Fabien G. Eyal

TRPV4 channels augment macrophage activation and ventilator-induced lung injury

We have previously implicated transient receptor potential vanilloid 4 (TRPV4) channels and alveolar macrophages in initiating the permeability increase in response to high peak inflation pressure (PIP) ventilation. Alveolar macrophages were harvested from TRPV4(-/-) and TRPV4(+/+) mice and instilled in the lungs of mice of the opposite genotype. Filtration coefficients (K(f)) measured in isolated perfused lungs after ventilation with successive 30-min periods of 9, 25, and 35 cmH(2)O PIP did not significantly increase in lungs from TRPV4(-/-) mice but increased >2.2-fold in TRPV4(+/+) lungs, TRPV4(+/+) lungs instilled with TRPV4(-/-) macrophages, and TRPV4(-/-) lungs instilled with TRPV4(+/+) macrophages after ventilation with 35 cmH(2)O PIP. Activation of TRPV4 with 4-alpha-phorbol didecanoate (4alphaPDD) significantly increased intracellular calcium, superoxide, and nitric oxide production in TRPV4(+/+) macrophages but not TRPV4(-/-) macrophages. Cross-sectional areas increased nearly 3-fold in TRPV4(+/+) macrophages compared with TRPV4(-/-) macrophages after 4alphaPDD. Immunohistochemistry staining of lung tissue for nitrotyrosine revealed increased amounts in high PIP ventilated TRPV4(+/+) lungs compared with low PIP ventilated TRPV4(+/+) or high PIP ventilated TRPV4(-/-) lungs. Thus TRPV4(+/+) macrophages restored susceptibility of TRPV4(-/-) lungs to mechanical injury. A TRPV4 agonist increased intracellular calcium and reactive oxygen and nitrogen species in harvested TRPV4(+/+) macrophages but not TRPV4(-/-) macrophages. K(f) increases correlated with tissue nitrotyrosine, a marker of peroxynitrite production.

Reduction in alveolar macrophages attenuates acute ventilator induced lung injury in rats

ObjectiveAlveolar macrophages are the sentinel cell for activation of the inflammatory cascade when the lung is exposed to noxious stimuli. We investigated the role of macrophages in mechanical lung injury by comparing the effect of high-volume mechanical ventilation with or without prior depletion of macrophages.Design and settingRandomized sham-controlled animal study in anesthetized rats.MethodsLung injury was induced by 15 min of mechanical ventilation (intermittent positive pressure ventilation) using high peak pressures and zero end-expiratory pressure. The mean tidal volume was 40 ± 0.7 ml/kg. One group of animals was killed immediately after this period of volutrauma (HV), while in a second group normoventilation was continued for 2 h at a tidal volume less than 10 ml/kg (HV-LV). One-half of the animals were depleted of alveolar macrophages by pretreatment with intratracheal liposomal clodronate (CL2MDP).MeasurementsArterial blood gas, blood pressure. After kill: lung static pressure volume curves, bronchoalveolar fluid concentration for protein, macrophage inflammatory protein 2, tumor necrosis factor α, and wet/dry lung weight ratio (W/D).ResultsDuring HV and HV+LV oxygenation, lung compliance, and alveolar stability were better preserved in animals pretreated with CL2MDP. In both groups W/D ratio was significantly greater in ventilated than in nonventilated animals (4.5 ± 0.6), but the increase in W/D was significantly less in CL2MDP treated HV and HV-LV groups (6.1 ± 0.4, 6.6 ± 0.6) than in the similarly ventilated nontreated groups (8.7 ± 0.2 and 9.2 ± 0.5).ConclusionsAlveolar macrophages participate in the early phase of ventilator-induced lung injury.

Cerebellar hemorrhage: a major morbidity in extremely preterm infants

Objective:To determine the impact of cerebellar hemorrhage (CH) on mortality and adverse neurodevelopmental (ND) outcome rates in extremely preterm infants admitted to a tertiary neonatal unit.Study Design:A total of 1120 eligible infants (<28 weeks gestation) were born from 1998 to 2008 and had at least one cranial ultrasound. ND outcome was determined at 12 to 18 months corrected age.Results:Most CH (75%) occurred in infants <25 weeks gestation. CH did not affect mortality rates, however, it was associated with both mental and motor impairments, with incidence rate ratios of 3.08 (1.71 to 4.84) and 2.12 (1.12 to 3.45), respectively. Moreover, the risk of cerebral palsy (CP) was increased in infants with CH involving the medial part of the cerebellum.Conclusion:Our findings substantiate recent reports about the cerebellum, highlighting its role in cognitive and executive functions, and associating early cerebellar injury not only with CP but also with learning, affective and behavioral disorders.

