Effective ventilation and chest compressions during neonatal resuscitation - the role of the respiratory device.

BACKGROUND: The success of cardiopulmonary resuscitation (CPR) in newborns largely depends on effective lung ventilation; however, a direct randomized comparison using different available devices has not yet been performed. METHODS: Thirty-six professionals were exposed to a realistic newborn CPR scenario. Ventilation with either a bag-valve mask (BVM), T-piece, or ventilator was applied in a randomized manner during CPR using a Laerdal manikin. The primary outcome was the number of unimpaired inflations, defined as the peak of the inflation occurring after chest compression and lasting at least 0.35 s before the following chest compression takes place. The secondary outcomes were tidal volume delivered and heart compression rate. To simulate potential distractions, the entire scenario was performed with or without a quiz. Statistically, a mixed model assessing fixed effects for experience, profession, device, and distraction was used to analyze the data. For direct comparison, one-way ANOVA with Bonferroni's correction was applied. RESULTS: The number of unimpaired inflations was highest in health care professionals using the BVM with a mean ± standard deviation of 12.8 ± 2.8 (target: 15 within 30 s). However, the tidal volumes were too large in this group with a tidal volume of 42.5 ± 10.9 ml (target: 25-30 ml). The number of unimpaired breaths with the mechanical ventilator and the T-piece system were 11.6 (±3.6) and 10.1 (±3.7), respectively. Distraction did not change these outcomes, except for the significantly lower tidal volumes with the T-piece during the quiz. CONCLUSIONS: In summary, for our health care professionals, ventilation using the mechanical ventilator seemed to provide the best approach during CPR, especially in a population of preterm infants prone to volutrauma.

Effects of inhaled nitric oxide (iNO) in pulmonary hypertension secondary to arteriovenous malformations: a retrospective cohort study from the European iNO registry.

This study aims to assess the effects of inhaled nitric oxide (iNO) on oxygenation in the management of pulmonary hypertension (PH) secondary to arteriovenous malformations (AVMs) in neonates. This is a matched retrospective cohort study from January 1, 2013, to December 31, 2017. The European inhaled nitric oxide registry from 43 neonatal and pediatric ICUs in 13 countries across Europe was used to extract data. The target population was neonates treated with iNO for the management of PH. The cases (PH secondary to AVMs treated with iNO) were matched (1:4 ratio) to controls (PH without AVMs treated with iNO). The main outcome measure was the absolute change of oxygenation index (OI) from baseline to 60 min after starting iNO in cases and controls. The primary outcome of our study was that the mean absolute change in OI from baseline to after 60 min was higher among cases 10.7 (14), than in controls 6 (22.5), and was not statistically different between the groups. The secondary outcome variable - death before discharge - was found to be significantly higher in cases (55%) than in controls (8%). All the other variables for secondary outcome measures remained statistically insignificant.   Conclusion: Infants with PH secondary to AVMs treated with iNO did not respond differently compared to those presented with PH without AVMs treated with iNO. Right ventricular dysfunction on echocardiography was higher in cases than controls (cases: 66.7% and controls: 28.6%) but was not statistically significant. What is Known: • Arterioenous malformation (AVM) is a well-known cause of persistent pulmonary hypertension in newborns. Inhaled nitric oxide (iNO) is most commonly used as first-line therapy for pulmonary hypertension in newborns. • Around 40-50% of vein of Galen malformations (VOGMs) are found to have congestive heart failure in the neonatal period. What is New: • Neonates may present with an isolated PH of the newborn as the main feature of the VOGMs. A large proportion of cases with AVMs have been associated with right ventricular cardiac dysfunction.  • Results from one of the largest database registries in the world for iNO have been used to answer our research question.

Frequency and duration of extreme hypoxemic and hyperoxemic episodes during manual and automatic oxygen control in preterm infants: a retrospective cohort analysis from randomized studies.

