Lung ultrasound detects regional aeration inhomogeneity in ventilated preterm lambs.

BACKGROUND: Inhomogeneous lung aeration is a significant contributor to preterm lung injury. EIT detects inhomogeneous aeration in the research setting. Whether LUS detects inhomogeneous aeration is unknown. The aim was to determine whether LUS detects regional inhomogeneity identified by EIT in preterm lambs. METHODS: LUS and EIT were simultaneously performed on mechanically ventilated preterm lambs. LUS images from non-dependent and dependent regions were acquired and reported using a validated scoring system and computer-assisted quantitative LUS greyscale analysis (Q-LUSMGV). Regional inhomogeneity was calculated by observed over predicted aeration ratio from the EIT reconstructive model. LUS scores and Q-LUSMGV were compared with EIT aeration ratios using one-way ANOVA. RESULTS: LUS was performed in 32 lambs (~125d gestation, 128 images). LUS scores were greater in upper anterior (non-dependent) compared to lower lateral (dependent) regions of the left (3.4 vs 2.9, p = 0.1) and right (3.4 vs 2.7, p < 0.0087). The left and right upper regions also had greater LUS scores compared to right lower (3.4 vs 2.7, p < 0.0087) and left lower (3.7 vs 2.9, p = 0.1). Q-LUSMGV yielded similar results. All LUS findings corresponded with EIT regional differences. CONCLUSION: LUS may have potential in measuring regional aeration, which should be further explored in human studies. IMPACT: Inhomogeneous lung aeration is an important contributor to preterm lung injury, however, tools detecting inhomogeneous aeration at the bedside are limited. Currently, the only tool clinically available to detect this is electrical impedance tomography (EIT), however, its use is largely limited to research. Lung ultrasound (LUS) may play a role in monitoring lung aeration in preterm infants, however, whether it detects inhomogeneous lung aeration is unknown. Visual LUS scores and mean greyscale image analysis using computer assisted quantitative LUS (Q-LUSMGV) detects regional lung aeration differences when compared to EIT. This suggests LUS reliably detects aeration inhomogeneity warranting further investigation in human trials.

Inflating Pressure and Not Expiratory Pressure Initiates Lung Injury at Birth in Preterm Lambs.

Rationale: Inflation is essential for aeration at birth, but current inflating pressure settings are without an evidence base. Objectives: To determine the role of inflating pressure (ΔP), and its relationship with positive end-expiratory pressure (PEEP), in initiating early lung injury pathways in the preterm lamb lung. Methods: Preterm (124 to 127 d) steroid-exposed lambs (n = 45) were randomly allocated (8-10 per group) to 15 minutes of respiratory support with placental circulation and 20 or 30 cm H2O ΔP, with an initial high PEEP (maximum, 20 cm H2O) recruitment maneuver known to facilitate aeration (dynamic PEEP), and compared with dynamic PEEP with no ΔP or 30 cm H2O ΔP and low (4 cm H2O) PEEP. Lung mechanics and aeration were measured throughout. After an additional 30 minutes of apneic placental support, lung tissue and bronchoalveolar fluid were analyzed for regional lung injury, including proteomics. Measurements and Main Results: The 30 cm H2O ΔP and dynamic PEEP strategies resulted in quicker aeration and better compliance but higher tidal volumes (often >8 ml/kg, all P < 0.0001; mixed effects) and injury. ΔP 20 cm H2O with dynamic PEEP resulted in the same lung mechanics and aeration, but less energy transmission (tidal mechanical power), as ΔP 30 cm H2O with low PEEP. Dynamic PEEP without any tidal inflations resulted in the least lung injury. Use of any tidal inflating pressures altered metabolic, coagulation and complement protein pathways within the lung. Conclusions: Inflating pressure is essential for the preterm lung at birth, but it is also the primary mediator of lung injury. Greater focus is needed on strategies that identify the safest application of pressure in the delivery room.

Dynamic positive end-expiratory pressure strategies using time and pressure recruitment at birth reduce early expression of lung injury in preterm lambs.

