Intratracheal Instillation of Budesonide-Surfactant for Prevention of Bronchopulmonary Dysplasia in Extremely Premature Infants.

OBJECTIVE: This study aimed to determine the effect of intratracheal instillation of a budesonide-surfactant combination on the incidence of bronchopulmonary dysplasia (BPD) or death compared with surfactant alone in extremely preterm infants. STUDY DESIGN: In this retrospective, single-center study, we included extremely preterm infants (<28 weeks' gestation) who received surfactant for respiratory distress in the first 3 days of life. We compared infants who received budesonide-surfactant combination (intervention group: infants born between February 2016 and October 2021) with surfactant alone (control group: infants born from January 2010 through January 2016). The primary outcome was a composite of BPD grade 2 or 3 (as defined by Jensen et al, 2019) or death before 36 weeks' postmenstrual age (PMA). RESULTS: We included 966 extremely preterm infants (528 in the control group and 438 in the intervention group). While the incidence of death/BPD grade 2 or 3 at 36 weeks of PMA was not different between the two groups (66% in the intervention group vs. 63% in the control group; adjusted relative risk [aRR], 0.99; 95% confidence interval [CI], 0.90-1.07; p-value = 0.69), budesonide was associated with a reduction in the primary outcome only in a subgroup of infants with birth weight ≥ 750 grams (36.8 vs. 43.5%, respectively; aRR 0.75; 95% CI, 0.57-0.98). Primary and secondary outcomes did not differ between the two groups within the subgroup of infants weighing <750 grams. CONCLUSION: In extremely preterm infants, the budesonide-surfactant combination therapy reduced the rates of BPD or death in infants weighing ≥750 grams; however, this beneficial effect was not seen in infants weighing <750 grams. Further investigation of this treatment may be indicated before it is considered a standard approach to management. KEY POINTS: · Intratracheal budesonide-surfactant therapy reduces BPD in preterm infants weighing ≥750 grams.. · Intratracheal budesonide-surfactant therapy does not affect BPD in preterm infants weighing <750 grams.. · Intratracheal budesonide-surfactant therapy does not affect the mortality rate in preterm infants..

Bevacizumab for Retinopathy of Prematurity: 2-Year Neurodevelopmental Follow-up.

OBJECTIVE: This study aimed to determine whether infants who were treated with intravitreal bevacizumab (IVB) for retinopathy of prematurity (ROP) were at higher risk of death or neurodevelopmental impairment (NDI) when compared with infants who were not treated with IVB (Laser only). STUDY DESIGN: This retrospective study included 146 infants born from 2009 through 2016 with a birth weight (BW) <1,000 g, gestational age <27 weeks, and required ROP therapy. Death and NDI rates were assessed at 18 to 24 months' corrected age. RESULTS: Rates of death or severe NDI were 62 and 53% in the IVB (n = 61) and Laser only (n = 85) groups, respectively. This difference was not statistically different despite sample selection bias in treating growth-restricted infants with IVB, BW (median [IQR]) was 481 (420-583) versus 547 (473-640) g in IVB and Laser only groups, respectively, p = 0.003. The adjusted odds ratio and 95% confidence interval of death or severe NDI was 0.86 (0.33-2.20). CONCLUSION: Bevacizumab therapy for ROP did not affect survival and neurodevelopment of extremely preterm infants. KEY POINTS: · Intravitreal bevacizumab therapy for retinopathy of prematurity may be safe in periviable preterm infants.. · Intravitreal bevacizumab therapy does not increase mortality rate in periviable preterm infants.. · Intravitreal bevacizumab therapy does not increase adverse neurodevelopmental outcome in periviable infants..

Nonsurgical Management of Persistent and Hemodynamically Significant Patent Ductus Arteriosus among Extremely Low Birth Weight Infants: A Propensity Score Matched Analysis.

OBJECTIVE: The objective of this study was to evaluate the impact of a nonsurgical approach (with the incorporation of late postnatal hydrocortisone treatment to facilitate extubation) in comparison to the surgical approach for the management of persistent hemodynamically significant patent ductus arteriosus (hsPDA) among chronically ventilator-dependent extremely low birth weight (ELBW) infants. METHODS: In this retrospective study, ELBW infants with a diagnosis of hsPDA (diagnosed based on the echocardiographic criteria and chronic ventilator dependence) that were persistent beyond 14 days of postnatal age despite adequate medical treatment were included. RESULTS: Out of 127 infants (surgical approach group, n = 67 and nonsurgical approach group, n = 60), 72 infants were matched based on the propensity scores. In the matched cohort, in comparison to infants managed with the surgical approach (control group, n = 36), infants in the nonsurgical approach group (treatment group, n = 36) had a lower rate of surgical ligation (14 vs. 100%, p = < 0.001), but there were no differences in both primary outcome (death or bronchopulmonary dysplasia) and secondary outcome measures. CONCLUSION: For chronically ventilator-dependent ELBW infants with persistent hsPDA, a nonsurgical management approach is associated with a reduced rate of surgical ligation of PDA, but not associated with increased risk of adverse major short-term neonatal outcomes.

