Publications by authors named "Pippa M Simpson"

118 Publications

Venovenous Versus Venoarterial Extracorporeal Membranous Oxygenation in Inotrope Dependent Pediatric Patients With Respiratory Failure.

ASAIO J 2021 Apr;67(4):457-462

From the Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI.

Patients with respiratory failure requiring inotropes or vasopressors are often placed on venoarterial (VA) extracorporeal membrane oxygenation (ECMO), as venovenous (VV) ECMO does not provide direct circulatory support. This retrospective multicenter study compared outcomes for 103 pediatric patients, with hemodynamic compromise, placed on VV ECMO for respiratory failure to those placed on VA ECMO. The primary outcome was survival to hospital discharge. Fifty-seven (55%) study participants were supported on VV ECMO. The two groups had similar PRISM III scores at pediatric intensive care unit (PICU) admission, and vasoactive-inotropic scores at ECMO cannulation. More VV ECMO patients received inhaled nitric oxide (iNO) (54.4 vs. 34.8%; p = 0.04) and had a higher oxygenation index (median 41.5 vs. 19.5; p = 0.04) pre-ECMO. More VA ECMO patients had cardiac dysfunction and cardiac arrest pre-ECMO (50 vs. 14%; p < 0.0001). In univariable analysis, survival to hospital discharge was higher in the VV vs. VA ECMO group (72 vs. 44%; p = 0.005), however, in multivariable models, cannulation type was confounded by cardiopulmonary resuscitation and was not independently associated with survival. VV survivors had longer ECMO duration compared with VA survivors (median, 7 vs. 4.5 days; p = 0.036) but similar PICU and hospital days. No significant difference was noted in functional outcomes or comorbidities at discharge. Cannulation type is not independently associated with survival to hospital discharge in pediatric patients on vasoactive infusions at the time of ECMO cannulation for respiratory indications.
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http://dx.doi.org/10.1097/MAT.0000000000001254DOI Listing
April 2021

The authors reply.

Crit Care Med 2021 Jan;49(1):e111-e112

Quantitative Health Sciences, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI.

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http://dx.doi.org/10.1097/CCM.0000000000004721DOI Listing
January 2021

Investigating the Effects of Cuing Medication Availability on Patient-controlled Analgesia Pump Usage in Pediatric Patients: Results of a Randomized Controlled Trial.

Clin J Pain 2021 Jan;37(1):1-10

Department of Anesthesiology.

Objectives: The study of patient-controlled analgesia (PCA) behaviors has led to a greater understanding of factors that affect the pain experience. Although PCA behaviors can be influenced by cues to medication availability, no studies have examined the effects of such cues in pediatric populations.

Materials And Methods: This randomized controlled trial examined patient satisfaction with pain management, PCA behaviors, opioid consumption, and state anxiety in a sample of 125 postsurgical children and adolescents (7 to 17 y). Patients were randomized to a "light" group (lockout period status cued by light on the PCA button) or control group (no cues to medication availability).

Results: Although cuing did not affect patient satisfaction with pain management (P=0.11), patients in the light group consumed significantly more opioid than those in the control group (adj. P=0.016). This effect was primarily because of children in the light group (median, 0.019; interquartile range, 0.012 to 0.036 mg/kg/h) consuming more opioid than children (12 y or younger) in control group (median, 0.015; interquartile range, 0.006 to 0.025 mg/kg/h) (P=0.007). In contrast to the control group, for patients in the light group, opioid consumption was unrelated to pain and the proportion of patients with a 1:1 injections:attempts ratio was higher (P<0.001) across the study period.

Discussion: The overall pattern of results suggests that patients in the light group used their PCA in response to the light more than in response to their pain, which likely reflects operant influences on PCA behavior by pediatric patients.
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http://dx.doi.org/10.1097/AJP.0000000000000892DOI Listing
January 2021

Total Cell-Free DNA Predicts Death and Infection Following Pediatric and Adult Heart Transplantation.

Ann Thorac Surg 2020 Oct 8. Epub 2020 Oct 8.

Herma Heart Center, Children's Wisconsin, and Medical College of Wisconsin, Milwaukee, WI. Electronic address:

Background: Elevated total cell-free DNA (TCF) concentration has been associated with critical illness in adults and elevated donor fraction (DF), the ratio of donor specific cell-free DNA to total cell-free DNA present in the recipient's plasma, is associated with rejection following cardiac transplantation. This study investigates relationships between TCF and clinical outcomes after heart transplantation.

Methods: A prospective, blinded, observational study of 87 heart transplantation recipients was performed. Samples were collected at transplantation, prior to endomyocardial biopsy, during treatment for rejection, and at hospital readmissions. Longitudinal clinical data were collected and entered into a RedCAP (Vanderbilt University) database. TCF and DF levels were correlated with endomyocardial biopsy and angiography results, as well as clinical outcomes. Logistic regression for modeling and repeated measures analysis using generalized linear modeling was used. The standard receiver operating characteristic curve, hazard ratios, and odds ratios were calculated.

Results: There were 257 samples from 87 recipients analyzed. TCF greater than 50 ng/mL were associated with increased mortality (P = .01, area under the curve 0.93, sensitivity 0.44, specificity 0.97) and treatment for infection (P < .005, area under the curve 0.68, sensitivity 0.45, specificity 0.96). Increased DF was not correlated with treatment for infection. DF was associated with rejection and cardiac allograft vasculopathy (P < .001), but TCF was not.

Conclusions: TCF elevation predicted death and treatment for infection. DF elevation predicted histopathologic acute rejection and cardiac allograft vasculopathy. Surveillance of TCF and DF levels may inform treatment after heart transplantation.
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http://dx.doi.org/10.1016/j.athoracsur.2020.08.006DOI Listing
October 2020

Measurement properties of Patient Reported Outcomes Measurement Information System domains for children with type 1 diabetes.

Pediatr Diabetes 2021 Mar 19;22(2):335-344. Epub 2020 Oct 19.

Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.

Objective: Patient Reported Outcomes Measurement Information System (PROMIS) includes numerous domains to assess functioning among the pediatric population. These domains, however, have not been evaluated for use in children with type 1 diabetes (T1D). The objective of this study was to determine the measurement properties of PROMIS domains (pain behavior, pain quality, physical stress experience, physical activity, strength impact, and profile-25) in children with T1D.

Methods: This is a cross-sectional study of children with T1Drecruited from tertiary care facilities. To determine construct validity, we compared PROMIS T-scores between known-groups based on (a) glycemic control, hemoglobin A1c (HbA1c%) and (b) self-reported general health, using t test or analysis of variance. Reliability was determined using Cronbach's alpha and item response theory reliability. We also determined agreement between parent-proxy and child self-report PROMIS scores.

Results: Our study included 192 children, mean age 12.7 (SD = 2.9) years, eligible to self-report PROMIS surveys. There were significant differences in physical stress experience and pain intensity between children with HbA1c < 10% and those with HbA1c ≥ 10%. There also were significant differences in T-scores for all domains except physical function mobility and strength impact among children with poor/fair, good, very good/excellent general health. All valid domains had reliability >0.70. More than 40% of child-parent pairs were in agreement, with intraclass correlations coefficients (ICC) ranging between 0.41 and 0.63 for all domains, except pain behavior (%agreement = 23%; ICC = 0.29).

