Amir M. Khan

Immune and Functional Role of Nitric Oxide in a Mouse Model of Respiratory Syncytial Virus Infection

BACKGROUND Respiratory syncytial virus (RSV) infection of respiratory epithelial cell cultures increases expression of inducible nitric oxide synthase (iNOS). The present study was designed to evaluate both the effect of RSV infection on expression of iNOS and the role of NO in the host responses to RSV infection in vivo. METHODS RSV infection was performed by nasal inoculation of BALB/c mice (6-8 weeks old). Total cell and differential counts were measured in bronchoalveolar lavage (BAL) fluid. Lung nitrates were measured in BAL fluid by use of the Greiss reaction, and cytokines were measured by enzyme-linked immunosorbent assay. Lung hyperresponsiveness to methacholine was measured by use of a Buxco unrestrained whole-body plethysmograph. RESULTS RSV infection increased levels of lung nitrites, levels of iNOS protein and activity, and levels of iNOS mRNA. RSV infection resulted in recruitment of neutrophils and lymphocytes into the lungs, enhanced levels of interferon (IFN)-gamma, and increased airway hyperresponsiveness (AHR). Treatment with iNOS inhibitors (2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine and N-nitro-L-arginine methyl ester) increased RSV titers in the lungs yet reduced lung inflammation and RSV-induced AHR. Inhibition of iNOS activity with either agent did not significantly alter levels of IFN-gamma or interleukin-4 in the lungs. CONCLUSIONS The results of the present study suggest that RSV-induced production of NO participates in complex host responses and may mediate important aspects of the clinical disease.

Effects of dexamethasone on meconium aspiration syndrome in newborn piglets.

We examined the effects of dexamethasone on lung function in a piglet model of meconium aspiration syndrome. We induced lung injury in 10 newborn piglets (age 5 ± 0.2 d) with 4 mL/kg body weight of 20% sterile human meconium in normal saline given via tracheostomy. Ventilator management was aimed at maintaining comparable values of end tidal carbon dioxide, Hb saturation, and arterial blood gases. Lung function was assessed using a BICORE CP100 neonatal monitor. Five piglets received 0.5 mg/kg of dexamethasone 2 and 8 h after meconium administration, whereas control piglets received normal saline at similar times. Ventilator settings, oxygen requirements, and lung compliance were similar between groups at the start of the study. Two hours after the instillation of meconium, there was marked lung dysfunction in both groups as evidenced by increased oxygen requirements [fraction of inspired oxygen (FiO2) 0.98 ± 0.01 versus FiO2 0.21 ± 0, p < 0.0001] and reduced lung compliance (0.35 ± 0.03 versus 0.8 ± 0.03 mL · kg-1 · cm-1 H2O, p < 0.0001). Administration of dexamethasone resulted in lower oxygen requirements (FiO2 0.27 ± 0.01 versus FiO2 1.0 ± 0.0, p < 0.00001), lower oxygenation index (2.17 ± 0.17 versus 22.64 ± 3.39, p < 0.0001), ventilatory efficiency index (0.30 ± 0.01 versus 0.07 ± 0.01, p < 0.0001), and improved lung compliance (0.68 ± 0.04 versus 0.34 ± 0.05 mL · kg-1 · cm-1 H2O, p < 0.001) compared with the control group. In summary, a two-dose course of 0.5 mg/kg of dexamethasone improved blood gases and lung function in a piglet model of meconium aspiration syndrome.

Role of cysteinyl leukotrienes in airway inflammation and responsiveness following RSV infection in BALB/c mice