Delayed cord clamping with and without cord stripping: a prospective randomized trial of preterm neonates.

OBJECTIVE: Autologous blood transfusion from the placenta to the neonate at birth has been proven beneficial. Transfusion can be accomplished by either delayed cord clamping or cord stripping. Both are equally effective in previous randomized trials. We hypothesized that combining these 2 techniques would further improve outcomes in preterm neonates. STUDY DESIGN: This was a prospective randomized trial for singleton deliveries with estimated gestational ages between 22 and 31 6/7 weeks. The control protocol required a 30-second delayed cord clamping, whereas the test protocol instructed a concurrent cord stripping during the delay. The primary outcome was initial fetal hematocrit. We also examined secondary outcomes of neonatal mortality, length of time on the ventilator, days to discharge, peak bilirubin, number of phototherapy days, and neonatal complication rates. RESULTS: Of the 67 patients analyzed, 32 were randomized to the control arm and 35 were randomized to the test arm. The gestational ages and fetal weights were similar between the arms. Mean hematocrit of the control arm was 47.75%, and the mean hematocrit for the test arm was 47.71% (P = .98). These results were stratified by gestational age, revealing the infants less than 28 weeks had an average hematocrit of 41.2% in the control arm and 44.7% in the test arm (P = .12). In the infants with gestational ages of 28 weeks or longer, the control arm had an average hematocrit of 52.9%, which was higher than the test arm, which averaged 49.5% (P = .04). The control arm received an average of 1.53 blood transfusions, whereas the test arm received 0.97 (P = .33). The control arm had 3 neonatal deaths, and the test arm had none (P = .10). The average number of days until discharge was 71.2 for the control arm and 67.8 for the test arm (P = .66). The average number of days on the ventilator was 4.86 for the control arm and 3.06 for the test arm (P = .34). CONCLUSION: Adding cord stripping to the delayed cord clamp does not result in an increased hematocrit. Data suggest trends in lower mortality and higher hematocrit in neonates born less than 28 weeks, but these were not statistically significant.

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.

Acidemia versus hypercapnia and risk for severe intraventricular hemorrhage.

In extremely low birth weight (ELBW) infants, levels of hypercapnia (Paco 2) > 60 mm Hg are considered a risk factor for severe intraventricular hemorrhage (IVH). Since cerebral vasoreactivity depends on arterial pH (apH) rather than Paco 2, we hypothesize that the role of mild-to-moderate hypercapnia (45-60 mm Hg) in the occurrence of severe IVH is modulated by the metabolic component of acid-base status. ELBW infants (n = 580, born < 28 wk gestation, and BW < 1,000 g) were separated into "high-base deficit (BD)" (n = 291) and "low-BD" (n = 289) groups if infants' median BD were > 4 mEq/L or ≤4 mEq/L, respectively. Rates of severe IVH were higher in "high-BD" (16%) than "low-BD" (9%) group. Although adjusted risk for severe IVH increased with higher Paco 2 and higher BD, apH was the sole predictor of severe IVH. In ELBW infants, higher degree of acidemia, rather than hypercapnia per se, during the first 48 hours of life, is associated with higher occurrences of severe IVH.

Neonatal Opioid Withdrawal Syndrome Following Prenatal Use of Supplements Containing Tianeptine.

