Surgery and magnetic resonance imaging increase the risk of hypothermia in infants.

AIM: Maintaining normothermia is a tenet of neonatal care. However, neonatal thermal care guidelines applicable to intra-hospital transport beyond the neonatal intensive care unit (NICU) and during surgery or magnetic resonance imaging (MRI) are lacking. The aim of this study is to determine the proportion of infants normothermic (36.5-37.5°C) on return to NICU after management during surgery and MRI, and during standard clinical care in both environments. METHODS: Sixty-two newborns requiring either surgery in the operating theatre (OT) (n = 41) or an MRI scan (n = 21) at the Royal Children's Hospital (Melbourne) NICU were prospectively studied. Core temperature, along with cardiorespiratory parameters, was continuously measured from 15 min prior to leaving the NICU until 60 min after returning. Passive and active warming (intra-operatively) was at clinician discretion. RESULTS: The study reported 90% of infants were normothermic before leaving NICU: 86% (MRI) and 93% (OT). Only 52% of infants were normothermic on return to NICU (relative risk (RR) 1.75; 95% confidence interval (CI) 1.39-2.31; number needed to harm (NNH) 2.6). Between departure from the NICU and commencement of surgery, core temperature decreased by mean 0.81°C (95% CI 0.30-1.33; P = 0.0001, analysis of variance), with only 24% of infants normothermic when surgery began (P < 0.0001; RR 3.80 (95% CI 2.33-6.74); NNH 1.5). After an MRI, infants were a mean 0.41°C (95% CI 0.16-0.67) colder than immediately before entering the scanner (P = 0.001, analysis of variance), with only 43% being normothermic (P = 0.003; RR 2.11 (95% CI 1.35-3.74); NNH 2.1). CONCLUSION: Unintentional hypothermia is a common occurrence during surgery in the OT and MRI in neonates, indicating that evidence-based warming strategies to prevent hypothermia should be developed.

Tidal Volume Delivery during the Anesthetic Management of Neonates Is Variable.

OBJECTIVES: To describe expiratory tidal volume (VT) during routine anesthetic management of neonates at a single tertiary neonatal surgical center, as well as the proportion of VT values within the range of 4.0-8.0 mL/kg. STUDY DESIGN: A total of 26 neonates needing surgery under general anesthesia were studied, of whom 18 were intubated postoperatively. VT was measured continuously during normal clinical care using a dedicated neonatal respiratory function monitor (RFM), with clinicians blinded to values. VT, pressure, and cardiorespiratory variables were recorded regularly while intubated intraoperatively, during postoperative transport, and for 15 minutes after returning to the neonatal intensive care unit (NICU). In addition, paired VT values from the anesthetic machine were documented intraoperatively. RESULTS: A total of 2597 VT measures were recorded from 26 neonates. Intraoperative and postoperative transport expiratory VT values were highly variable compared with the NICU VT (P < .0001, Kruskal-Wallis test), with 51% of inflations outside the 4.0-8.0 mL/kg range (35% and 38% of VT >8.0 mL/kg, respectively), compared with 29% in the NICU (P < .001, χ2 test). The use of a flow-inflating bag resulted in a median (range) VT of 8.5 mL/kg (range, 5.3-11.4 mL/kg) vs 5.6 ml/kg (range, 4.3-7.9 mL/kg) using a Neopuff T-piece system (P < .0001, Mann-Whitney U test). The mean anesthetic machine expiratory VT was 3.2 mL/kg (95% CI, -4.5 to 10.8 mL/kg) above RFM. CONCLUSIONS: VT is highly variable during the anesthetic care of neonates, and potentially injurious VT is frequently delivered; thus, we suggest close VT monitoring using a dedicated neonatal RFM.

Effectiveness of individualized lung recruitment strategies at birth: an experimental study in preterm lambs.

Respiratory transition at birth involves rapidly clearing fetal lung liquid and preventing efflux back into the lung while aeration is established. We have developed a sustained inflation (SIOPT) individualized to volume response and a dynamic tidal positive end-expiratory pressure (PEEP) (open lung volume, OLV) strategy that both enhance this process. We aimed to compare the effect of each with a group managed with PEEP of 8 cmH2O and no recruitment maneuver (No-RM), on gas exchange, lung mechanics, spatiotemporal aeration, and lung injury in 127 ± 1 day preterm lambs. Forty-eight fetal-instrumented lambs exposed to antenatal steroids were ventilated for 60 min after application of the allocated strategy. Spatiotemporal aeration and lung mechanics were measured with electrical impedance tomography and forced-oscillation, respectively. At study completion, molecular and histological markers of lung injury were analyzed. Mean (SD) aeration at the end of the SIOPT and OLV groups was 32 (22) and 38 (15) ml/kg, compared with 17 (10) ml/kg (180 s) in the No-RM (P = 0.024, 1-way ANOVA). This translated into better oxygenation at 60 min (P = 0.047; 2-way ANOVA) resulting from better distal lung tissue aeration in SIOPT and OLV. There was no difference in lung injury. Neither SIOPT nor OLV achieved homogeneous aeration. Histological injury and mRNA biomarker upregulation were more likely in the regions with better initial aeration, suggesting volutrauma. Tidal ventilation or an SI achieves similar aeration if optimized, suggesting that preventing fluid efflux after lung liquid clearance is at least as important as fluid clearance during the initial inflation at birth.

