Reducing Time to First Dose of Antibiotic: The Example of Asymptomatic Neonates Exposed to Chorioamnionitis.

Time of medication delivery from the onset of illness is one factor that determines disease outcomes. In this study, we aimed to reduce the average time from admission to the first dose of antibiotic by at least 30% and increase the percentage of neonates receiving the first antibiotic dose within 1 hour of neonatal intensive care unit arrival to 50% over 12 months in asymptomatic neonates 34 weeks and older estimated gestational age with exposure to maternal chorioamnionitis as a sample population. METHOD: This study involved 135 infants 34 weeks and older gestational age exposed to chorioamnionitis. We documented the demographic characteristics of mothers and infants. We monitored time to the administration of the first dose of antibiotics through multiple plan-do-study-act cycles. We identified barriers to timely antibiotic administration and targeted them with multipronged interventions in plan-do-study-act cycles. Process measures were displayed monthly using X-bar/S control charts and P charts. We applied established rules for detecting a special cause. RESULTS: We reduced the meantime to the first dose of antibiotics from 130 to 78 minutes (40% reduction). The percentage of infants who received the first antibiotic dose within 60 minutes rose from 5.8% to 36.3% during the study period. Special cause improvement was seen in all process measures. The most significant improvement seen was in the time to obtain a blood culture and the interval between intravenous access placement and antibiotic delivery. CONCLUSION: Multipronged interventions can help improve timely medication delivery to neonates in the neonatal intensive care unit in this example of infants exposed to chorioamnionitis.

Improving the neonatal team handoff process in a level IV NICU: reducing interruptions and handoff duration.

BACKGROUND: Neonatal intensive care unit (NICU) patients are at increased risk for handoff communication failures due to complexity and prolonged length of stay. We report a quality initiative aimed at reducing avoidable interruptions during neonatal handoffs while monitoring handoff duration and provider satisfaction. METHODS: Observational time series between August 2015 and March 2018 in an academic level IV NICU. NICU I-PASS and process changes were implemented using plan-do-study-act cycle, and statistical process control charts were used in the analysis. Unmatched preintervention and postintervention satisfaction surveys were compared using Mann-Whitney U tests. RESULTS: There was special cause variation in the mean number of avoidable interruptions per handoff from 4 to 0.3 (92% reduction). The mean duration of handoff was reduced ~1 min/patient. Provider satisfaction with the quality of handoffs also improved from a mean of 3.36 to 3.75 on a 1-5 Likert scale (p=0.049). CONCLUSIONS: Standardisation of NICU handoff with NICU I-PASS and process changes led to the sustained reduction in avoidable interruptions with the added benefit of reduced handoff length and improved provider satisfaction.

Assessment of neonatal ventilation during high-frequency oscillatory ventilation.

OBJECTIVE: To determine alterations in high-frequency oscillatory ventilation (HFOV) performance during clinical ventilator management. DESIGN: Clinical investigation. SETTING: Two level III intensive care nurseries in Wilmington, Delaware, and Philadelphia, Pennsylvania. PATIENTS: Thirty infants 1.49 +/- 1.01 kg with respiratory distress receiving HFOV. INTERVENTIONS: Due to the demonstrated benchtop load sensitivity of the HFOV (SensorMedics 3100), we hypothesized that measured tidal volume (Vt/kg) and high-frequency minute ventilation (HFMV) would vary inversely with respiratory rate adjustments and that ventilator performance will be affected with endotracheal tube (ETT) suctioning. Both Vt/kg and HFMV were recorded using a novel hot-wire anemometry technique at the time of ETT suctioning or changes in ventilator settings. MEASUREMENTS AND MAIN RESULTS: During HFOV it was found that Vt/kg = 2.52 +/- 0.68 mL/kg and HFMV = 69 +/- 45 ([mL/kg]2 x Hz); effective ventilation was observed in the range of HFMV = 29-113 ([mL/kg]2 x Hz). HFMV decreased with an increase in breathing frequency. Although there was a significant increase in the mean Vt/kg after suctioning events, there was no difference in Vt/kg or HFMV after disconnection of the ETT alone. There were significant alterations in HFOV performance as a result of clinical adjustments in respiratory rate and suctioning. In addition, we found that measured Vt during clinically effective HFOV is at least equivalent to expected deadspace. CONCLUSIONS: Measurement of tidal volume and HFMV may be clinically important in optimizing HFOV performance both during ETT suctioning and adjustments to breathing frequency.