OBJECTIVE: Neonatal exposure to episodic hypoxemia and hyperoxemia is highly relevant to outcomes. Our goal was to investigate the differences in the frequency and duration of extreme low and high SpO2 episodes between automated and manual inspired oxygen control. DESIGN: Post-hoc analysis of a cohort from prospective randomized cross-over studies. SETTING: Seven tertiary care neonatal intensive care units. PATIENTS: Fifty-eight very preterm neonates (32 or less weeks PMA) receiving respiratory support and supplemental oxygen participating in an automated versus manual oxygen control cross-over trial. MAIN MEASURES: Extreme hypoxemia was defined as a SpO2 < 80%, extreme hyperoxemia as a SpO2 > 98%. Episode duration was categorized as < 5 seconds, between 5 to < 30 seconds, 30 to < 60 seconds, 60 to < 120 seconds, and 120 seconds or longer. RESULTS: The infants were of a median postmenstrual age of 29 (28-31) weeks, receiving a median FiO2 of 0.28 (0.25-0.32) with mostly receiving non-invasive respiratory support (83%). While most of the episodes were less than 30 seconds, longer episodes had a marked effect on total time exposure to extremes. The time differences in each of the three longest durations episodes (30, 60, and 120 seconds) were significantly less during automated than during manual control (p < 0.001). Nearly two-third of the reduction of total time spent at the extremes between automated and manual control (3.8 to 2.1% for < 80% SpO2 and 3.0 to 1.6% for > 98% SpO2) was seen in the episodes of at least 60 seconds. CONCLUSIONS: This study shows that the majority of episodes preterm infants spent in SpO2 extremes are of short duration regardless of manual or automated control. However, the infrequent longer episodes not only contribute the most to the total exposure, but also their reduction in frequency to the improvement associated with automated control.

Cerebral Oxygenation in Preterm Infants Developing Cerebral Lesions.

Background: We investigated the association between cerebral tissue oxygen saturation (cStO2) measured by near-infrared spectroscopy (NIRS) and cerebral lesions including intraventricular hemorrhage (IVH) and periventricular leukomalacia (PVL). Methods: Preterm infants <1,500 g received continuous cStO2 monitoring, initiated at the earliest time possible and recorded until 72 h of life. Mean cStO2 over periods of 5, 15, 30 min and 1 h were calculated. To calculate the burden of cerebral hypoxia, we defined a moving threshold based on the 10th percentile of cStO2 of healthy study participants and calculated the area under the threshold (AUT). cStO2 <60% for >5 min was regarded a critical event. The study was registered on clinicaltrials.gov (ID NCT01430728, URL: https://clinicaltrials.gov/ct2/show/NCT01430728?id=NCT01430728&draw=2&rank=1). Results: Of 162 infants (gestational age: mean 27.2 weeks, standard deviation 20 days; birth weight: mean 852 g, standard deviation 312 g) recorded, 24/12 (14.8%/7.4) developed any/severe IVH/PVL. Mean cStO2 was significantly lower in infants with IVH/PVL as well as severe IVH/PVL. In addition, we observed critical events defined by mean cStO2 over 5 min <60% in four infants with severe IVH/PVL during NIRS monitoring. AUT showed no statistically significant difference between outcome groups. Conclusion: These findings suggest that cStO2 is lower in infants developing IVH/PVL. This may be related to lower oxygenation and/or perfusion and implies that cStO2 could potentially serve as an indicator of imminent cerebral lesions.

Comparison of Cardiac Output Measurement by Electrical Velocimetry with Echocardiography in Extremely Low Birth Weight Neonates.

INTRODUCTION: Electrical velocimetry (EV) offers a noninvasive tool for continuous cardiac output (CO) measurements which might facilitate hemodynamic monitoring and targeted therapy in low birth neonates, in whom other methods of CO measurement are not practicably feasible. METHODS: This prospective observational study compared simultaneous cardiac output measurements by electrical velocimetry (COEV) with transthoracic echocardiography (COTTE) in extremely low birth weight (ELBW) neonates in the neonatal intensive care unit (NICU). Echocardiography was performed by 1 single examiner. Data were analyzed by Bland-Altman analysis and independent-samples analysis of variance. A mean percentage error (MPE) of <30% and limits of agreement (LOA) up to ±30% were considered clinically acceptable. RESULTS: Thirty-eight ELBW neonates were studied and yielded 85 pairs of COEV and COTTE measurements. Bland-Altman analysis showed an overall bias (the mean difference) and LOA of -126 and -305 to +52 mL min-1, respectively, and an MPE of 66%. Patients with patent ductus arteriosus had a higher bias with LOA and MPE of -166.8, -370.7 to +37 mL min-1, and 69%, respectively. The overall true precision was 58%. CONCLUSION: This study showed high bias and lack of agreement between EV and TTE for measurement of CO in ELBW infants in NICU, limiting applicability of EV to monitor absolute values.

"Current concepts in assisted mechanical ventilation in the neonate" - Part 2: Understanding various modes of mechanical ventilation and recommendations for individualized disease-based approach in neonates.