Conclusions: Most of the PROMIS domains tested are valid, reliable, and able to differentiate children with T1D who report different general health states. There is moderate agreement between child-parent pairs for all domains except pain behavior.
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http://dx.doi.org/10.1111/pedi.13134DOI Listing
March 2021

Serum soluble urokinase plasminogen activator receptor in adolescents: interaction of chronic pain and obesity.

Pain Rep 2020 Jul-Aug;5(4):e836. Epub 2020 Jul 22.

Department of Anesthesiology, Medical College of Wisconsin and the Jane B. Pettit Pain and Headache Center, Children's Wisconsin, Milwaukee, WI, USA.

Introduction: Obesity in adolescents is increasing in frequency and is associated with short-term and long-term negative consequences that include the exacerbation of co-occurring chronic pain.

Objective: To determine whether the interaction between chronic pain and obesity would be reflected in changes in serum soluble urokinase plasminogen activator receptor (suPAR) concentrations, a novel marker of systemic inflammation associated with obesity, insulin resistance, and cardiovascular disease.

Methods: We measured serum suPAR levels in 146 adolescent males and females with no pain or obesity (healthy controls; n = 40), chronic pain with healthy weight (n = 37), obesity alone (n = 41), and the combination of chronic pain and obesity (n = 28).

Results: Serum suPAR (median [interquartile range]) was not increased by chronic pain alone (2.2 [1.8-2.4] ng/mL) or obesity alone (2.2 [2.0-2.4] ng/mL) but was increased significantly with the combination of chronic pain and obesity (2.4 [2.1-2.7] ng/mL; < 0.019). This finding confirms the proposition that pain and obesity are inflammatory states that display a classic augmenting interaction.

Conclusion: We propose that measurement of serum suPAR can be added to the armamentarium of serum biomarkers useful in the evaluation of mechanisms of inflammation in adolescent obesity and chronic pain.
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http://dx.doi.org/10.1097/PR9.0000000000000836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7382552PMC
July 2020

Rituximab and antimetabolite treatment of granulomatous and lymphocytic interstitial lung disease in common variable immunodeficiency.

J Allergy Clin Immunol 2021 Feb 1;147(2):704-712.e17. Epub 2020 Aug 1.

Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wis; Division of Asthma, Allergy and Clinical Immunology, Medical College of Wisconsin, Milwaukee, Wis. Electronic address:

Background: Granulomatous and lymphocytic interstitial lung disease (GLILD) is a life-threatening complication in patients with common variable immunodeficiency (CVID), but the optimal treatment is unknown.

Objective: Our aim was to determine whether rituximab with azathioprine or mycophenolate mofetil improves the high-resolution computed tomography (HRCT) chest scans and/or pulmonary function test results in patients with CVID and GLILD.

Methods: A retrospective chart review of clinical and laboratory data on 39 patients with CVID and GLILD who completed immunosuppressive therapy was performed. Chest HRCT scans, performed before therapy and after the conclusion of therapy, were blinded, randomized, and scored independently by 2 radiologists. Differences between pretreatment and posttreatment HRCT scan scores, pulmonary function test results, and lymphocyte subsets were analyzed. Whole exome sequencing was performed on all patients.

Results: Immunosuppressive therapy improved patients' HRCT scan scores (P < .0001), forced vital capacity (P = .0017), FEV (P = .037), and total lung capacity (P = .013) but not their lung carbon monoxide diffusion capacity (P = .12). Nine patients relapsed and 6 completed retreatment, with 5 of 6 of these patients (83%) having improved HRCT scan scores (P = .063). Relapse was associated with an increased number of B cells (P = .016) and activated CD4 T cells (P = .016). Four patients (10%) had pneumonia while undergoing active treatment, and 2 patients (5%) died after completion of therapy. Eight patients (21%) had a damaging mutation in a gene known to predispose (TNFRSF13B [n = 3]) or cause a CVID-like primary immunodeficiency (CTLA4 [n = 2], KMT2D [n = 2], or BIRC4 [n = 1]). Immunosuppression improved the HRCT scan scores in patients with (P = .0078) and without (P < .0001) a damaging mutation.

Conclusions: Immunosuppressive therapy improved the radiographic abnormalities and pulmonary function of patients with GLILD. A majority of patients had sustained remissions.
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http://dx.doi.org/10.1016/j.jaci.2020.07.021DOI Listing
February 2021

Rates of Venous Thromboembolism and Central Line-Associated Bloodstream Infections Among Types of Central Venous Access Devices in Critically Ill Children.

Crit Care Med 2020 Sep;48(9):1340-1348

Pediatric Critical Care, Children's Hospital of Wisconsin, Milwaukee, WI.

Objectives: Central venous access devices, including peripherally inserted central catheters and central venous catheters, are often needed in critically ill patients, but also are associated with complications, including central-line associated bloodstream infections and venous thromboembolism. We compared different central venous access device types and these complications in the PICU.

Design: Multicenter, cohort study.

Setting: One hundred forty-eight participating Virtual PICU Systems, LLC, hospital PICU sites.

Patients: Pediatric patients with central venous access placed from January 1, 2010, to December 31, 2015.

Interventions: None.

Measurements And Main Results: Patient and central venous access device variables postulated to be associated with central-line associated bloodstream infection and venous thromboembolism were included. Data were analyzed using Pearson chi-square test or Fisher exact test for categorical variables, Mann-Whitney U test for continuous variables, and logistic regression and classification trees for multivariable analysis that examined significant predictors of venous thromboembolism or central-line associated bloodstream infection. Analysis included 74,196 first lines including 4,493 peripherally inserted central catheters and 66,194 central venous catheters. An increased rate of venous thromboembolism (peripherally inserted central catheter: 0.93%, central venous catheter: 0.52%; p = 0.001) (peripherally inserted central catheter: 8.65/1,000 line days, central venous catheter: 6.29/1,000 line days) and central-line associated bloodstream infection (peripherally inserted central catheter: 0.73%, central venous catheter: 0.24%; p = 0.001) (peripherally inserted central catheter: 10.82/1,000 line days, central venous catheter: 4.97/1,000 line days) occurred in peripherally inserted central catheters. In multivariable analysis, central venous catheters had decreased association with central-line associated bloodstream infection (odds ratio, 0.505; 95% CI, 0.336-0.759; p = 0.001) and venous thromboembolism (odds ratio, 0.569; 95% CI, 0.330-0.982; p = 0.043) compared with peripherally inserted central catheters.

Conclusions: Peripherally inserted central catheters are associated with higher rates of central-line associated bloodstream infection and venous thromboembolism than central venous catheters in children admitted to the PICU.
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http://dx.doi.org/10.1097/CCM.0000000000004461DOI Listing
September 2020

Assessment of pediatric asthma exacerbation with the use of new PROMIS measures.

J Asthma 2020 Jul 9:1-9. Epub 2020 Jul 9.

Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA.