Growth and development in a heliox incubator environment: a long-term safety study.

BACKGROUND: Neonates exposed to mechanical ventilation may develop bronchopulmonary dysplasia (BPD). BPD neonates exhibit a 25-30% increase in energy expenditure which may decrease the rate of growth and development. Heliox has been shown to improve pulmonary function and may decrease energy expenditure. We hypothesized that heliox would provide a safe environment for sustained growth and development. OBJECTIVE: To assess the safety of the heliox environment we observed developmental milestones; recorded changes in weight, total length, limb length and head circumference; measured blood chemistries; compared primary organ and muscle weights, and analyzed muscle enzymatic activity. DESIGN/METHODS: Four-day-old rabbit pups (n = 27) were randomized into control (21% O(2); 79% N(2)) or heliox (21% O(2); 79% He) groups, then raised for 14 days at 26.7 degrees C and 50% relative humidity. Pups were euthanized on day 14, blood drawn and primary organs, diaphragm and gastrocnemius weighed and snap-frozen. RESULTS: All pups thrived in both environments, achieving expected developmental milestones. There were no physiologically significant group differences in weight, growth factors, tissue weight, blood chemistry or muscle enzyme activity. CONCLUSIONS: No observed long-term differences in growth or development. RESULTS demonstrated that long-term heliox exposure is safe in this rabbit model. These data suggest that heliox administration may provide time for pulmonary improvement in the BPD population, warranting appropriate clinical trials.

Optimizing the neonatal thermal environment.

Devices used to maintain thermal stability in preterm infants have advanced over time from the first incubator reported by Jean-Louis-Paul Denuce in 1857 to the latest Versalet Incuwarmer and Giraffe Omnibed devices today. Optimizing the thermal environment has proven significant for improving the chances of survival for small infants. Understanding the basic physiologic principles and current methodology of thermoregulation is important in the clinical care of these tiny infants. This article highlights principles of thermoregulation and the technologic advances that provide thermal support to our vulnerable

A prototype infant incubator for heliox therapy.

Heliox (Hx) gas has been shown to improve pulmonary function in infants, but methods for its delivery are invasive and problematic. To this end, we modified an Isolette (Hill-Rom Air-Shields) infant incubator (Hxl) to deliver Hx respiratory gas mixtures noninvasively while providing thermal stability for neonatal care in the Neonatal Intensive Care Unit (NICU). In vitro tests and in vivo animal studies were performed to compare the original design specifications and established baseline performance criteria for the Hxl design. The experimental environments at 50% and 80% relative humidity (RH) consisted of helium (He) with 21% and 50% O2 and control (C) of 21% and 50% O2 with the balance nitrogen (N). Elapsed times to steady state (SS) and recovery time back to SS (OCDss) due to opening and closing the door were recorded for each variable. All rabbits survived and appeared comfortable during all experimental conditions. These data show that the newly designed Isolette provides similar thermal, O2, CO2, and RH responses as the control incubator. Based on these positive safety/efficacy studies, study of the therapeutic impact of Hxl care on neonatal growth and development is in progress.

Matrix metalloproteinase and tissue inhibitor of matrix metalloproteinase expression profiles in tracheal aspirates do not adequately reflect tracheal or lung tissue profiles in neonatal respiratory distress: observations from an animal model.