Mechanical ventilation is a lifesaving intervention in critically ill preterm and term neonates. However, it has the potential to cause significant damage to the lungs resulting in long-term complications. Understanding the pathophysiological process and having a good grasp of the basic concepts of conventional and high-frequency ventilation is essential for any medical or allied healthcare practitioner involved in the neonates' respiratory management. This review aims to describe the various types and modes of ventilation usually available in neonatal units. It also describes recommendations of an individualized disease-based approach to mechanical ventilation strategies implemented in the authors' institutions.

Inhaled nitric oxide (iNO) for preventing prematurity-related bronchopulmonary dysplasia (BPD): 7-year follow-up of the European Union Nitric Oxide (EUNO) trial.

OBJECTIVES: Most studies of inhaled nitric oxide (iNO) for prevention of bronchopulmonary dysplasia (BPD) in premature infants have focused on short-term mortality and morbidity. Our aim was to determine the long-term effects of iNO. METHODS: A 7-year follow-up was undertaken of infants entered into a multicenter, double-blind, randomized, placebo-controlled trial of iNO for prevention of BPD in premature infants born between 24 and 28 weeks plus six days of gestation. At 7 years, survival and hospital admissions since the 2-year follow-up, home oxygen therapy in the past year, therapies used in the previous month and growth assessments were determined. Questionnaires were used to compare general health, well-being, and quality of life. RESULTS: A total of 305 children were assessed. No deaths were reported. Rates of hospitalization for respiratory problems (6.6 vs. 10.5%, iNO and placebo group, respectively) and use of respiratory medications (6.6 vs. 9.2%) were similar. Two patients who received iNO and one who received placebo had received home oxygen therapy. There were no significant differences in any questionnaire-documented health outcomes. CONCLUSIONS: iNO for prevention of BPD in very premature infants with respiratory distress did not result in long-term benefits or adverse long-term sequelae. In the light of current evidence, routine use of iNO cannot be recommended for prevention of BPD in preterm infants.

"Current concepts of mechanical ventilation in neonates" - Part 1: Basics.

Mechanical ventilation is potentially live saving in neonatal patients with respiratory failure. The main purpose of mechanical ventilation is to ensure adequate gas exchange, including delivery of adequate oxygenation and enough ventilation for excretion of CO2. The possibility to measure and deliver small flows and tidal volumes have allowed to develop very sophisticated modes of assisted mechanical ventilation for the most immature neonates, such as volume targeted ventilation, which is used more and more by many clinicians. Use of mechanical ventilation requires a basic understanding of respiratory physiology and pathophysiology of the disease leading to respiratory failure. Understanding pulmonary mechanics, elastic and resistive forces (compliance and resistance), and its influence on the inspiratory and expiratory time constant, and the mechanisms of gas exchange are necessary to choose the best mode of ventilation and adequate ventilator settings to minimize lung injury. Considering the pathophysiology of the disease allows a physiology-based approach and application of these concepts in daily practice for decision making regarding the use of modes and settings of mechanical ventilation, with the ultimate aim of providing adequate gas exchange and minimising lung injury.

Transthoracic Echocardiography of the Neonatal Laboratory Piglet.

Background: Newborn piglets are commonly used in biomedical research. However, cardiovascular imaging of this species is quite challenging. For point of care diagnostics of heart function transthoracic echocardiography may be used, which appears to differ comparing newborn piglets with adult pigs. To date, there are few data or studies on the feasibility and quality of measurement of functional echocardiographic parameters in very small neonatal piglets. Objectives: To study the feasibility of transthoracic echocardiography in very small newborn piglets in supine position. Methods: In 44 anesthetized and intubated newborn piglets, positioned in supine position [age 32 h (12-44 h), weight 1,220 g (1,060-1,495 g), median (IQR)] transthoracic echocardiography was performed using a point of care ultrasound device (M-Turbo©, FujiFilm SonoSite BV, Amsterdam, Netherlands), and a standard ultrasound transducer. Results: Using 2D- and M-mode-imaging left- and right-sided heart structures were accessible to transthoracic echocardiography in neonatal piglets. Diameters of the interventricular septum, the left ventricle, and the posterior wall were measured and ejection fraction and shortening fraction was calculated. Both left and right ventricular outflow tract could be imaged, and ventricular filling and systolic function could be evaluated. Furthermore, we were able to assess shunts of fetal circulation, such as patent ductus arteriosus, structure of the heart valves and congenital heart defects including ventricular septal defect. Conclusions: In summary, transthoracic echocardiography is feasible for assessment of cardiovascular function even in very small newborn laboratory piglets in supine position.