Objective: Patient reported outcome measures, such as the Patient Reported Outcomes Measurement Information System (PROMIS) may be used to assess patient functioning for asthma and aid in understanding the impact of asthma exacerbation. These domains may be utilized as endpoints in clinical trials and to guide clinical care. The purpose of this study was to determine psychometric properties of the new PROMIS measures for children with asthma, at baseline and with exacerbation.

Methods: We conducted a cross-sectional analysis of children with acute asthma exacerbation or at baseline health. Psychometric properties of validity (using known groups and correlation) and reliability (using Cronbach's alpha and IRT) for the new PROMIS measures were determined.

Results: Our study included 220 subjects, 102 were enrolled during an acute exacerbated state. Cronbach's alpha and IRT reliability was greater or equal to 0.75. Our subjects experiencing an acute exacerbated state reported worse T-scores for pain related domains: pain behavior 45.7 vs 53.5 ( < 0.001), pain quality sensory 44.4 vs 48.5 ( < 0.005), pain quality affective 42.5 vs 51.3 ( < 0.001), and physical stress experience 60.5 vs 65.4 ( < 0.001); and asthma impact 47.9 vs 61.0 ( < 0.001), than subjects at baseline. Child and parent-proxy agreement ranged from 35% to 56%.

Conclusions: The new Pediatric PROMIS domains are valid and reliable for use in children with asthma, for both child-reported and parent-proxy reported outcomes. It was determined that children with acute asthma exacerbation have worse patient reported outcomes (PROs) for the new pain related domains and asthma impact.
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http://dx.doi.org/10.1080/02770903.2020.1786114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794085PMC
July 2020

Quantitative Sensory Testing in Adolescents with Co-occurring Chronic Pain and Obesity: A Pilot Study.

Children (Basel) 2020 Jun 2;7(6). Epub 2020 Jun 2.

Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.

Factors such as gender, ethnicity, and age affect pain processing in children and adolescents with chronic pain. Although obesity has been shown to affect pain processing in adults, almost nothing is known about pediatric populations. The aim of this pilot study was to explore whether obesity alters sensory processing in adolescents with chronic pain. Participants were recruited from a chronic pain clinic (Chronic Pain (CP), = 12 normal weight; Chronic Pain + Obesity (CPO), = 19 overweight/obesity) and from an obesity clinic (Obesity alone (O), = 14). The quantitative sensory testing protocol included assessments of thermal and mechanical pain thresholds and perceptual sensitization at two sites with little adiposity. The heat pain threshold at the hand was significantly higher in the CPO group than in either the CP or O groups. Mechanical pain threshold (foot) was significantly higher in the CPO group than the CP group. No differences were found on tests of perceptual sensitization. Correlations between experimental pain and clinical pain parameters were found for the CPO group, but not for the CP group. This preliminary study provides important lessons learned for subsequent, larger-scale studies of sensory processing for youth with co-occurring chronic pain and obesity.
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http://dx.doi.org/10.3390/children7060055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7346135PMC
June 2020

Can PROMIS domains of pain and physical functioning detect changes in health over time for children with sickle cell disease?

Pediatr Blood Cancer 2020 05 6;67(5):e28203. Epub 2020 Feb 6.

Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin.

Background: The Patient-Reported Outcomes Measurement Information System (PROMIS) includes multiple domains that measure pain and physical functioning which are valid and reliable for use in children with sickle cell disease. The responsiveness of these measures to detect changes in health status over time among children with sickle cell disease is unknown.

Procedure: We conducted a prospective cohort study of children presenting to emergency department (ED) with vaso-occlusive crises. Children completed PROMIS surveys in the ED and at two follow-up time points (7-10 days and 1-3 months) after their acute care visit. Linear mixed models were used to determine if there were significant changes in PROMIS T scores over time. We used a patient's global assessment of change in pain question to anchor the changes in PROMIS scores (mean and 95% confidence interval). A change was considered statistically significant if the 95% CI did not include 0.

Results: We found that patients improved significantly in all domains 1 to 3 months after discharge from an acute care visit for pain. In addition, the pain and physical stress experience domains were responsive to change 7 to 10 days after discharge. Using the anchor of change in pain, for children who had considerable improvement in pain, there were significant changes in PROMIS T scores ranging from 6 to 15.

Conclusions: Relevant PROMIS domains detect changes in children experiencing acute vaso-occlusive crises. These domains can be used in research and clinic settings to measure clinically relevant change in children with sickle cell disease.
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http://dx.doi.org/10.1002/pbc.28203DOI Listing
May 2020

Donor fraction cell-free DNA and rejection in adult and pediatric heart transplantation.

J Heart Lung Transplant 2020 05 29;39(5):454-463. Epub 2019 Nov 29.

Division of Pediatric Cardiothoracic Surgery, Department of Surgery, Medical College of Wisconsin, Herma Heart Institute, Milwaukee, Wisconsin. Electronic address:

Background: Endomyocardial biopsy (EMB) is the current standard for rejection surveillance in heart transplant recipients. The quantification of donor-specific cell-free DNA (cfDNA) may be an appropriate biomarker for non-invasive rejection surveillance. A multicenter prospective blinded study (DNA-Based Transplant Rejection Test, DTRT) investigated the value of donor fraction (DF), defined as the ratio of cfDNA specific to the transplanted organ to the total amount of cfDNA present in a blood sample.

Methods: A total of 241 heart transplant patients were recruited from 7 centers. Age at transplant ranged from 8 days to 73 years, with 146 subjects <18 years and 95 ≥18 years. All the patients were followed for at least 1 year, with blood samples drawn at routine and for-cause biopsies. A total of 624 biopsy-paired samples were included for analysis through a commercially available cfDNA assay (myTAI, TAI Diagnostics Inc.). A blinded analysis of repeated measures compared the outcomes using receiver operating characteristic (ROC) curves. All primary clinical end-points were monitored at 100%. All analysis and conclusions were reviewed by both an independent external oversight committee and the National Institutes of Health-mandated DTRT steering committee.

Results: DF in acute cellular rejection (ACR) 1R/2R (n = 15) was higher than ACR 0R (n = 42) (p = 0.02); DF in antibody-mediated rejection pAMR1 (n = 8) and pAMR2 (n = 12) (p = 0.05) were higher than pAMR0 (n = 466) (p = 0.04 and p = 0.05 respectively). An optimal DF threshold was determined by the use of an ROC analysis, which ruled out the presence of either ACR or antibody-mediated rejection.

Conclusions: The cell-free DNA DF holds promise as a non-invasive diagnostic test to rule out acute rejection in both adult and pediatric heart transplant populations.
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http://dx.doi.org/10.1016/j.healun.2019.11.015DOI Listing
May 2020

Platelet Function Changes during Neonatal Cardiopulmonary Bypass Surgery: Mechanistic Basis and Lack of Correlation with Excessive Bleeding.

Thromb Haemost 2020 Jan 21;120(1):94-106. Epub 2019 Nov 21.

Versiti-Blood Research Institute, Milwaukee, Wisconsin, United States.