Positive end-expiratory pressure (PEEP) is critical to the preterm lung at birth, but the optimal PEEP level remains uncertain. The objective of this study was to determine the effect of maximum PEEP levels at birth on the physiological and injury response in preterm lambs. Steroid-exposed preterm lambs (124-127 days gestation; n = 65) were randomly assigned from birth to either 1) positive pressure ventilation (PPV) at 8 cmH2O PEEP or 3-min dynamic stepwise PEEP strategy (DynPEEP), with either 2) 20 cmH2O maximum PEEP (10 PEEP second steps) or 3) 14 cmH2O maximum PEEP (20-s steps), all followed by standardized PPV for 90 min. Lung mechanics, gas exchange, regional ventilation and aeration (electrical impedance tomography), and histological and molecular measures of lung injury were compared between groups. Dynamic compliance was greatest using a maximum 20 cmH2O (DynPEEP). There were no differences in gas exchange, end-expiratory volume, and ventilator requirements. Regional ventilation became more uniform with time following all PEEP strategies. For all groups, gene expression of markers of early lung injury was greater in the gravity nondependent lung, and inversely related to the magnitude of PEEP, being lowest in the 20 cmH2O DynPEEP group overall. PEEP levels had no impact on lung injury in the dependent lung. Transient high maximum PEEP levels using dynamic PEEP strategies may confer more lung protection at birth.

Regional ventilation characteristics during non-invasive respiratory support in preterm infants.

OBJECTIVES: To determine the regional ventilation characteristics during non-invasive ventilation (NIV) in stable preterm infants. The secondary aim was to explore the relationship between indicators of ventilation homogeneity and other clinical measures of respiratory status. DESIGN: Prospective observational study. SETTING: Two tertiary neonatal intensive care units. PATIENTS: Forty stable preterm infants born <30 weeks of gestation receiving either continuous positive airway pressure (n=32) or high-flow nasal cannulae (n=8) at least 24 hours after extubation at time of study. INTERVENTIONS: Continuous electrical impedance tomography imaging of regional ventilation during 60 min of quiet breathing on clinician-determined non-invasive settings. MAIN OUTCOME MEASURES: Gravity-dependent and right-left centre of ventilation (CoV), percentage of whole lung tidal volume (VT) by lung region and percentage of lung unventilated were determined for 120 artefact-free breaths/infant (4770 breaths included). Oxygen saturation, heart and respiratory rates were also measured. RESULTS: Ventilation was greater in the right lung (mean 69.1 (SD 14.9)%) total VT and the gravity-non-dependent (ND) lung; ideal-actual CoV 1.4 (4.5)%. The central third of the lung received the most VT, followed by the non-dependent and dependent regions (p<0.0001 repeated-measure analysis of variance). Ventilation inhomogeneity was associated with worse peripheral capillary oxygen saturation (SpO2)/fraction of inspired oxygen (FiO2) (p=0.031, r2 0.12; linear regression). In those infants that later developed bronchopulmonary dysplasia (n=25), SpO2/FiO2 was worse and non-dependent ventilation inhomogeneity was greater than in those that did not (both p<0.05, t-test Welch correction). CONCLUSIONS: There is high breath-by-breath variability in regional ventilation patterns during NIV in preterm infants. Ventilation favoured the ND lung, with ventilation inhomogeneity associated with worse oxygenation.

Respiratory mechanics during initial lung aeration at birth in the preterm lamb.

Despite recent insights into the dynamic processes during lung aeration at birth, several aspects remain poorly understood. We aimed to characterize changes in lung mechanics during the first inflation at birth and their relationship to changes in lung volume. Intubated preterm lambs (gestational age, 124-127 days; n = 17) were studied at birth. Lung volume changes were measured by electrical impedance tomography (VLEIT). Respiratory system resistance (R5) and oscillatory compliance (Cx5) were monitored with the forced oscillation technique at 5 Hz. Lambs received 3-7 s of 8 cmH2O of continuous distending pressure (CDP) before delivery of a sustained inflation (SI) of 40 cmH2O. The SI was then applied until either Cx5 or the VLEIT or the airway opening volume was stable. CDP was resumed for 3-7 s before commencement of mechanical ventilation. The exponential increases with time of Cx5 and VLEIT from commencement of the SI were characterized by estimating their time constants (τCx5 and τVLEIT, respectively). During SI, a fast decrease in R5 and an exponential increase in Cx5 and VLEIT were observed. Cx5 and VLEIT provided comparable information on the dynamics of lung aeration in all lambs, with τCx5 and τVLEIT being highly linearly correlated (r2 = 0.87, P < 0.001). Cx5 and VLEIT decreased immediately after SI. Despite the standardization of the animal model, changes in Cx5 and R5 both during and after SI were highly variable. Lung aeration at birth is characterized by a fast reduction in resistance and a slower increase in oscillatory compliance, the latter being a direct reflection of the amount of lung aeration.