Tianeptine is an opioid receptor agonist that is prescribed as an antidepressant in many countries. In the United States, tianeptine is not approved for medical use because of its potential for abuse and addiction. Nonetheless, products containing tianeptine are easily obtainable and are marketed as dietary supplements. There are increasing reports of adverse effects and fatal toxicities resulting from tianeptine use among adolescents and adults. This emerging public health threat could escalate the opioid epidemic and drive increased newborn perinatal exposure. The impact of in utero exposure to tianeptine has not been studied, and to our knowledge, the authors of only 1 report have documented possible neonatal effects. Here, we describe a case of chronic prenatal exposure to tianeptine in the setting of maternal dependence on dietary supplements. This infant developed signs of severe withdrawal shortly after birth that were refractory to treatment with oral phenobarbital but responded to subsequent oral morphine therapy. On further questioning, the mother revealed the use of a tianeptine-containing dietary supplement. We did not perform confirmatory toxicology testing because tianeptine is not assayed by usual urine drug screening tests. For infants with clinical signs of opioid withdrawal without known etiology, we suggest that the maternal interview should inquire about the use of neurotropic over-the-counter drugs.

Back vs. chest ECG electrode placement in neonatal resuscitation: A pilot randomized controlled trial.

BACKGROUND: The recent Neonatal Resuscitation Program advises the early utilization of an electrocardiogram (ECG) for non-vigorous newborns in the delivery room. However, placing ECG electrodes on the chest may delay obtaining a reliable heart rate (HR) and could interfere with chest compressions. Our previous study showed that preset ECG electrodes, attached to the back of the newborn, are quicker than a pulse oximeter (POX) for detecting HR. AIM: To compare time to detect a reliable HR using back-placed ECG electrodes versus standard front placement. METHODS: Infants were randomly assigned to back (n = 85) or chest (n = 89) electrode placement. Time measurement began upon placing infants on a Panda warmer ResusView. Failure was defined as no HR detected within 5 minutes. Intention-to-treat analysis compared HR signal acquisition time between groups. RESULTS: Both groups showed similar proportions of detectable HR within the first minute. Median (IQR) time to obtain HR was 26 (13,38) seconds for the chest group and 21 (12,54) seconds for the back group (p = 0.91). A large number of vigorous infants were included. In the chest group, these vigorous infants had shorter HR acquisition times than non-vigorous infants (Mean ± SD of 34 ± 48 seconds vs. 50 ± 44 seconds respectively; p = 0.049). Failure rates and time to acquire a HR for infants who were non-vigorous and required advanced resuscitation were similar between the back and chest groups (p = 0.51). CONCLUSION: Preset back ECG electrodes have shown encouraging results in neonates requiring advanced resuscitation. Further studies are needed to enhance guidance during neonatal resuscitation.

The Impact of a Prenatal Education Program for Opioid-Dependent Mothers on Breastfeeding Rates of Infants at Risk for Neonatal Abstinence Syndrome.

INTRODUCTION: This study aimed to determine the effect of a prenatal education program for opioid-dependent women on breastfeeding frequency, newborn hospital length of stay, and cost of care for neonates at risk of developing neonatal abstinence syndrome. METHODS: From January 1, 2015 to January 1, 2020, opioid-dependent obstetric patients were educated on non-pharmacological preventative measures for neonatal abstinence syndrome (NAS), with focused counseling on breastfeeding. Data were collected and compared to a control group of opioid-dependent pregnant women who received standard care before initiation of the education program. RESULTS: Sample size calculation revealed that to detect doubling of the breastfeeding rate from 25% to 50% with 80% power and α error of 0.05, 66 participants were required in each group. CONCLUSION: There were 75 women with opioid use disorder who had prenatal NAS education (study group) and 108 women with opioid use disorder who underwent standard care before NAS education (control group). Prenatal NAS education participants significantly increased breastfeeding initiation rates compared to the control group. Newborn length of stay significantly decreased after initiation of prenatal NAS education compared to the 36 months before NAS education program.

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.

Correction to: A single-dose indomethacin prophylaxis for reducing perinatal brain injury in extremely low birth weight infants: a non-inferiority analysis.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Aerosolized Calfactant for Newborns With Respiratory Distress: A Randomized Trial.