Thrombocytopenia and platelet dysfunction induced by extracorporeal blood circulation are thought to contribute to postsurgical bleeding complications in neonates undergoing cardiac surgery with cardiopulmonary bypass (CPB). In this study, we examined how changes in platelet function relate to changes in platelet count and to excessive bleeding in neonatal CPB surgery. Platelet counts and platelet P-selectin exposure in response to agonist stimulation were measured at four times before, during, and after CPB surgery in neonates with normal versus excessive levels of postsurgical bleeding. Relative to baseline, platelet counts were reduced in patients while on CPB, as was platelet activation by the thromboxane A2 analog U46619, thrombin receptor activating peptide (TRAP), and collagen-related peptide (CRP). Platelet activation by adenosine diphosphate (ADP) was instead reduced after platelet transfusion. We provide evidence that thrombocytopenia is a likely contributor to CPB-associated defects in platelet responsiveness to U46619 and TRAP, CPB-induced collagen receptor downregulation likely contributes to defective platelet responsiveness to CRP, and platelet transfusion may contribute to defective platelet responses to ADP. Platelet transfusion restored to baseline levels platelet counts and responsiveness to all agonists except ADP but did not prevent excessive bleeding in all patients. We conclude that platelet count and function defects are characteristic of neonatal CPB surgery and that platelet transfusion corrects these defects. However, since CPB-associated coagulopathy is multifactorial, platelet transfusion alone is insufficient to treat bleeding events in all patients. Therefore, platelet transfusion must be combined with treatment of other factors that contribute to the coagulopathy to prevent excessive bleeding.
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http://dx.doi.org/10.1055/s-0039-1700517DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7003188PMC
January 2020

Cardiomyocyte-Specific Prevents Inflammation in the Heart.

J Am Heart Assoc 2019 11 13;8(22):e012792. Epub 2019 Nov 13.

Division of Neonatology Department of Pediatrics Developmental Vascular Biology Program, Children's Research Institute Medical College of Wisconsin Milwaukee WI.

Background The SNRK (sucrose-nonfermenting-related kinase) enzyme is critical for cardiac function. However, the underlying cause for heart failure observed in cardiac conditional knockout mouse is unknown. Methods and Results Previously, 6-month adult mice knocked out for in cardiomyocytes (CMs) displayed left ventricular dysfunction. Here, 4-month adult mice, on angiotensin II (Ang II) infusion, show rapid decline in cardiac systolic function, which leads to heart failure and death in 2 weeks. These mice showed increased expression of nuclear factor κ light chain enhancer of activated B cells (NF-κB), inflammatory signaling proteins, proinflammatory proteins in the heart, and fibrosis. Interestingly, under Ang II infusion, mice knocked out for in endothelial cells did not show significant systolic or diastolic dysfunction. Although an NF-κB inflammation signaling pathway was increased in knockout endothelial cells, this did not lead to fibrosis or mortality. In hearts of adult mice knocked out for in CMs, we also observed NF-κB pathway activation in CMs, and an increased presence of Mac2 macrophages was observed in basal and Ang II-infused states. In vitro analysis of knockdown HL-1 CMs revealed similar upregulation of the NF-κB signaling proteins and proinflammatory proteins that was exacerbated on Ang II treatment. The Ang II-induced NF-κB pathway-mediated proinflammatory effects were mediated in part through protein kinase B or AKT, wherein AKT inhibition restored the proinflammatory signaling protein levels to baseline in knockdown HL-1 CMs. Conclusions During heart failure, SNRK acts as a cardiomyocyte-specific repressor of cardiac inflammation and fibrosis.
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http://dx.doi.org/10.1161/JAHA.119.012792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6915262PMC
November 2019

A Pilot Randomized Controlled Trial of Outcomes Associated with Parent-Nurse Controlled Analgesia vs. Continuous Opioid Infusion in the Neonatal Intensive Care Unit.

Pain Manag Nurs 2020 02 4;21(1):72-80. Epub 2019 Sep 4.

Jane B. Pettit Pain and Headache Center, Children's Hospital of Wisconsin, Milwaukee, Wisconsin; Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin; Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin.

Purpose: Prospectively compare parent/nurse controlled analgesia (PNCA) to continuous opioid infusion (COI) in the post-operative neonatal intensive care unit (NICU) population.

Design/methods: A randomized controlled trial compared neonates treated with morphine PNCA to those treated with morphine COI. The primary outcome was average opioid consumption up to 3 post-operative days. Secondary outcomes included 1) pain intensity, 2) adverse events that may be directly related to opioid consumption, and 3) parent and nurse satisfaction.

Results: The sample consisted of 25 post-operative neonates and young infants randomized to either morphine PNCA (n = 16) or COI (n = 9). Groups differed significantly on daily opioid consumption, with the PNCA group receiving significantly less opioid (P = .02). Groups did not differ on average pain score or frequency of adverse events (P values > .05). Parents in both groups were satisfied with their infant's pain management and parents in the PNCA group were slightly more satisfied with their level of involvement (P = .03). Groups did not differ in nursing satisfaction.

Conclusions: PNCA may be an effective alternative to COI for pain management in the NICU population. This method may also substantially reduce opioid consumption, provide more individualized care, and improve parent satisfaction with their level of participation.

Clinical Implications: Patients in the NICU represent one of our most vulnerable patient populations. As nurses strive to provide safe and effective pain management, results of this study suggest PNCA may allow nurses to maintain their patients' comfort while providing less opioid and potentially improving parental perception of involvement.

Study Type: Treatment study.

Level Of Evidence: I.
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http://dx.doi.org/10.1016/j.pmn.2019.08.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6980456PMC
February 2020

Antibiotic modulation of mucins in otitis media; should this change our approach to watchful waiting?

Int J Pediatr Otorhinolaryngol 2019 Oct 4;125:134-140. Epub 2019 Jul 4.

Division of Pediatric Otolaryngology, Medical College of Wisconsin, USA; Department of Otolaryngology and Communication Sciences, Medical College of Wisconsin, USA. Electronic address:

Background: Gel-forming mucins (GFMs) play important roles in otitis media (OM) pathogenesis. Increased mucin expression is activated by pathogens and proinflammatory cytokines. Bacterial biofilms influence inflammation and resolution of OM and may contribute to prolonged mucin production. The influence of specific pathogens on mucin expression and development of chronic OM with effusion (OME) remains an area of significant knowledge deficit.

Objectives: To assess the relationship between GFM expression, specific pathogens, middle ear mucosal (MEM) changes, biofilm formation, and antibiotic utilization.

Methods: Mixed gender chinchillas were inoculated with nontypeable Haemophilus influenzae (NTHi) strain 86028NP or Streptococcus pneumoniae (SP) strain TIGR4 via transbulla injection. Antibiotic was administered on day 3-5 post inoculation. GFM expression was measured by quantitative PCR. Biofilm formation was identified and middle ear histologic changes were measured.

Results: SP infection resulted in higher incidence of biofilm and ME effusion compared with NTHi infection. However, NTHi persisted in the ME longer than SP with no substantive bacterial clearance detected on day 10 compared with complete bacterial clearance on day 10 for 50-60% of the SP-infected chinchillas. Both infections increased MEM inflammatory cell infiltration and thickening. NTHi upregulated the Muc5AC, Muc5B and Muc19 expression on day 10 (p = 0.0004, 0.003, and 0.002 respectively). SP-induced GFM upregulations were trended toward significant. In both NTHi and SP infections, the degree of GFM upregulation had a direct relationship to increased MEM hypertrophy, inflammatory cell infiltration and biofilm formation. Antibiotic treatment reduced the incidence of ME effusion and biofilm, limited the MEM changes and reversed the GFM upregulation. In NTHi infection, the rate of returning to baseline level of GFMs in treated chinchillas was quicker than those without treatment.