Cysteinyl leukotrienes (CysLTs) contribute to the development of airway obstruction and inflammation in asthma; however little information is available on the role of these molecules in the pathophysiology of respiratory syncytial virus (RSV) bronchiolitis. This study was designed to evaluate the effects of RSV infection on CysLTs production in a well‐established mouse infection model. Furthermore, we assessed the effect of anti‐inflammatory agents (a leukotriene receptor antagonist, MK‐571, and dexamethasone) on the functional and immune changes induced by RSV infection. Six to 8‐wk‐old BALB/c mice were infected with human RSV (strain A2). Measurements of airway function were performed using whole body plethysmography. Lung inflammation was assessed by cell counts, measurement of cytokines and CysLTs in bronchoalveolar lavage fluid (BALF) in the absence and presence of treatment with MK‐571 or dexamethasone. RSV infection produced a marked increase in CysLTs in the BALF and lung tissue, recruitment of neutrophils and lymphocytes into the airways, increased IFN‐γ levels and airway hyperresponsiveness (AHR). Treatment with MK‐571 decreased RSV‐induced AHR without affecting the cellular and inflammatory responses to RSV. Dexamethasone decreased AHR and markedly reduced the recruitment of inflammatory cells and production of IFN‐γ. Our findings suggest CysLTs play an important role in the pathogenesis of RSV‐induced airway dysfunction. Treatment with MK‐571 decreases RSV‐induced AHR but does not appear to alter the lung inflammatory responses to RSV. In contrast, dexamethasone decreases RSV‐induced AHR but interferes with recruitment of inflammatory cells, resulting in decreased Th1 cytokines (a potentially Th2‐prone environment) in this model. These studies support recent reports on the beneficial effects of CysLT receptor antagonist in human trials and provide a model for investigating the role of CysLTs in RSV bronchiolitis.

Exhaled volatile organic compounds discriminate patients with chronic obstructive pulmonary disease from healthy subjects.

Chronic obstructive pulmonary disease (COPD) is a chronic airway inflammatory disease characterized by incompletely reversible airway obstruction. This clinically heterogeneous group of patients is characterized by different phenotypes. Spirometry and clinical parameters, such as severity of dyspnea and exacerbation frequency, are used to diagnose and assess the severity of COPD. The purpose of this study was to investigate whether volatile organic compounds (VOCs) could be detected in the exhaled breath of patients with COPD and whether these VOCs could distinguish COPD patients from healthy subjects. Moreover, we aimed to investigate whether VOCs could be used as biomarkers for classifying patients into different subgroups of the disease. Ion mobility spectrometry was used to detect VOCs in the exhaled breath of COPD patients. One hundred and thirty-seven peaks were found to have a statistically significant difference between the COPD group and the combined healthy smokers and nonsmoker group. Six of these VOCs were found to correctly discriminate COPD patients from healthy controls with an accuracy of 70%. Only 15 peaks were found to be statistically different between healthy smokers and healthy nonsmokers. Furthermore, by determining the cutoff levels for each VOC peak, it was possible to classify the COPD patients into breathprint subgroups. Forced expiratory volume in 1 second, body mass index, and C-reactive protein seem to play a role in the discrepancies observed in the different breathprint subgroups.

Utilizing a line maintenance team to reduce central-line-associated bloodstream infections in a neonatal intensive care unit.

Objective:To determine the association of a central-line maintenance team on the incidence of central-line-associated bloodstream infections (CLABSIs) in the neonatal intensive care unit (NICU).Study Design:Central line maintenance in the NICU was limited to a line team starting in March 2008. CLABSI rates were determined before (December 2006 to February 2008) and after implementation of the line team ( March 2008 to August 2010) utilizing consistent National Healthcare Safety Network definitions. Rates were calculated by birth weight categories and overall. Data analysis was performed by two-proportion t test using Minitab.Result:Overall CLABSI decreased by 65% after implementation of the line team. Pre intervention, mean overall CLABSI rate was 11.6 /1000, as compared with 4.0/1000 after intervention (P<0.001). Birth-weight-specific CLABSI rates also decreased significantly. Decreased infection rates were sustained over time.Conclusion:A line team provided for standardized, consistent central-line maintenance care leading to a significant, sustained decrease in CLABSI in a NICU.