A dedicated respiratory function monitor to improve tidal volume delivery during neonatal anesthesia.

BACKGROUND: Tight control of tidal volume using accurate monitoring may improve neonatal outcomes. However, respiratory function monitors incorporated in current anesthetic workstations are generally inaccurate at tidal volumes used for infants. AIMS: To determine if a specific respiratory function monitor for neonatal infants improved expired tidal volume delivery during anesthesia. METHOD: Infants <3 months old requiring intubation for surgery in the operating theater were studied. After intubation a Phillips NM3, Acutronic Florian, or Novametrix Ventcheck Respiratory Function Monitor was integrated into the circuit, and clinicians given access to the display for the duration of anesthesia. Breath-to-breath expired tidal volume delivery, leak, and delivered pressure were recorded, with cardiorespiratory parameters. These were compared with a matched control group with clinicians blinded to respiratory function monitor display. RESULTS: A total of 10 055 and 2569 inflations were measured in the respiratory function monitor visible (n = 32) and masked (n = 33) groups, respectively, with mean (standard deviation) delivered expired tidal volume 7.5 (2.4) mL/kg and 7.7 (3.0) mL/kg, respectively; mean difference (95% confidence interval) -0.2 (-1.1, 0.8) mL/kg (Welch's t test). In the visible group, 55.6% of expired tidal volumes were between 4 and 8 mL/kg compared to 51.7% in the masked group; relative benefit (95% confidence interval), 1.08 (1.03, 1.12). Expired tidal volume was less likely to be <4 mL/kg in the visible group compared to masked group; 6.4% vs 9.8%, 1.53 (1.33, 1.76). The use of a respiratory function monitor also reduced the number of inflations >10 mL/kg; 13.0% vs 22.0%, 1.11 (1.09, 1.14). CONCLUSION: Tidal volumes <4 mL/kg and >10 mL/kg are frequently delivered during neonatal anesthesia. The inclusion of an accurate respiratory function monitor may reduce the risk of exposure to potentially harmful tidal volumes.

Preterm Lung Exhibits Distinct Spatiotemporal Proteome Expression at Initiation of Lung Injury.

The development of regional lung injury in the preterm lung is not well understood. This study aimed to characterize time-dependent and regionally specific injury patterns associated with early ventilation of the preterm lung using a mass spectrometry-based proteomic approach. Preterm lambs delivered at 124-127 days gestation received 15 or 90 minutes of mechanical ventilation (positive end-expiratory pressure = 8 cm H2O, Vt = 6-8 ml/kg) and were compared with unventilated control lambs. At study completion, lung tissue was taken from standardized nondependent and dependent regions, and assessed for lung injury via histology, quantitative PCR, and proteomic analysis using Orbitrap-mass spectrometry. Ingenuity pathway analysis software was used to identify temporal and region-specific enrichments in pathways and functions. Apoptotic cell numbers were ninefold higher in nondependent lung at 15 and 90 minutes compared with controls, whereas proliferative cells were increased fourfold in the dependent lung at 90 minutes. The relative gene expression of lung injury markers was increased at 90 minutes in nondependent lung and unchanged in gravity-dependent lung. Within the proteome, the number of differentially expressed proteins was fourfold higher in the nondependent lung than the dependent lung. The number of differential proteins increased over time in both lung regions. A total of 95% of enriched canonical pathways and 94% of enriched cellular and molecular functions were identified only in nondependent lung tissue from the 90-minute ventilation group. In conclusion, complex injury pathways are initiated within the preterm lung after 15 minutes of ventilation and amplified by continuing ventilation. Injury development is region specific, with greater alterations within the proteome of nondependent lung.

Gradual Aeration at Birth Is More Lung Protective Than a Sustained Inflation in Preterm Lambs.