Conclusions: In an animal model of OM, GFM genes are upregulated in conjunction with MEM hypertrophy and biofilm formation. This upregulation is less robust and more quickly ameliorated to a significant degree in the NTHi infection with appropriate antibiotic therapy. These findings contribute to the understanding of pathogen specific influences on mucin expression during OM pathogenesis and provide new data which may have implications in clinical approach for OM treatment.
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http://dx.doi.org/10.1016/j.ijporl.2019.07.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6742428PMC
October 2019

Microbiome Signatures Associated With Steatohepatitis and Moderate to Severe Fibrosis in Children With Nonalcoholic Fatty Liver Disease.

Gastroenterology 2019 10 27;157(4):1109-1122. Epub 2019 Jun 27.

Department of Pediatrics, Division of Gastroenterology, Medical College of Wisconsin, Milwaukee, Wisconsin; Center for Microbiome Research, Medical College of Wisconsin, Milwaukee, Wisconsin. Electronic address:

Background & Aims: The intestinal microbiome might affect the development and severity of nonalcoholic fatty liver disease (NAFLD). We analyzed microbiomes of children with and without NAFLD.

Methods: We performed a prospective, observational, cross-sectional study of 87 children (age range, 8-17 years) with biopsy-proven NAFLD and 37 children with obesity without NAFLD (controls). Fecal samples were collected and microbiome composition and functions were assessed using 16S ribosomal RNA amplicon sequencing and metagenomic shotgun sequencing. Microbial taxa were identified using zero-inflated negative binomial modeling. Genes contributing to bacterial pathways were identified using gene set enrichment analysis.

Results: Fecal microbiomes of children with NAFLD had lower α-diversity than those of control children (3.32 vs 3.52, P = .016). Fecal microbiomes from children with nonalcoholic steatohepatitis (NASH) had the lowest α-diversity (control, 3.52; NAFLD, 3.36; borderline NASH, 3.37; NASH, 2.97; P = .001). High abundance of Prevotella copri was associated with more severe fibrosis (P = .036). Genes for lipopolysaccharide biosynthesis were enriched in microbiomes from children with NASH (P < .001). Classification and regression tree model with level of alanine aminotransferase and relative abundance of the lipopolysaccharide pathway gene encoding 3-deoxy-d-manno-octulosonate 8-phosphate-phosphatase identified patients with NASH with an area under the receiver operating characteristic curve value of 0.92. Genes involved in flagellar assembly were enriched in the fecal microbiomes of patients with moderate to severe fibrosis (P < .001). Classification and regression tree models based on level of alanine aminotransferase and abundance of genes encoding flagellar biosynthesis protein had good accuracy for identifying case children with moderate to severe fibrosis (area under the receiver operating characteristic curve, 0.87).

Conclusions: In an analysis of fecal microbiomes of children with NAFLD, we associated NAFLD and NASH with intestinal dysbiosis. NAFLD and its severity were associated with greater abundance of genes encoding inflammatory bacterial products. Alterations to the intestinal microbiome might contribute to the pathogenesis of NAFLD and be used as markers of disease or severity.
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http://dx.doi.org/10.1053/j.gastro.2019.06.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6756995PMC
October 2019

Longitudinal changes in the gut microbiome of infants on total parenteral nutrition.

Pediatr Res 2019 07 9;86(1):107-114. Epub 2019 Apr 9.

Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA.

Background: Animal studies suggest that total parenteral nutrition (TPN) may alter bacterial colonization of the intestinal tract and contribute to complications. Progressive changes in gut microbiome of infants receiving TPN are not well understood.

Methods: Infants with and without TPN/soy lipid were enrolled in a prospective, longitudinal study. Weekly fecal samples were obtained for the first 4 weeks of life. High throughput pyrosequencing of 16S rDNA was used for compositional analysis of the gut microbiome.

Results: 47 infants were eligible for analyses, 25 infants received TPN, and 22 infants did not (control). Although similar between TPN and control groups in the first week, fecal bacterial alpha diversity was significantly lower in the TPN group compared to controls at week 4 (Shannon index 1.0 vs 1.5, P-value = 0.03). The TPN group had significantly lower Bacteroidetes and higher Verrucomicrobia abundance compared to controls (P-values < 0.05), and these differences became more pronounced over time. At the genus level, TPN was associated with lower abundance of Bacteroides and Bifidobacterium in all weeks.

Conclusions: TPN is associated with significant loss of biodiversity and alterations in the pattern of gut microbial colonization of infants over time. TPN-associated dysbiosis may predispose infants to adverse NICU outcomes.
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http://dx.doi.org/10.1038/s41390-019-0391-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594895PMC
July 2019

Risk of hypotensive reactions is increased when using partial saline replacement for therapeutic plasma exchange.

J Clin Apher 2019 Oct 19;34(5):524-527. Epub 2019 Mar 19.

Medical Sciences Institute, BloodCenter of Wisconsin, part of Versiti, Milwaukee, Wisconsin.

Background: Partial normal saline replacement during plasma exchange procedures is a common practice to reduce procedure costs but may increase the risk of adverse events, such as hypotension and citrate reactions. The goal of this study was to compare adverse event rates for the patients that used albumin or albumin/saline as replacement.

Study Design And Methods: A retrospective chart review was done of plasma exchange procedures that used all albumin or 80% albumin to 20% normal saline (80/20) as replacement. The procedure type (all albumin vs 80/20), the percent of normal saline used, age, gender, and adverse events during the procedure were recorded.

Results: During the study period, 3624 procedures were documented for 401 patients (46% female), age range 0 to 93 years, of which 2453 (67.7%) used 80/20. Overall 91 procedures (2.5%) resulted in a hypotensive event, 26 (0.7%) of which were classified as moderate to severe hypotension, and 40 (1.1%) had reported citrate toxicity. After adjusting for age, gender, and diagnosis using a generalized linear mixed model and backward model selection, results showed that 100% albumin had a significantly lower risk of having hypotension than 80/20 (odds ratio (OR): 0.531 [0.298, 0.946], P = 0.032) and moderate to severe hypotension (odds ratio: 0.140 [95% confidence interval (CI): 0.031, 0.628], P = 0.010). Older age was also predictive of having hypotensive reactions (OR[95%CI] = 1.017,[1.0, 1.034], P = 0.047).

Conclusion: Partial saline use as a replacement fluid with albumin during plasma exchange is associated with an increased risk of hypotension. Use of saline as replacement fluid during plasma exchange should be minimized especially in older patients.
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http://dx.doi.org/10.1002/jca.21703DOI Listing
October 2019

Cystic Fibrosis Plasma Blunts the Immune Response to Bacterial Infection.

Am J Respir Cell Mol Biol 2019 09;61(3):301-311

Division of Pulmonary Medicine, Department of Pediatrics, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois.