BACKGROUND: Exogenous surfactants to treat respiratory distress syndrome (RDS) are approved for tracheal instillation only; this requires intubation, often followed by positive pressure ventilation to promote distribution. Aerosol delivery offers a safer alternative, but clinical studies have had mixed results. We hypothesized that efficient aerosolization of a surfactant with low viscosity, early in the course of RDS, could reduce the need for intubation and instillation of liquid surfactant. METHODS: A prospective, multicenter, randomized, unblinded comparison trial of aerosolized calfactant (Infasurf) in newborns with signs of RDS that required noninvasive respiratory support. Calfactant was aerosolized by using a Solarys nebulizer modified with a pacifier adapter; 6 mL/kg (210 mg phospholipid/kg body weight) were delivered directly into the mouth. Infants in the aerosol group received up to 3 treatments, at least 4 hours apart. Infants in the control group received usual care, determined by providers. Infants were intubated and given instilled surfactant for persistent or worsening respiratory distress, at their providers' discretion. RESULTS: Among 22 NICUs, 457 infants were enrolled; gestation 23 to 41 (median 33) weeks and birth weight 595 to 4802 (median 1960) grams. In total, 230 infants were randomly assigned to aerosol; 225 received 334 treatments, starting at a median of 5 hours. The rates of intubation for surfactant instillation were 26% in the aerosol group and 50% in the usual care group (P < .0001). Respiratory outcomes up to 28 days of age were no different. CONCLUSIONS: In newborns with early, mild to moderate respiratory distress, aerosolized calfactant at a dose of 210 mg phospholipid/kg body weight reduced intubation and surfactant instillation by nearly one-half.

A single-dose indomethacin prophylaxis for reducing perinatal brain injury in extremely low birth weight infants: a non-inferiority analysis.

OBJECTIVE: To evaluate whether rates of perinatal brain injury among extremely low birth weight infants are comparable between two treatments: single-dose indomethacin prophylaxis (SGL-IP) (0.2 mg/kg, given once) vs. standard-dose indomethacin prophylaxis (STD-IP) (0.1 mg/kg/day, 3 days). METHODS: In this retrospective study, the primary outcome was perinatal brain injury (neuro-imaging evidence of intraventricular hemorrhage or periventricular leukomalacia) or death before discharge. A non-inferior efficacy of an SGL-IP regimen compared with a STD-IP regimen was determined by calculating the adjusted difference in the risk of the primary outcome using a multivariable logistic regression model. A 10-percentage point non-inferiority margin was favored. RESULTS: Prevalence rates of primary outcome were 41.7% in the SGL-IP group (n = 403) and 42.5% in the STD-IP group (n = 509) (adjusted risk difference: -1.2, 95% CI: -7.6 to +5.2, p = 0.71). CONCLUSION: Use of a single prophylactic indomethacin dose was as effective as a standard regimen in preventing perinatal brain injury.

Presetting ECG electrodes for earlier heart rate detection in the delivery room.

AIM: To determine whether heart rate (HR) could be detected earlier than by pulse oximeter (POX), using a novel method of application of electrocardiogram (ECG) electrodes during neonatal resuscitation in the delivery room. METHODS: ECG electrodes were set before delivery to be applied to the back of infants' thorax. Time to detect HR was recorded as soon as a numerical HR along with a recognizable and persistent QRS complex was observed on ECG monitor (HRECG) and a plethysmographic waveform was seen on POX monitor (HRPOX). RESULTS: Out of 334 infants, 49 were <31 weeks of gestational age. Overall, the median (interquartile range, IQR) time to detect HRECG was significantly shorter [29 (5, 60) seconds] than time by POX [60 (45,120) seconds], (p < 0.001). Similarly, in <31-week infants, the median (IQR) time to detect HRECG was 10 (2, 40) seconds compared to 60 (30,120) seconds by POX, (p < 0.001). Failure to have HR detected by 1 minute occurred in 30%, 54% and 20% of infants by ECG, POX and either of the devices, respectively. CONCLUSION: In the delivery room, electrodes applied by the study method are more effective than pulse oximetry in providing the neonatal team with timely HR information that is necessary for proper resuscitative actions.

Comparison of the Pharmacoeconomics of Calfactant and Poractant Alfa in Surfactant Replacement erapy.

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 Children's and Women's 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 $1160.62 for poractant alfa, 38% higher than the average per patient cost for calfactant ($838.34). Using poractant alfa for 22 months is estimated to have cost $202,732.75 more than it would have cost if the hospital had continued using calfactant. CONCLUSION: Our experience showed a strong pharmacoeconomic advantage for the use of calfactant compared to the use of poractant alfa because of similar average dosing and lower per patient drug costs.