OBJECTIVE: Matrix metalloproteinase (MMP)/tissue inhibitor of matrix metalloproteinase (TIMP) expression in tracheal aspirates (TA) is commonly assayed to represent the protein profile in the lung. This study tests the hypothesis that the profile of MMPs 2, 7, and 9 and the profile of TIMPs 1 and 2 will be different in TA, tracheal tissue, and lung tissue in neonatal respiratory distress. DESIGN: Interventional laboratory study. SETTING: An academic medical research facility in northeastern United States. SUBJECTS: Oleic acid-injured, spontaneously breathing newborn piglets. INTERVENTIONS: Ten piglets (3-4 days old, 2.4 +/- 0.4 kg) were instrumented, injured by intravenous administration of oleic acid, and supported on continuous positive airway pressure of 2-5 cm H2O, with or without exogenous surfactant, depending on physiologic requirements. MEASUREMENT AND MAIN RESULTS: After 6 hrs, TA, trachea, and lung were obtained for MMP/TIMP analysis by substrate zymography/reverse zymography. TA contained less active (p < .01) and more latent (p < .05) MMP-2 than trachea and lung, and the active/latent ratio was less in TA than in both tissues (p < .01). TA and trachea contained more total (p < .05) and active (p < .01) MMP-9 than did the lung; TA contained more active MMP-9 than trachea (p < .01). MMP-7 was greater in all forms relative to total protein (p < .01) from both tissues compared with TA. Trachea contained more latent MMP-7 than lung (p < .01). TIMP-1 was different across protein sources (p < .01) where TA < trachea < lung. The active MMP-2/TIMP-2 ratio was lower in TA than in lung (p < .01); the MMP-9/TIMP-1 ratio had a significant trend (p < .01) where TA > trachea > lung. CONCLUSIONS: The MMP/TIMP profiles in TA do not adequately represent the profiles in either trachea or lung. Thus, MMP/TIMP profiles from TA are limited and should be interpreted for trends rather than actual tissue levels.

Expression of matrix metalloproteinases 2, 7 and 9, and their tissue inhibitors 1 and 2, in developing rabbit tracheae.

BACKGROUND: Structural changes in the developing conducting airway impact the rigidity of the airway, altering the airway's ability to sustain its shape during ventilation. The developmental changes in airway compliance oppose the changes in compliance of the developing lung; thus the expression profiles of matrix modeling proteins likely are also opposite in these developing organs. OBJECTIVES: To determine the profiles of matrix metalloproteinases (MMPs) -2, -7, and -9 and tissue inhibitors (TIMPs) -1 and -2 in the developing trachea and test the hypothesis these profiles would contrast those previously reported for the lung. METHODS: Rabbits tracheae were harvested at 21 days of gestation, 3 and 17 days postgestation and at adulthood. Tissue homogenates were analyzed by substrate zymography for the activity of MMPs, and reverse zymography for TIMPs. Immunostainings on neonatal lamb tracheal rings were used to localize MMP-2 and 9. RESULTS: Analysis revealed an age-dependent decrease in total MMP-2 quantity and the ratio of active to latent forms. TIMP-2 shows a time-dependent increase throughout airway development. Total MMP-9 and TIMP-1 quantities were unchanged across these ages, although MMP-9 protein was found predominantly in its latent form during development and predominantly in its active form during adulthood. Respiratory epithelial cells reacted positive for both MMP-2 and 9 and trachealis muscle fibers were positive for MMP-2. No MMP-7 expression was identified in the rabbit airway. CONCLUSIONS: The opposing developmental patterns in MMP-2 expression between the airway and lung lead to speculation regarding the role of MMP-2 activity on changes in organ compliance.

Heliox attenuates lung inflammation and structural alterations in acute lung injury.

Low-density gas mixtures, such as heliox, were shown to reduce the work of breathing and facilitate the distribution of inspired gas. Since supplemental ventilatory and oxygen requirements may lead to pulmonary inflammation and structural alterations, we hypothesized that by reducing these requirements, heliox breathing may attenuate the acute inflammatory and structural changes associated with acute lung injury. Spontaneously breathing neonatal pigs were anesthetized, instrumented, supported with continuous positive airway pressure (CPAP), injured with oleic acid, and randomized to nitrox (n = 6) or heliox (n = 5).F(I)O(2) was titrated for pulse oximetry (SpO(2)) 95 +/- 2% for 4 hr. Gas exchange and pulmonary mechanics were measured. Lungs were analyzed for myeloperoxidase (MPO), interleukin-8 (IL-8), and histomorphometery. Relationships between physiologic indices and cumulative lung structure and inflammatory indices were evaluated. With heliox, compliance was significantly greater, while tidal volume, frequency, minute ventilation, F(I)O(2), arterial carbon dioxide tension (PaCO(2)), MPO, and IL-8 were significantly lower compared to nitrox. The expansion index and number of exchange units were significantly greater with heliox, while the exchange unit area (EUA) was smaller. MPO was significantly and positively correlated with F(I)O(2) (r = 0.76) and EUA (r = 0.63), and negatively correlated with number of open exchange units/field (r = -0.73). Compared to breathing nitrox, these data indicate that heliox improved the distribution of inspired gas, thereby recruiting more gas exchange units, improving gas exchange efficiency, reducing ventilatory and oxygen requirements, and attenuating lung inflammation. These data suggest that heliox breathing may have the combined therapeutic benefits of attenuating lung inflammation by reducing mechanical and oxidative stress in the clinical management of acute lung injury.

