axiom arrays. Numerous regions of homozygosity were identified, including regions in genes associated with synaptic function and neurotransmitters, as well as energy and mitochondria-associated genes, and developmentally-associated genes. The loci identified in the present study represent regions that may be further investigated, which could reveal novel changes and variations associated with ASD, reinforcing the complex inheritance of the disease.

Dermatomyositis paraneoplastic syndrome before symptomatic tonsillar squamous cell carcinoma: a case report.

BACKGROUND: Paraneoplastic syndromes are systemic or organ-related functional tumor-associated changes that arise distant to the tumor. METHODS AND RESULTS: We present a rare case of a 63-year-old man with dermatomyositis as a paraneoplastic syndrome developing more than a year before clinical manifestations of tonsillar squamous cell carcinoma (SCC). He subsequently developed stage T1N2bM0 IVA tonsillar SCC. He was treated on a research protocol with 3 weeks of neoadjuvant rapamycin therapy before right transoral lateral pharyngectomy and modified radical neck dissection with preservation of CN XI. His symptoms of dermatomyositis subsequently improved and he was weaned off immunosuppressive therapy. CONCLUSION: To our knowledge, this is the first report of dermatomyositis as a paraneoplastic syndrome of tonsillar SCC in North America. We suggest that clinicians should monitor for signs of persistent or recurrent dermatomyositis symptoms as this may herald development or a return of the underlying malignancy.

Role of proopiomelanocortin neuron Stat3 in regulating arterial pressure and mediating the chronic effects of leptin.

Although signal transducer and activator of transcription 3 (Stat3) is a key second messenger by which leptin regulates appetite and body weight, its role in specific neuronal populations in metabolic regulation and in mediating the chronic effects of leptin on blood pressure is unknown. The current study tested the hypothesis that Stat3 signaling in proopiomelanocortin (POMC) neurons mediates the chronic effects of leptin on mean arterial pressure (MAP), as well as on glucose regulation, energy expenditure, and food intake. Stat3(flox/flox) mice were crossed with POMC-Cre mice to generate mice with Stat3 deletion specifically in POMC neurons (Stat3(flox/flox)/POMC-Cre). Oxygen consumption (Vo2), carbon dioxide respiration (Vco2), motor activity, heat production, food intake, and MAP were measured 24 hours/d. After baseline measurements, leptin was infused (4 µg/kg per min, IP) for 7 days. Stat3(flox/flox)/POMC-Cre mice were hyperphagic, heavier, and had increased respiratory quotients compared with control Stat3(flox/flox) mice. Baseline MAP was not different between the groups, and chronic leptin infusion reduced food intake similarly in both groups (27 versus 29%). Vo2, Vco2, and heat production responses to leptin were not significantly different in control and Stat3(flox/flox)/POMC-Cre mice. However, leptin-mediated increases in MAP were completely abolished, and blood pressure responses to acute air-jet stress were attenuated in male Stat3(flox/flox)/POMC-Cre mice. These results indicate that Stat3 signaling in POMC neurons is essential for leptin-mediated increases in MAP, but not for anorexic or thermogenic effects of leptin.

Chronic central ghrelin infusion reduces blood pressure and heart rate despite increasing appetite and promoting weight gain in normotensive and hypertensive rats.

Acute studies showed that ghrelin acts on the central nervous system (CNS) to reduce blood pressure (BP), heart rate (HR) and sympathetic activity. However, the long-term CNS cardiovascular actions of ghrelin are still unclear. We tested whether chronic intracerebroventricular (ICV) infusion of ghrelin causes sustained reductions in BP, HR and whether it alters baroreceptor sensitivity (BRS) and autonomic input to the heart. A cannula was placed in the lateral ventricle of male Sprague-Dawley (SD) rats for ICV infusions via osmotic minipump (0.5 µl/h). BP and HR were measured 24-h/day by telemetry. After 5 days of control measurements, ghrelin (0.21 nmol/h) or saline vehicle were infused ICV for 10 days followed by a 5-day post-treatment period. Chronic ICV ghrelin infusion increased food intake (22±3 to 26±1 g/day) leading to ~50 g body weight gain. BP fell slightly during ghrelin infusion while HR decreased by ~26 bpm. In control animals BP and HR increased modestly. ICV Ghrelin infusion caused a 50% reduction in sympathetic tone to the heart but did not alter BRS. We also tested if the depressor responses to ICV ghrelin infusion were enhanced in spontaneously hypertensive rats (SHR) due to their high basal sympathetic tone. However, we observed similar BP and HR responses compared to normotensive rats. These results indicate that ghrelin, acting via direct actions on the CNS, has a sustained effect to lower HR and a modest impact to reduce BP in normotensive and hypertensive animals despite increasing appetite and body weight.