High-frequency oscillatory ventilation versus conventional ventilation in a piglet model of early meconium aspiration.

OBJECTIVE To compare the cardiopulmonary effects of high-frequency oscillatory ventilation (HFO) and conventional ventilation (CV) in a piglet model of meconium aspiration syndrome. DESIGN Prospective, randomized control study. SUBJECTS Piglets 1 to 2 wks of age. INTERVENTIONS Meconium aspiration was induced in 30 piglets. They were then randomized to CV, HFO at 10 Hz, or HFO at 15 Hz. MEASUREMENTS AND MAIN RESULTS Arterial blood gas, and systemic and pulmonary hemodynamics were measured serially. Airway opening pressure (P-Flex), static lung compliance (Crs), and trapped gas volume (TGV) were derived. Meconium instillation produced similar stable decreases in Crs (6.7 +/- 0.7 [SEM] to 4.7 +/- 0.4 mL/cm) and increases in pulmonary vascular resistance (68 +/- 6.4 vs. 91.9 +/- 8.5 mm Hg/mL/kg/min). A greater proportion of animals (40%, p< .007) remained hypercarbic during HFO at 15 Hz. Oxygenation indices were similar for all groups. In regards to high-frequency support, both power and deltaP were higher in the HFO at 15 Hz group (p< .001). When compared with both CV and HFO at 10 Hz, the TGV in the HFO at 15 Hz group was significantly higher following randomization to ventilator type. P-Flex was also greatest in the 15 Hz group, followed by the 10 Hz group and the CV group. Higher airway opening pressures, given identical compliance, suggest that HFO at 15 Hz resulted in greater large airway obstruction. With HFOs inherent low tidal volumes, progression of meconium to the distal airways may be delayed. CONCLUSIONS Early institution of HFO at 15 Hz in meconium aspiration may exacerbate air trapping. HFO at lower rates may be the optimal method of respiratory support in meconium aspiration syndrome. HFO may extend the window of time available for removal of meconium.

A practical and reliable method of measuring blood pressure in the neonate by pulse oximetry

OBJECTIVE We investigated the reliability of the plethysmographic waveform of the pulse oximeter to measure systolic blood pressure in sick neonates. METHODS Fifty infants admitted to the neonatal intensive care unit, with indwelling arterial catheters placed for their ongoing care, were enrolled. Median gestational age was 31 weeks (range, 24 to 40 weeks), and the mean birth weight was 1711 gm (range, 546 to 3856 gm). Blood pressure was recorded by an oscillometric method as well as from a transducer connected to an arterial catheter. Additionally, pulse oximeter blood pressures were obtained by gradually inflating an appropriately sized blood pressure cuff in increments of 2 to 5 mm Hg, on the same extremity as the oximeter probe, until the waveform just disappeared. The cuff was then rapidly inflated another 20 mm Hg and then gradually deflated in increments of 2 to 5 mm Hg until the waveform reappeared on the oximeter screen display. The pulse oximeter blood pressures were calculated both as the blood pressure noted at disappearance of the pulse oximeter waveform and as the blood pressure noted by the average pulse oximeter blood pressure at the disappearance and reappearance of the waveform. The mean intraarterial systolic blood pressure was 54 mm Hg (range, 36 to 82 mm Hg). RESULTS Blood pressures obtained by pulse oximetry showed a significantly better correlation with intraarterial measurements in comparison with those obtained by oscillometric instruments. Additionally, the limits of agreement (mean difference +/- 2 SD) between blood pressures obtained by intraarterial measurements and those obtained by pulse oximetry were within a clinically acceptable range as opposed to those obtained by the comparison of intraarterial and oscillometric methods. CONCLUSION Measurements of blood pressure in the neonate by means of pulse oximetry waveform analysis are easily obtainable and more accurate than those obtained by the oscillometric method.