Treatment of severe theophylline toxicity with hemodialysis in a preterm neonate

Abstract. Theophylline, a drug frequently used to treat apnea of prematurity, has a prolonged half-life of 30 h in neonates. Severe overdoses of theophylline have an associated 10% mortality and significant morbidity. We describe a 1220-g neonate who developed status epilepticus due to a theophylline overdose. Hemodialysis was instituted to increase elimination of theophylline. The patient tolerated the procedure without complication. The half-life of theophylline was 0.7 h during dialysis. No reported therapies used in neonates have achieved this magnitude of clearance. In fact, the clearance of theophylline in this neonate approached that obtained with hemoperfusion, the standard therapy for theophylline overdose in adult patients. This case demonstrates that hemodialysis is a safe and effective means of enhancing theophylline elimination for neonatal theophylline overdose.

Utility of daily head ultrasonography for infants on extracorporeal membrane oxygenation

BACKGROUND/PURPOSE Intracranial hemorrhage (ICH) is a major concern during extracorporeal membrane oxygenation (ECMO). Daily cranial ultrasonography has been used by many ECMO centers as a diagnostic tool for both detecting and following ICH while infants are on bypass. The purpose of this patient review was to look at the usefulness of performing daily cranial ultrasonography (HUS) in infants on ECMO in detecting intraventricular hemorrhage of a magnitude sufficient to alter patient treatment. METHODS The authors reviewed retrospectively all of the records of all neonates treated with ECMO at the Hermann Childrens Hospital, Wilford Hall USAF Medical Center, Cincinnati Childrens Hospital, The University of Texas Medical Branch at Galveston, and Texas Childrens Hospital between February 1986 to March 1995. Two hundred ninety-eight patients were placed on ECMO during this period. All patients had HUS before, and daily while on ECMO, and all were reviewed by the staff radiologists. A total of 2,518 HUS examinations were performed. RESULTS Fifty-two of 298 patients (17.5%) had an intraventricular hemorrhage seen on ultrasound scan. Nine of 52 patients (17.3%) had an ICH seen on the initial HUS examination before ECMO, all of which were grade I, and 43 of 52 patients (82.7%) had ICH while on ECMO. Of these ICH, 15 were grade I, 10 were grade II, 10 were grade III, and eight were grade IV. Forty of these ICH (93%) were diagnosed by HUS during the first 5 days of the ECMO course. Seven hundred eighty-six HUS were performed after day 5, at an estimated cost of

It is not what you do, it is the way that you do it: impact of a care pathway for appendicitis

300,000 to

Thirdhand smoke contamination in hospital settings: assessing exposure risk for vulnerable paediatric patients

450,000 (charges), demonstrating three new intraventricular hemorrhages, one grade I, and one grade IV on day 7 and one grade I on day 8. Eight patients were taken off ECMO because of ICH diagnosed within the first 5 days. One patient was taken off ECMO because of ICH diagnosed after 5 days. This patient had clinical symptoms suggestive of ICH. CONCLUSIONS Almost all ICH occur during the first 5 days of an ECMO course. Unless there is a clinical suspicion, it is not cost effective to perform HUS after the fifth day on ECMO, because subsequent HUS examinations are unlikely to yield information significant enough to alter management.

Meconium Enhances the Release of Nitric Oxide in Human Airway Epithelial Cells

BACKGROUND/PURPOSE Appendicitis is the most common surgical emergency in children. However, management varies widely. The aim of this study was to assess the impact of introducing a care pathway on the management of childhood appendicitis. METHODS Data were collected prospectively for 3 successive cohorts: All patients operated for suspected appendicitis were included. The pathway was modified after interim analysis of group B data. P < .05 was significant. RESULTS Six hundred patients were included. When compared with group A, group C patients were more likely to receive preoperative antibiotics (P < .0001), undergo formal pain assessment (P < .0001), and be operated before midnight (P = .025). There was a significant decrease in readmission rates from 10.0% to 4.2% (P = .023) despite an increase in cases of gangrenous and perforated appendicitis (P = .010). CONCLUSIONS The introduction of a care pathway resulted in improved compliance with antibiotic regimens, more frequent pain assessment, and fewer post-midnight operations. Postappendicectomy readmission rates were reduced despite an increase in disease severity. This was achieved by critical reevaluation of outcomes and pathway redesign where appropriate.