Rationale: The preterm lung is susceptible to injury during transition to air breathing at birth. It remains unclear whether rapid or gradual lung aeration at birth causes less lung injury.Objectives: To examine the effect of gradual and rapid aeration at birth on: 1) the spatiotemporal volume conditions of the lung; and 2) resultant regional lung injury.Methods: Preterm lambs (125 ± 1 d gestation) were randomized at birth to receive: 1) tidal ventilation without an intentional recruitment (no-recruitment maneuver [No-RM]; n = 19); 2) sustained inflation (SI) until full aeration (n = 26); or 3) tidal ventilation with an initial escalating/de-escalating (dynamic) positive end-expiratory pressure (DynPEEP; n = 26). Ventilation thereafter continued for 90 minutes at standardized settings, including PEEP of 8 cm H2O. Lung mechanics and regional aeration and ventilation (electrical impedance tomography) were measured throughout and correlated with histological and gene markers of early lung injury.Measurements and Main Results: DynPEEP significantly improved dynamic compliance (P < 0.0001). An SI, but not DynPEEP or No-RM, resulted in preferential nondependent lung aeration that became less uniform with time (P = 0.0006). The nondependent lung was preferential ventilated by 5 minutes in all groups, with ventilation only becoming uniform with time in the No-RM and DynPEEP groups. All strategies generated similar nondependent lung injury patterns. Only an SI caused greater upregulation of dependent lung gene markers compared with unventilated fetal controls (P < 0.05).Conclusions: Rapidly aerating the preterm lung at birth creates heterogeneous volume states, producing distinct regional injury patterns that affect subsequent tidal ventilation. Gradual aeration with tidal ventilation and PEEP produced the least lung injury.

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.

Is selective echocardiography in duodenal atresia the future standard of care?

BACKGROUND: Duodenal atresia (DA) is associated with cardiac defects that may have perioperative care implications. Standard preoperative care includes echocardiography to identify such cardiac defects, but this dogma has been challenged. We aimed to assess selective and selective strategies for preoperative echocardiography in DA patients. METHODS: Single-center retrospective review of neonates with DA over a 16-year period was performed. Data included preoperative cardiovascular and respiratory examination, chest x-ray, and echocardiography. We compared the current nonselective versus selective strategies, limiting preoperative echocardiogram to those in whom: (1) cardiac or respiratory or chest x-ray examination was abnormal, or (2) cardiac or respiratory examination was abnormal. Sensitivity, specificity, positive and negative predictive values were compared with chi-square tests. RESULTS: Seventy-one of 109 (65%) consecutive neonates with DA underwent preoperative echocardiography according to a nonselective, physician-determined strategy. Forty of 71 (56%) patients had cardiac defects, including 16/40 (27%) major defects. Sixteen additional postoperative echocardiograms revealed 2 missed major defects. In the same cohort, selective strategies would have performed 17-24% fewer echocardiograms without significant detriment in performance. CONCLUSIONS: All strategies considered missed some major cardiac defects. A selective strategy, determining DA patients not requiring preoperative echocardiogram, could reduce the number of echocardiograms performed without compromising patient safety. TYPE OF STUDY: Retrospective study. LEVEL OF EVIDENCE: Level II.

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.

The addition of tramadol to the standard of i.v. acetaminophen and morphine infusion for postoperative analgesia in neonates offers no clinical benefit: a randomized placebo-controlled trial.

BACKGROUND: Tramadol is used following neonatal cardiac and general surgery. However, its ability to opioid-spare or facilitate earlier extubation in postoperative neonates is unquantified. OBJECTIVE: This randomized placebo-controlled trial aimed to assess whether tramadol's addition to standard analgesia resulted in earlier extubation or reduced analgesic/sedative requirements in postsurgical neonates. METHODS: Neonates born ≥32 weeks postmenstrual age received either tramadol [T] 2 mg·kg(-1) or placebo [P] 6-hourly for up to 5 days postthoracoabdominal surgery in addition to morphine (commenced at 20 mcg·kg(-1) ·h(-1)) and 6-hourly i.v. acetaminophen. Time to extubation, morphine and midazolam amounts, hourly pain scores, and seizure activity were compared using an intention-to-treat and per-protocol analysis. RESULTS: Seventy-one neonates participated. Median survival time to extubation was similar between the groups (T 67 h [95% CI 51, 84] vs P 52 h [95%CI 43, 65]; P = 0.4), and similar numbers were extubated by 96 h (T 69% vs P 77%; difference -8%, 95%CI -28, 13%). Morphine and midazolam exposure was similar, with low pain scores in both groups (mean percentage of time with a pain score >5/20 during the 5 days: T 13% vs P 11%, difference in means 2.8 [95% CI -1.8, 7.6], P = 0.20). Most participants had normal cranial ultrasounds (T 86% vs P 86%); no seizures occurred clinically or electroencephalographically. CONCLUSION: Tramadol's addition to standard analgesia in this small group of postsurgical neonates did not appear to have any positive effect on time to extubation, morphine or midazolam exposure, or pain scores. This questions the benefit of tramadol for postsurgical neonates. Importantly, no seizures occurred in these ill neonates who may potentially be at greater risk of tramadol toxicity compared with adults.