Tracheal gas insufflation-augmented continuous positive airway pressure in a spontaneously breathing model of neonatal respiratory distress.

Respiratory distress syndrome (RDS) in neonates is characterized by labored breathing and poor gas exchange, often requiring ventilatory support. Continuous positive airway pressure (CPAP) is a preferred intervention to support spontaneous ventilatory efforts by sustaining lung volume recruitment, while it prevents derecruitment during exhalation by maintaining end-expiratory pressure. However, CO2 retention during CPAP often results in the need for mechanical ventilation. Since tracheal gas insufflation (TGI) promotes CO2 elimination by reducing prosthetic dead space, we hypothesized that TGI used with CPAP may reduce the need for more invasive therapies. The objective of this study was to evaluate the physiologic effect of TGI with CPAP in a spontaneously breathing model of acute lung injury with respect to gas exchange and pulmonary mechanics. Nineteen spontaneously breathing neonatal pigs (2.4 +/- 0.4 kg) were anesthetized, sedated, instrumented, and placed on CPAP at 5 cmH2O. All piglets were injured with intravenous oleic acid (0.08 ml/kg), and then randomized to receive CPAP with TGI (TGI; n = 9) or CPAP alone (control; n = 10). FiO2 was titrated at 0.05 every 15 min during the protocol to maintain SaO2 > 93%. Vital signs, arterial blood gases, pulmonary mechanics, and thoracoabdominal motion (TAM) were evaluated 30 min after injury and at 1-hr intervals for 4 hr. Following the 4-hr measurement, the piglets were sacrificed and the lungs were grossly examined. After initiation of treatment, we found that the PaCO2 was lower (33.1 +/- 5.0 vs. 47.0 +/- 10.3 mmHg; P < 0.01), while the oxygenation indices were greater (PaO2, SaO2, a/A ratio; P < 0.01) in the TGI group than with control animals. Subsequently, the pH was greater (7.45 +/- 0.08 vs. 7.36 +/- 0.08; P < 0.01) and closer to baseline values with TGI. By 4 hr, the FiO2 was titrated lower (0.37 +/- 0.06 vs. 0.49 +/- 0.15; P < 0.05) and ventilation was accomplished with a lower minute ventilation (MV) in the TGI group than in the control group (445 +/- 113 vs. 581 +/- 223 ml/kg/min; P < 0.01). Respiratory compliance was greater with TGI than control (0.76 +/- 0.13 vs. 0.63 +/- 0.11 ml/cmH2O/kg; P < 0.01), whereas resistance and TAM were similar between groups. We conclude that the use of TGI with CPAP in the treatment of RDS results in improved gas exchange and pulmonary mechanics. As such, TGI-augmented CPAP may prevent infants from requiring more invasive ventilation by reducing CO2 retention.

Physiologic effects of CPAP: application and monitoring.

Although a wide array of respiratory care modalities has been employed to manage neonatal respiratory distress syndrome (RDS), the recent focus has emphasized strategies that correct lung pathophysiology while protecting the lung from further insult. Continuous positive airway pressure (CPAP) has remained a viable option for NICU infants since its introduction in 1971. Current methods of monitoring allow clinicians to troubleshoot and better understand the physiologic and clinical impact of administering CPAP to neonates with RDS. This article highlights the renewed interest in CPAP therapy and current methods of monitoring.

Intensive care management of the term neonate: are there regional differences in outcome?