Cystic fibrosis (CF) is caused by mutations of the gene encoding the CF transmembrane conductance regulator. It remains unclear whether the abnormal immune response in CF involves extrinsic signals released from the external or internal environment. We sought to characterize the peripheral immune signatures in CF and its association with clinical phenotypes. Healthy peripheral blood mononuclear cells (PBMCs) were cultured with plasma from CF probands (CFPs) or healthy control subjects (HCs) followed by nCounter gene and microRNA (miRNA) profiling. A discovery cohort of 12 CFPs and 12 HCs and a validation cohort of 103 CFPs and 31 HCs (our previous microarray data [GSE71799]) were analyzed to characterize the composition of cultured immune cells and establish a miRNA‒mRNA network. Cell compositions and miRNA profiles were associated with clinical characteristics of the cohorts. Significantly differentially expressed genes and abundance of myeloid cells were downregulated in PMBCs after culture with CF plasma ( < 0.05). Top-ranked miRNAs that increased in response to CF plasma (adjusted  < 0.05) included miR-155 and miR-146a, which target many immune-related genes, such as IL-8. infection was negatively associated with abundance of monocytes and the presence of those regulatory miRNAs. Extrinsic signals in plasma from patients with CF led to monocyte inactivation and miRNA upregulation in PBMCs. An improved understanding of the immune effects of extrinsic factors in CF holds great promise for integrating immunomodulatory cell therapies into current treatment strategies in CF.
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http://dx.doi.org/10.1165/rcmb.2018-0114OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6839930PMC
September 2019

Use of the new pediatric PROMIS measures of pain and physical experiences for children with sickle cell disease.

Pediatr Blood Cancer 2019 05 28;66(5):e27633. Epub 2019 Jan 28.

Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin.

Background: There are new pediatric domains to measure patients' pain and physical experiences in the Patient-Reported Outcomes Measurement Information System (PROMIS). The objective of this study was to establish the psychometric properties of these domains for children with sickle cell disease (SCD).

Procedure: We conducted a cross-sectional analysis of PROMIS assessments of children with SCD recruited from a pediatric tertiary care clinic. Validity of the new PROMIS domains was determined by comparing scores between known groups and describing their correlations with previously validated PROMIS measures. Cronbach's alpha and item response theory (IRT) reliability were used to assess internal consistency reliability. Agreement between parent-proxy and child self-report was determined for all domains.

Results: Our study included 164 subjects, of whom 117 were eligible to self-report. The mean T-scores for physical stress experience, strength impact, pain behavior, and pain quality sensory scores were significantly different between children who used pain medications in the prior week and those who did not. There were also differences in T-scores across children reporting mild, moderate, and severe pain on the pain intensity scale. All measures had Cronbach's alpha and IRT reliability > 0.80. The percentage of agreement between child and parent-proxy PROMIS domains ranged from 36% to 60% depending on the domain.

Conclusions: The new PROMIS domains of physical stress experience, strength impact, pain behavior, and pain quality sensory domains are valid and reliable for children with SCD. The low-moderate agreement between parent-proxy and child self-report scores support the complementary information provided by the two perspectives.
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http://dx.doi.org/10.1002/pbc.27633DOI Listing
May 2019

Characterization of Endothelial Cilia Distribution During Cerebral-Vascular Development in Zebrafish ( Danio rerio).

Arterioscler Thromb Vasc Biol 2018 12;38(12):2806-2818

Division of Neonatology, Department of Pediatrics (S.P., P.M.S., R.R.), Medical College of Wisconsin, Milwaukee.

Objective- Endothelial cells (ECs) sense and respond to flow-induced mechanical stress, in part, via microtubule-based projections called primary cilia. However, many critical steps during vascular morphogenesis occur independent of flow. The involvement of cilia in regulating these stages of cranial vascular morphogenesis is poorly understood because cilia have not been visualized in primary head vessels. The objective of this study was to investigate involvement of cilia in regulating the early stages of cranial vascular morphogenesis. Approach and Results- Using high-resolution imaging of the Tg(kdrl:mCherry-CAAX) ;(bactin::Arl13b:GFP) zebrafish line, we showed that cilia are enriched in the earliest formed cranial vessels that assemble via vasculogenesis and in angiogenic hindbrain capillaries. Cilia were more prevalent around the boundaries of putative intravascular spaces in primary and angiogenic vessels. Loss of cardiac contractility and blood flow, because of knockdown of cardiac troponin T type 2a ( tnnt2a) expression, did not affect the distribution of cilia in primary head vasculature. In later stages of development, cilia were detected in retinal vasculature, areas of high curvature, vessel bifurcation points, and during vessel anastomosis. Loss of genes crucial for cilia biogenesis ( ift172 and ift81) induced intracerebral hemorrhages in an EC-autonomous manner. Exposure to high shear stress induced premature cilia disassembly in brain ECs and was associated with intracerebral hemorrhages. Conclusions- Our study suggests a functional role for cilia in brain ECs, which is associated with the emergence and remodeling of the primary cranial vasculature. This cilia function is flow-independent, and cilia in ECs are required for cerebral-vascular stability.
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http://dx.doi.org/10.1161/ATVBAHA.118.311231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6309420PMC
December 2018

Identification of molecular signatures of cystic fibrosis disease status with plasma-based functional genomics.

Physiol Genomics 2019 01 12;51(1):27-41. Epub 2018 Dec 12.

Division of Endocrinology, Department of Pediatrics, Medical College of Wisconsin , Milwaukee, Wisconsin.

Although cystic fibrosis (CF) is attributed to dysfunction of a single gene, the relationships between the abnormal gene product and the development of inflammation and progression of lung disease are not fully understood, which limits our ability to predict an individual patient's clinical course and treatment response. To better understand CF progression, we characterized the molecular signatures of CF disease status with plasma-based functional genomics. Peripheral blood mononuclear cells (PBMCs) from healthy donors were cultured with plasma samples from CF patients ( n = 103) and unrelated, healthy controls ( n = 31). Gene expression levels were measured with an Affymetrix microarray (GeneChip Human Genome U133 Plus 2.0). Peripheral blood samples from a subset of the CF patients ( n = 40) were immunophenotyped by flow cytometry, and the data were compared with historical data for age-matched healthy controls ( n = 351). Plasma samples from another subset of CF patients ( n = 56) and healthy controls ( n = 16) were analyzed by multiplex enzyme-linked immunosorbent assay (ELISA) for numerous cytokines and chemokines. Principal component analysis and hierarchical clustering of induced transcriptional data revealed disease-specific plasma-induced PBMC profiles. Among 1,094 differentially expressed probe sets, 51 genes were associated with pancreatic sufficient status, and 224 genes were associated with infection with Pseudomonas aeruginosa. The flow cytometry and ELISA data confirmed that various immune modulators are relevant contributors to the CF molecular signature. This study provides strong evidence for distinct molecular signatures among CF patients. An understanding of these molecular signatures may lead to unique molecular markers that will enable more personalized prognoses, individualized treatment plans, and rapid monitoring of treatment response.
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http://dx.doi.org/10.1152/physiolgenomics.00109.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6383551PMC
January 2019

Impact of the Timing of Placement of an Intracranial Pressure Monitor on Outcomes in Children with Severe Traumatic Brain Injury.