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

BACKGROUND: Judicious use of antibiotic therapy in preterm infants is necessary as prolonged and unwarranted use of antibiotics have been associated with adverse short-term and long-term outcomes. LOCAL PROBLEM: Our baseline data review revealed overuse and unnecessary prolonged antibiotic exposure among preterm infants despite a low suspicion for sepsis. METHODS AND INTERVENTIONS: The baseline overall AUR was calculated retrospectively from our pharmacy database for a period of 4 months prior to the quality improvement (QI) initiative (pre-QI phase). The principal QI intervention included the development and implementation of guidance algorithms for evaluation and management of suspected sepsis incorporating key QI measures, such as an emphasis on early discontinuation of antibiotics by 36 h if blood culture remained negative and the introduction of multiplex polymerase chain reaction assay for early identification of causative organisms. This QI initiative was implemented through multiple Plan-Do-Study-Act cycles, starting in February 2016 (QI phase), with an objective to achieve a 10% reduction in the baseline overall AUR by December 2016, in preterm infants with gestational ages between 250/7 and 336/7 weeks. Data for the QI phase of the study were collected prospectively. RESULT: The overall AUR (outcome measure) decreased from 154.8 to 138.4 days of treatment per 1000 hospital days (10.6% decrease, p < 0.05) over the 11-month period. However, the overall rate of adherence to guidance algorithm (process measure) remained below the target goal of 90%. CONCLUSION: This multiphase QI initiative was able to reduce the overall AUR at our NICU. The beneficial impact of this decrease in AUR in preterm infants remains to be determined.

Clinical trial of safety and efficacy of INH-A21 for the prevention of nosocomial staphylococcal bloodstream infection in premature infants.

OBJECTIVE: To determine if INH-A21, an intravenous immune globulin (IGIV) derived from donors with high titers of antibody to surface adhesins of Staphylococcus epidermidis and S. aureus prevents late-onset sepsis (LOS) in very low birth weight (VLBW) infants. STUDY DESIGN: In this double-blind, placebo-controlled study, infants with birth weights 500 to 1250 g were randomized to receive up to four doses of INH-A21 (Veronate) or placebo. The primary objective was to determine the safety and efficacy of INH-A21 versus placebo for prevention of S. aureus LOS in VLBW infants. RESULTS: A total of 1983 infants from 95 neonatal intensive care units were randomized, and received at least one dose of study drug. S. aureus LOS developed in 50 of 989 (5%) and 60 of 994 (6%) infants who received placebo or INH-A21, respectively (P = .34). No differences were found in the frequencies of LOS caused by coagulase-negative staphylococci (CoNS), Candida spp, or overall mortality. No adverse events were statistically significantly associated with INH-A21 infusions compared with placebo. CONCLUSION: INH-A21 failed to reduce the incidence of staphylococcal LOS or candidemia in premature infants.

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

OBJECTIVE: Alveolar 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 SETTING: Randomized sham-controlled animal study in anesthetized rats. METHODS: Lung 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). MEASUREMENTS: Arterial blood gas, blood pressure. After kill: lung static pressure volume curves, bronchoalveolar fluid concentration for protein, macrophage inflammatory protein 2, tumor necrosis factor alpha, and wet/dry lung weight ratio (W/D). RESULTS: During 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). CONCLUSIONS: Alveolar macrophages participate in the early phase of ventilator-induced lung injury.

Clara cell secretory protein and phospholipase A2 activity modulate acute ventilator-induced lung injury in mice.

Lung vascular permeability is acutely increased by high-pressure and high-volume ventilation. To determine the roles of mechanically activated cytosolic PLA2 (cPLA2)and Clara cell secretory protein (CCSP), a modulator of cPLA2 activity, we compared lung injury with and without a PLA2 inhibitor in wild-type mice and CCSP-null mice (CCSP-/-) ventilated with high and low peak inflation pressures (PIP) for 2- or 4-h periods. After ventilation with high PIP, we observed significant increases in the bronchoalveolar lavage albumin concentrations, lung wet-to-dry weight ratios, and lung myeloperoxidase in both genotypes compared with unventilated controls and low-PIP ventilated mice. All injury variables except myeloperoxidase were significantly greater in the CCSP-/- mice relative to wild-type mice. Inhibition of cPLA2 in wild-type and CCSP-/- mice ventilated at high PIP for 4 h significantly reduced bronchoalveolar lavage albumin and total protein and lung wet-to-dry weight ratios compared with vehicle-treated mice of the same genotype. Membrane phospho-cPLA2 and cPLA2 activities were significantly elevated in lung homogenates of high-PIP ventilated mice of both genotypes but were significantly higher in the CCSP-/- mice relative to the wild-type mice. Inhibition of cPLA2 significantly attenuated both the phospho-cPLA2 increase and increased cPLA2 activity due to high-PIP ventilation. We propose that mechanical activation of the cPLA2 pathway contributes to acute high PIP-induced lung injury and that CCSP may reduce this injury through inhibition of the cPLA2 pathway and reduction of proinflammatory products produced by this pathway.