Predictive Value of Thompson-Score for Long-Term Neurological and Cognitive Outcome in Term Newborns with Perinatal Asphyxia and Hypoxic-Ischemic Encephalopathy Undergoing Controlled Hypothermia Treatment.

BACKGROUND: The so-called Thompson-score (TS) for newborns with hypoxic-ischemic encephalopathy (HIE) was developed before the introduction of controlled hypothermia as clinical routine. Information on the predictive value of TS in newborns undergoing therapeutic hypothermia to estimate long-term outcome is limited. OBJECTIVES: To determine the predictive value of TS to estimate long-term cognitive and neurological outcome in newborns with perinatal asphyxia treated with controlled hypothermia. METHODS: Thirty-six term newborns with HIE undergoing controlled hypothermia were followed using Wechsler Preschool and Primary Scale of intelligence III test and standardized neurological examination. The primary outcome was survival without cognitive impairment, defined as an IQ ≥85. Secondary outcomes were motor outcomes, survival without relevant neurological impairment, death and epilepsy. RESULTS: Follow-up was done in 33 out of 36 (91.6%) infants at 53 ± 12 months (mean ± SD). For all investigated parameters, a statistically significant relationship with peak TS was demonstrated. A one-point increase in peak TS indicated an OR (95% CI) of 1.5 (1.1-2.0, p = 0.006) for death or cognitive impairment, an OR (95% CI) of 2.2 (1.3-3.8, p = 0.004) for death or relevant neurologic impairment, an OR (95% CI) of 2.1 (1.3-3.5, p = 0.005) for death or epilepsy and an OR (95% CI) of 1.5 (1.1-2.1, p = 0.02) for death. Although the TS for newborns with adverse outcome (death or cognitive impairment) compared to normal outcome tended to be higher (13 [4-16] vs. 9 [0-13], d1; 15 [5-19] vs. 9 [1-14], d2; 14 [5-21] vs. 8 [2-15], d3; median [range]), there was a considerable overlap during the first 3 days of life between both groups. CONCLUSIONS: The TS seems to be a prognostic tool for predicting the long-term outcome in asphyxiated term newborns undergoing controlled hypothermia after the third day of life. A higher score appears to be significantly associated with an adverse outcome.

Successful Resuscitation in a Model of Asphyxia and Hemorrhage to Test Different Volume Resuscitation Strategies. A Study in Newborn Piglets After Transition.

Background: Evidence for recommendations on the use of volume expansion during cardiopulmonary resuscitation in newborn infants is limited. Objectives: To develop a newborn piglet model with asphyxia, hemorrhage, and cardiac arrest to test different volume resuscitation on return of spontaneous circulation (ROSC). We hypothesized that immediate red cell transfusion reduces time to ROSC as compared to the use of an isotonic crystalloid fluid. Methods: Forty-four anaesthetized and intubated newborn piglets [age 32 h (12-44 h), weight 1,220 g (1,060-1,495g), Median (IQR)] were exposed to hypoxia and blood loss until asystole occurred. At this point they were randomized into two groups: (1) Crystalloid group: receiving isotonic sodium chloride (n = 22). (2) Early transfusion group: receiving blood transfusion (n = 22). In all other ways the piglets were resuscitated according to ILCOR 2015 guidelines [including respiratory support, chest compressions (CC) and epinephrine use]. One hour after ROSC piglets from the crystalloid group were randomized in two sub-groups: late blood transfusion and infusion of isotonic sodium chloride to investigate the effects of a late transfusion on hemodynamic parameters. Results: All animals achieved ROSC. Comparing the crystalloid to early blood transfusion group blood loss was 30.7 ml/kg (22.3-39.6 ml/kg) vs. 34.6 ml/kg (25.2-44.7 ml/kg), Median (IQR). Eleven subjects did not receive volume expansion as ROSC occurred rapidly. Thirty-three animals received volume expansion (16 vs. 17 in the crystalloid vs. early transfusion group). 14.1% vs. 10.5% of previously extracted blood volume in the crystalloid vs. early transfusion group was infused before ROSC. There was no significant difference in time to ROSC between groups [crystalloid group: 164 s (129-198 s), early transfusion group: 163 s (162-199 s), Median (IQR)] with no difference in epinephrine use. Conclusions: Early blood transfusion compared to crystalloid did not reduce time to ROSC, although our model included only a moderate degree of hemorrhage and ROSC occurred early in 11 subjects before any volume resuscitation occurred.

Influence of PCO2 Control on Clinical and Neurodevelopmental Outcomes of Extremely Low Birth Weight Infants.