Acquired Left-Sided Pulmonary Vein Stenosis in an Extremely Premature Infant: A New Entity?

t c F p p p a ( large patent ductus arteriosus (PDA) was surgically ligated in a 22-week preterm infant after failed attempts at pharmacological closure with ibuprofen. The results of multile echocardiograms performed early were negative for other cardiac bnormalities. By 3 months of age, the child was off all respiratory upport. At 6 months, he had a respiratory deterioration requiring e-intubation and mechanical ventilation. With echocardiography, evere pulmonary hypertension and left lower pulmonary vein steosis were demonstrated. Inhaled nitric oxide (iNO) and sildenafil herapy was initiated. Although the child was extubated in 3 days, e had continued pulmonary hypertension for the next 16 months, equiring near continuous nasal cannula iNO therapy. During his ospital stay, a pulmonary perfusion scan was performed, which emonstrated decreased perfusion of the left lung (Figure 1). At 23 onths, the child had an acute respiratory decompensation and ied. At autopsy, stenosis of the left lower pulmonary vein was onfirmed (Figure 2A). Histological sectioning at the stenotic site howed narrowing of the pulmonary vein lumen and medial thickning (Figure 2B). Acquired pulmonary vein stenosis resulted in late onset pulonary hypertension in this child. Although pulmonary vein steosis after cardiovascular surgery in children is described, less is now about acquired pulmonary vein stenosis in extremely premaure infants. The long-term prognosis for children with acquired ulmonary vein stenosis is poor, with most having relentless proression of pulmonary hypertension. The unilateral left-sided steosis in our patient is intriguing. In preterm infants with a hemoynamically significant PDA such as this patient, left-to-right shunt ow may preferentially stream into the left pulmonary artery, thus ncreasing blood flow through the left pulmonary veins. This uniigure 1. Quantitative radionucleotide lung perfusion scan shows ecreased perfusion of the left lung.

Pilot study of a new mathematical algorithm for early detection of late-onset sepsis in very low-birth-weight infants.

BACKGROUND Diagnosis of late onset sepsis (LOS) in very low birth weight (VLBW) preterm infants relies mainly on clinical suspicion, whereas prognosis depends on early initiation of antibiotic treatment. RALIS is a mathematical algorithm for early detection of LOS incorporating six vital signs measured every 2 hours. OBJECTIVE The aim of this study is to study RALIS ability to detect LOS before clinical suspicion. STUDY DESIGN A total of 118 VLBW preterm infants (gestational age < 33 weeks, birth weight < 1,500 g) were enrolled in a prospective multicentered study. Vital signs were recorded prospectively up to day 21 of life in a blinded manner, with no effect on standard care. The primary end point was comparison of the rates and timing of detection of LOS between RALIS and clinical/culture evidence of LOS. RESULTS Of the 2,174 monitoring days, RALIS indicated sepsis in 590 days, and LOS was positively diagnosed in 229 days. Sensitivity, specificity, positive, and negative predictive values were 74.6, 80.7, 38.8, and 95.1%, respectively. RALIS provided an indication for sepsis 3 days on the average before clinical suspicion. CONCLUSION RALIS has a promising potential as an easy to implement noninvasive early indicator of LOS, especially for ruling out LOS in VLBW high-risk infants.

Respiratory Failure Secondary to Barotrauma Is Effectively Treated by Exogenous Surfactant or Bronchoalveolar Lavage with Dilute Surfactant

Respiratory Failure Secondary to Barotrauma Is Effectively Treated by Exogenous Surfactant or Bronchoalveolar Lavage with Dilute Surfactant

Comparison of the Pharmacoeconomics of Calfactant and Poractant Alfa in Surfactant Replacement Therapy

OBJECTIVE To compare the pharmacy costs of calfactant (Infasurf, ONY, Inc.) and poractant alfa (Curosurf, Chiesi USA, Inc., Cary, NC). METHODS The University of South Alabama Childrens and Womens Hospital switched from calfactant to poractant alfa in 2013 and back to calfactant in 2015. Retrospectively, we used deidentified data from pharmacy records that provided type of surfactant administered, gestational age, birth weight, and number of doses on each patient. We examined differences in the number of doses by gestational ages and the differences in costs by birth weight cohorts because cost per dose is based on weight. RESULTS There were 762 patients who received calfactant and 432 patients who received poractant alfa. The average number of doses required per patient was 1.6 administrations for calfactant-treated patients and 1.7 administrations for poractant alfa-treated patients, p = 0.03. A higher percentage of calfactant patients needed only 1 dose (53%) than poractant alfa patients (47%). The distribution of the number of doses for calfactant-treated patients was significantly lower than for the poractant alfa-patients, p < 0.001. Gestational age had no consistent effect on the number of doses required for either calfactant or poractant alfa. Per patient cost was higher for poractant alfa than for calfactant in all birth weight cohorts. Average per patient cost was

Reducing antibiotic utilization rate in preterm infants: a quality improvement initiative

1160.62 for poractant alfa, 38% higher than the average per patient cost for calfactant (