Pediatr Neurosurg 2018 7;53(6):379-386. Epub 2018 Nov 7.

Section of Critical Care, Children's Hospital of Wisconsin, Milwaukee, Wisconsin, USA,

Background: Severe traumatic brain injury (sTBI) is the leading cause of morbidity and mortality from trauma. Brain Trauma Foundation guidelines recommend intracranial pressure (ICP) monitoring in sTBI. We hypothesized that early ICP monitor placement was associated with better outcomes in children.

Methods: This was a retrospective study of children with sTBI admitted to the participating pediatric intensive care units (PICUs) and entered into the Virtual Pediatric Systems (VPS), LLC, database between 1 January 2010 and 31 December 2015. We compared outcomes of patients who had an ICP monitor placed early (≤6 h from PICU admission) to those with later placement (> 6 to < 72 h). We collected demographics, diagnoses, procedure data, illness severity scores, outcomes, and site data. Multivariable regression analysis was used to identify variables independently associated with outcomes.

Results: Twenty-seven percent of 3,608 patients with sTBI underwent ICP monitoring, 355 in the early and 156 in the later ICP monitoring groups, respectively. A higher proportion of patients in the early ICP monitoring group had worse markers of illness/injury severity; unadjusted analysis showed higher mortality in this group (31.3 vs. 21.8%, p = 0.029). Multivariable regression analysis showed that ICP monitoring was not independently associated with any of the outcomes.

Conclusion: Time to ICP monitoring was not associated with outcomes after pediatric sTBI.
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http://dx.doi.org/10.1159/000494028DOI Listing
January 2019

Enteral Nutrition Initiation in Children Admitted to Pediatric Intensive Care Units After Traumatic Brain Injury.

Neurocrit Care 2019 02;30(1):193-200

Division of Critical Care, Department of Pediatrics, Children's Hospital of Wisconsin/Medical College of Wisconsin, 9000 W. Wisconsin Avenue, Milwaukee, WI, 53226, USA.

Background: Traumatic brain injury (TBI) is the leading cause of death and long-term disability among injured children. Early feeding has been shown to improve outcomes in adults, with some similar evidence in children with severe TBI. We aimed to examine the current practice of initiation of enteral nutrition in children with TBI and to evaluate the risk factors associated with delayed initiation of enteral nutrition.

Methods: This retrospective, multicenter study used the Pediatric Trauma Assessment and Management Database including all children with head trauma discharged from five pediatric intensive care units (PICU) at pediatric trauma centers between January 1, 2013 and December 31, 2013. We compared demographics, injury and procedure data, time to initiation of nutrition, and injury and illness severity scores between patients who received enteral nutrition early (≤ 48 h) and late (> 48 h). Fisher's exact and Mann-Whitney U tests compared discrete and continuous variables. Univariate and multivariable analyses evaluated variables associated with delayed initiation of feeding. Outcomes of interest included mortality, complications, ventilator days, hospital and ICU length of stay, and functional status at ICU discharge.

Results: In the 416 patients in the study, the overall mortality was 2.6%. The majority of patients (83%; range 69-88% between five sites, p = 0.0008) received enteral nutrition within 48 h of PICU admission. Lower Glasgow Coma Scale scores and higher Injury Severity Score (ISS) were independently associated with delayed initiation of enteral nutrition. Delayed enteral nutrition was independently associated with worse functional status at PICU discharge (p = 0.02) but was not associated with mortality or increased length of stay.

Conclusions: Children with severe TBI and higher ISS were more likely to have delayed initiation of enteral nutrition. Delayed enteral nutrition was an independent risk factor for worse functional status at ICU discharge for the entire cohort, but not for the severe TBI group.
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http://dx.doi.org/10.1007/s12028-018-0597-6DOI Listing
February 2019

Comparison of Complication Rates of Central Venous Catheters Versus Peripherally Inserted Central Venous Catheters in Pediatric Patients.

Pediatr Crit Care Med 2018 Dec;19(12):1097-1105

Division of Critical Care Medicine, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI.

Objectives: The purpose of our study is to compare the rate of central line-associated blood stream infections and venous thromboembolism in central venous catheters versus peripherally inserted central catheters in hospitalized children. There is a growing body of literature in adults describing an increased rate of venous thromboembolisms and similar rates of central line-associated blood stream infection associated with peripherally inserted central catheters versus central venous catheters. It is not known if the rate of central line-associated blood stream infection and venous thromboembolism differs between peripherally inserted central catheters and central venous catheters in children. Based on current adult literature, we hypothesize that central line-associated blood stream infection rates for peripherally inserted central catheters and central venous catheters will be similar, and the rate of venous thromboembolism will be higher for peripherally inserted central catheters versus central venous catheters.

Design: This is a cohort study using retrospective review of medical records and prospectively collected hospital quality improvement databases.

Setting: Quaternary-care pediatric hospital from October 2012 to March 2016.

Patients: All patients age 1 day to 18 years old with central venous catheters and peripherally inserted central catheters placed during hospital admission over the study dates were included. Central venous catheters that were present upon hospital admission were excluded. The primary outcomes were rate of central line-associated blood stream infection and rate of venous thromboembolism.

Interventions: None.

Measurements And Main Results: Of 2,709 catheters included in the study, 1,126 were peripherally inserted central catheters and 1,583 were central venous catheters. Peripherally inserted central catheters demonstrated a higher rate of both infection and venous thromboembolism than central venous catheters in all reported measures. In multivariable analysis, peripherally inserted central catheters had increased association with central line-associated blood stream infection (odds ratio of 3.15; 95% CI, 1.74-5.71; p = 0.0002) and increased association with venous thromboembolism (odds ratio of 2.71; 95% CI, 1.65-4.45; p < 0.0001) compared with central venous catheters.

Conclusions: Rates of central line-associated blood stream infection and venous thromboembolism were higher in hospitalized pediatric patients with peripherally inserted central catheters as compared to central venous catheters. Our study confirms the need for further investigation into the safety of central access devices to assist in proper catheter selection.
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http://dx.doi.org/10.1097/PCC.0000000000001707DOI Listing
December 2018

A Pilot Study of Iyengar Yoga for Pediatric Obesity: Effects on Gait and Emotional Functioning.

Children (Basel) 2018 Jul 4;5(7). Epub 2018 Jul 4.

Jane B. Pettit Pain and Headache Center, Department of Anesthesiology and Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee, WI 53226, USA.

Obesity negatively impacts the kinematics and kinetics of the lower extremities in children and adolescents. Although yoga has the potential to provide several distinct benefits for children with obesity, this is the first study to examine the benefits of yoga for gait (primary outcome) in youths with obesity. Secondary outcomes included health-related quality of life (HRQoL), physical activity, and pain. Feasibility and acceptability were also assessed. Nine youths (11⁻17 years) participated in an eight-week Iyengar yoga intervention (bi-weekly 1-h classes). Gait, HRQOL (self and parent-proxy reports), and physical activity were assessed at baseline and post-yoga. Pain was self-reported at the beginning of each class. Significant improvements were found in multiple gait parameters, including hip, knee, and ankle motion and moments. Self-reported and parent-proxy reports of emotional functioning significantly improved. Time spent in physical activity and weight did not change. This study demonstrates that a relatively brief, non-invasive Iyengar yoga intervention can result in improved malalignment of the lower extremities during ambulation, as well as in clinically meaningful improvements in emotional functioning. This study extends current evidence that supports a role for yoga in pediatric obesity.
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http://dx.doi.org/10.3390/children5070092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6068554PMC
July 2018

Rotational Thromboelastometry Rapidly Predicts Thrombocytopenia and Hypofibrinogenemia During Neonatal Cardiopulmonary Bypass.