Selection of Reference Genes for Gene Expression Studies related to lung injury in a preterm lamb model.

Preterm newborns often require invasive support, however even brief periods of supported ventilation applied inappropriately to the lung can cause injury. Real-time quantitative reverse transcriptase-PCR (qPCR) has been extensively employed in studies of ventilation-induced lung injury with the reference gene 18S ribosomal RNA (18S RNA) most commonly employed as the internal control reference gene. Whilst the results of these studies depend on the stability of the reference gene employed, the use of 18S RNA has not been validated. In this study the expression profile of five candidate reference genes (18S RNA, ACTB, GAPDH, TOP1 and RPS29) in two geographical locations, was evaluated by dedicated algorithms, including geNorm, Normfinder, Bestkeeper and ΔCt method and the overall stability of these candidate genes determined (RefFinder). Secondary studies examined the influence of reference gene choice on the relative expression of two well-validated lung injury markers; EGR1 and IL1B. In the setting of the preterm lamb model of lung injury, RPS29 reference gene expression was influenced by tissue location; however we determined that individual ventilation strategies influence reference gene stability. Whilst 18S RNA is the most commonly employed reference gene in preterm lamb lung studies, our results suggest that GAPDH is a more suitable candidate.

Pulmonary monoclonal antibody delivery via a portable microfluidic nebulization platform.

Nebulizers have considerable advantages over conventional inhalers for pulmonary drug administration, particularly because they do not require coordinated breath actuation to generate and deliver the aerosols. Nevertheless, besides being less amenable to miniaturization and hence portability, some nebulizers are prone to denature macromolecular drugs due to the large forces generated during aerosolization. Here, we demonstrate a novel portable acoustomicrofluidic device capable of nebulizing epidermal growth factor receptor (EGFR) monoclonal antibodies into a fine aerosol mist with a mass median aerodynamic diameter of approximately 1.1 µm, optimal for deep lung deposition via inhalation. The nebulized monoclonal antibodies were tested for their stability, immunoactivity, and pharmacological properties, which confirmed that nebulization did not cause significant degradation of the antibody. In particular, flow cytometry demonstrated that the antigen binding capability of the antibody is retained and able to reduce phosphorylation in cells overexpressing the EGFR, indicating that the aerosols generated by the device were loaded with stable and active monoclonal antibodies. The delivery of antibodies via inhalation, particularly for the treatment of lung cancer, is thus expected to enhance the efficacy of this protein therapeutic by increasing the local concentration where they are needed.

Effective pulmonary delivery of an aerosolized plasmid DNA vaccine via surface acoustic wave nebulization.

BACKGROUND: Pulmonary-delivered gene therapy promises to mitigate vaccine safety issues and reduce the need for needles and skilled personnel to use them. While plasmid DNA (pDNA) offers a rapid route to vaccine production without side effects or reliance on cold chain storage, its delivery to the lung has proved challenging. Conventional methods, including jet and ultrasonic nebulizers, fail to deliver large biomolecules like pDNA intact due to the shear and cavitational stresses present during nebulization. METHODS: In vitro structural analysis followed by in vivo protein expression studies served in assessing the integrity of the pDNA subjected to surface acoustic wave (SAW) nebulisation. In vivo immunization trials were then carried out in rats using SAW nebulized pDNA (influenza A, human hemagglutinin H1N1) condensate delivered via intratracheal instillation. Finally, in vivo pulmonary vaccinations using pDNA for influenza was nebulized and delivered via a respirator to sheep. RESULTS: The SAW nebulizer was effective at generating pDNA aerosols with sizes optimal for deep lung delivery. Successful gene expression was observed in mouse lung epithelial cells, when SAW-nebulized pDNA was delivered to male Swiss mice via intratracheal instillation. Effective systemic and mucosal antibody responses were found in rats via post-nebulized, condensed fluid instillation. Significantly, we demonstrated the suitability of the SAW nebulizer to administer unprotected pDNA encoding an influenza A virus surface glycoprotein to respirated sheep via aerosolized inhalation. CONCLUSION: Given the difficulty of inducing functional antibody responses for DNA vaccination in large animals, we report here the first instance of successful aerosolized inhalation delivery of a pDNA vaccine in a large animal model relevant to human lung development, structure, physiology, and disease, using a novel, low-power (<1 W) surface acoustic wave (SAW) hand-held nebulizer to produce droplets of pDNA with a size range suitable for delivery to the lower respiratory airways.