The objective of this study was to evaluate the patterns of hospitalization of term infants in 3 major metropolitan areas. We hypothesized that regional practice variation occurred in the care of term infants and that these differences would be reflected in the hospitalization patterns of infants. All infants cared for in an Intensive Care Nursery (ICN) after maternal discharge in 1 of 3 major metropolitan areas followed up by the same neonatal management company were compared (n=4,487). Term infants were grouped into 1 of 2 categories based on illness severity: Group 1 (G1) infants-those who required supplemental oxygen or ventilation for 24 hours or more (n=611); and Group 2 (G2) infants-those infants without an oxygen or ventilation requirement (n=1,549). Excluded were infants in the following categories: birth weight <2,500 grams, major congenital anomalies, surgical patients, extracorporeal membrane oxygenation (ECMO) support, or babies who died before discharge. The number of infants in each of these categories was compared as a percentage of the total number of infants cared for in that region. The average length of stay (ALOS) and percentage of patient days attributed to infants in each category were compared across regions using multiple comparison tests (Tukey). The total ALOS was greatest in City A, as was the ALOS for sick term infants. Patient days for sick term infants were lowest in City C, and healthier term infants comprised the lowest percentage of patient days in City A. This difference resulted in the lowest percentage of patient days for all term admissions in City A. These data demonstrated that significant variation existed in the delivery of care to term neonates among major metropolitan regions. Cities that admitted fewer term infants for observation periods (G2) tended to have sicker term neonates with higher acuity hospitalizations (GI) and longer lengths of stay (LOS). These findings suggested that a conservative admission policy for this population can decrease overall LOS.

Managing our first breaths: a reflection on the past several decades of neonatal pulmonary therapy.

Lung disease has been a leading cause of significant morbidity and mortality since neonates first drew breath. Over the past few decades, many treatment options have evolved to aid us in our ability to support neonatal breathing. The history of neonatal pulmonary care, both its successes and controversies, can teach us a great deal about the future of this dynamic field. As new developments occur, we constantly modify the therapies we offer to preterm and term infants. Understanding traditional therapeutic options and knowing what may be on the horizon can help caregivers to better match treatment plans with individual infants. This article reviews advances in mechanical ventilation, adjuvant therapies, and respiratory drugs through the past few decades and speculates on future directions in this field.

The impact of cobedding on sleep patterns in preterm twins.

Interest in cobedding multiple-gestation infants has grown as focus has increased on the developmental approach to the care of the neonate. Little data, however, exist on the infants' response to cobedding. It is important to evaluate the safety, efficacy, and physiologic impact of this practice. Cobedding was offered to parents of twin infants < 37 weeks gestation, without arterial lines or ventilator requirements, by the health care team according to standard practice in our nursery. After parental informed consent, infants were placed on an event-recording cardiorespiratory monitor for 12 hours before cobedding and for the first 12 hours of cobedding. Recordings were evaluated by an investigator blinded to the bedding status of the infant. Apnea (a pause of respiration > 10 seconds, central apnea), bradycardia (a decline in heart rate to < 80 beats per minute), periodic breathing (a respiratory pattern in which there are > or = 3 pauses in respiration of > or = 3 seconds with < 20 seconds of breathing between pauses), adverse events (changes in medication, changes in oxygen requirements, temperature instability, the need for sepsis evaluation, or death) were evaluated. Other physiologic parameters were obtained through the use of standard bedside monitoring. Eleven sets of preterm infants, n = 22, with a mean gestation of 31.8+/-2.9 weeks and a mean birth weight of 1,698.7+/-552.0 grams were studied. Infants were evaluated at a corrected gestational age of 33.5+/-1.9 weeks and a mean weight of 1,713.2+/-484.0 grams. The number of events of central apnea before cobedding (57) was greater than those recorded during cobedding (18), p<0.05. There was no difference found in any of the other parameters compared. The numbers of events recorded before and during cobedding were compared by Student's t-test and significance was determined by p < 0.05. No adverse events (AE) were noted, and all infants remained cobedded throughout the study. This preliminary study suggests that cobedding of healthy preterm twins showed no increase in adverse events. Of the physiologic parameters studied, only the occurrence of central apnea changed with cobedding. This decrease in central apnea may reflect a change in sleep pattern due to more frequent arousal by the twin. Alternatively, a more regular breathing pattern may reflect a positive physiological response to contact between twins.