World J Pediatr Congenit Heart Surg 2018 07;9(4):424-433

8 Section of Pediatric Cardiothoracic Surgery, Department of Cardiothoracic Surgery, Medical College of Wisconsin, Milwaukee, WI, USA.

Background: Thrombocytopenia and hypofibrinogenemia during neonatal cardiopulmonary bypass (CPB) contribute to bleeding and morbidity. Rotational thromboelastometry (ROTEM) is a viscoelastic assay with a rapid turnaround time. Data validating ROTEM during neonatal cardiac surgery remain limited. This study examined perioperative hemostatic trends in neonates treated with standardized platelet and cryoprecipitate transfusion during CPB. We hypothesized that ROTEM would predict thrombocytopenia, hypofibrinogenemia, and the correction thereof.

Methods: Forty-four neonates undergoing CPB were included in this prospective observational study. Blood samples were obtained at Baseline, On CPB, Post-CPB, and Postoperative. The ROTEM analysis included extrinsically activated (Extem) and fibrinogen-specific (Fibtem) assays. Platelet-specific thromboelastometry (Pltem) values were calculated. Platelet and cryoprecipitate transfusion was initiated prior to termination of CPB.

Results: Platelet count and Extem amplitude decreased significantly On CPB ( P < .0001), increased significantly Post-CPB ( P < .0001), and Postoperative values were not significantly different from Baseline. Extem amplitude at 10 minutes (A10) > 46.5 mm (AUC = 0.941) and Pltem A10 > 37.5 mm [area under curve (AUC) = 0.960] predicted platelet count > 100 × 10/μL, and they highly correlated with platelet count ( R = 0.89 and R = 0.90, respectively). Fibrinogen concentration and Fibtem amplitude decreased significantly On CPB ( P ≤ .0001) and normalized after cryoprecipitate transfusion. Fibtem A10 > 9.5 mm predicted fibrinogen >200 mg/dL (AUC = 0.817), but it correlated less well with fibrinogen concentration ( R = 0.65).

Conclusions: ROTEM analysis during neonatal cardiac surgery is sensitive and specific for thrombocytopenia and hypofibrinogenemia, identifying deficits within 10 minutes. Platelet and cryoprecipitate transfusion during neonatal CPB normalizes platelet count, fibrinogen level, and ROTEM amplitudes.
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http://dx.doi.org/10.1177/2150135118771318DOI Listing
July 2018

Multicenter Review of Current Practices Associated With Venous Thromboembolism Prophylaxis in Pediatric Patients After Trauma.

Pediatr Crit Care Med 2018 09;19(9):e448-e454

Division of Critical Care, Department of Pediatrics, Children's Hospital of Wisconsin/Medical College of Wisconsin, Milwaukee, WI.

Objectives: Frequency of venous thromboembolism in pediatric trauma patients admitted to PICUs is not insignificant, ranging up to 6%. Risk factors have been identified in this population. However, there is little consensus of actual venous thromboembolism prophylaxis practice. We examined factors associated with venous thromboembolism prophylaxis in PICUs.

Design: A retrospective study evaluating associations with mechanical venous thromboembolism prophylaxis, pharmacologic venous thromboembolism prophylaxis, or dual therapy (DUAL) prophylaxis compared with no venous thromboembolism prophylaxis. Multivariable logistic regression explored the relationship between prophylaxis type and selected covariates with stepwise selection method to identify the independent predictors of venous thromboembolism prophylaxis utilization.

Setting: Five level I/II pediatric trauma centers in the United States.

Patients: Children less than 18 years from January 1, 2013, to December 31, 2013, admitted to the PICU after a trauma, identified through combined trauma registry and Virtual Pediatric Systems database.

Interventions: None.

Measurements And Main Results: Six hundred ninety-two patients were included in the database, with 55 excluded for missing data. Of the remaining 637 patients, 538 (84.5%) had no venous thromboembolism prophylaxis by 48 hours, 77 (12.1%) had only mechanical venous thromboembolism prophylaxis, 11 (1.7%) had DUAL, and 11 (1.7%) had pharmacologic venous thromboembolism prophylaxis alone. Multivariable analysis showed increased age, and orthopedic procedure was associated with all forms of prophylaxis. Orthopedic procedures were associated with higher utilization of dual prophylaxis use (odds ratio, 5.2; 95% CI, 1.2-21.8), pharmacologic venous thromboembolism prophylaxis (odds ratio, 8.5; 95% CI, 2.3-31.7), and mechanical venous thromboembolism prophylaxis (odds ratio, 2.2; 95% CI, 1.1-4.2) alone. Brain/spinal cord procedures (odds ratio, 3.7; 95% CI, 1.9-7.3) and abdominal procedures (odds ratio, 6.6; 95% CI, 2.5-17.1) were associated with mechanical venous thromboembolism prophylaxis. Head injury was associated with a decreased use of any prophylaxis (odds ratio, 0.5; 95% CI, 0.3-0.9). Patient comorbidities were associated with decreased use of mechanical venous thromboembolism prophylaxis (odds ratio, 0.5; 95% CI, 0.3-1.0).

Conclusions: Pharmacologic venous thromboembolism prophylaxis is not common in critically ill children after trauma. Patient age, orthopedic and vascular procedures, and higher injury severity are associated with pharmacologic venous thromboembolism prophylaxis.
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http://dx.doi.org/10.1097/PCC.0000000000001614DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6123256PMC
September 2018

Central Venous Catheter-associated Venous Thromboembolism in Children With Hematologic Malignancy.

J Pediatr Hematol Oncol 2018 11;40(8):e519-e524

Department of Pediatrics, Medical College of Wisconsin.

In pediatric oncology, the diagnosis of a hematologic malignancy and presence of a central venous catheter (CVC) have been identified as significant risk factors for the development of a venous thromboembolism (VTE). There remain little data regarding CVC factors associated with CVC-related VTE. Using the VTE and oncology database in a quaternary care center, a retrospective cohort study was conducted in children below 18 years old with hematologic cancer from November 5, 2012 to April 4, 2016. Patient, CVC factors, and VTE occurrence were analyzed to identify significant patient and CVC factors associated with the development of clinically identified CVC-related VTE. Utilizing the χ, Mann-Whitney, and the Fisher exact tests, patient factors were compared across VTE yes/no groups. Of the 198 study patients, 22 VTE cases were identified. Eighteen VTE events were CVC-associated, occurring in 9% of study population. Peripherally inserted central catheter lines and older ages were associated with VTE. The use of tissue-plasminogen activator for CVC occlusion was associated with decreased VTE rates, suggesting a protective potential.
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http://dx.doi.org/10.1097/MPH.0000000000001229DOI Listing
November 2018