BACKGROUND: Levels or fluctuations in the partial pressure of CO2 (PCO2) may affect outcomes for extremely low birth weight infants. OBJECTIVES: In an exploratory analysis of a randomized trial, we hypothesized that the PCO2 values achieved could be related to significant outcomes. METHODS: On each treatment day, infants were divided into 4 groups: relative hypocapnia, normocapnia, hypercapnia, or fluctuating PCO2. Ultimate assignment to a group for the purpose of this analysis was made according to the group in which an infant spent the most days. Statistical analyses were performed with analysis of variance (ANOVA), the Kruskal-Wallis test, the χ2 test, and the Fisher exact test as well as by multiple logistic regression. RESULTS: Of the 359 infants, 57 were classified as hypocapnic, 230 as normocapnic, 70 as hypercapnic, and 2 as fluctuating PCO2. Hypercapnic infants had a higher average product of mean airway pressure and fraction of inspired oxygen (MAP × FiO2). For this group, mortality was higher, as was the likelihood of having moderate/severe bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), and poorer neurodevelopment. Multiple logistic regression analyses showed an increased risk for BPD or death associated with birth weight (p < 0.001) and MAP × FiO2 (p < 0.01). The incidence of adverse neurodevelopment was associated with birth weight (p < 0.001) and intraventricular hemorrhage (IVH; p < 0.01). CONCLUSIONS: Birth weight and respiratory morbidity, as measured by MAP × FiO2, were the most predictive of death or BPD and NEC, whereas poor neurodevelopmental outcome was associated with low birth weight and IVH. Univariate models also identified PCO2. Thus, hypercapnia seems to reflect greater disease severity, a likely contributor to differences in outcomes.

Inflammatory Mediators in Tracheal Aspirates of Preterm Infants Participating in a Randomized Trial of Permissive Hypercapnia.

BACKGROUND: Ventilator-induced lung injury is considered to be a main factor in the pathogenesis of bronchopulmonary dysplasia (BPD). Optimizing ventilator strategies may reduce respiratory morbidities in preterm infants. Permissive hypercapnia has been suggested to attenuate lung injury. We aimed to determine if a higher PCO2 target range results in less lung injury compared to the control target range and possibly reduces pro-inflammatory cytokines and acid sphingomyelinase (ASM) in tracheal aspirates (TA), which has not been addressed before. METHODS: During a multicenter trial of permissive hypercapnia in extremely low birthweight infants (PHELBI), preterm infants (birthweight 400-1,000 g, gestational age 23 0/7-28 6/7 weeks) requiring mechanical ventilation within 24 h of birth were randomly assigned to a high PCO2 target or a control group. The high target group aimed at PCO2 values of 55-65, 60-70, and 65-75 mmHg and the control group at PCO2 values of 40-50, 45-55 and 50-60 mmHg on postnatal days 1-3, 4-6, and 7-14, respectively. TA was analyzed for pro-inflammatory cytokines from postnatal day 2-21. BPD was determined at a postmenstrual age of 36 weeks ± 2 days. MAIN FINDINGS: Levels of inflammatory cytokines and ASM were similar in both groups: interleukin (IL)-6 (p = 0.14), IL-8 (p = 0.43), IL-10 (p = 0.24), IL-1ß (p = 0.11), macrophage inflammatory protein 1α (p = 0.44), albumin (p = 0.41), neuropeptide Y (p = 0.52), leukotriene B4 (p = 0.11), transforming growth factor-ß1 (p = 0.68), nitrite (p = 0.15), and ASM (p = 0.94). Furthermore, most inflammatory mediators were strongly affected by the age of the infants and increased from postnatal day 2 to 21. BPD or death was observed in 14 out of 62 infants, who were distributed evenly between both groups. CONCLUSION: The results suggest that high PCO2 target levels did not result in lower pulmonary inflammatory activity and thus reflect clinical results. This indicates that high PCO2 target ranges are not effective in reducing ventilator-induced lung injury in preterm infants, as compared to control targets. TRIAL REGISTRATION: ISRCTN56143743.

Cerebral oxygenation and desaturations in preterm infants - a longitudinal data analysis.

OBJECTIVE: Hypoxemic episodes commonly occur in very preterm infants and may be associated with several adverse effects. Cerebral tissue oxygen saturation (StO2) as measured by near infrared spectroscopy (NIRS) may be a useful measure to assess brain oxygenation. However, knowledge on variability of StO2 is limited in preterm infants at this time, so StO2 dependency on arterial oxygenation (SpO2) and heart rate (HR) was assessed in preterm infants using statistical methods of time series analysis. STUDY DESIGN: StO2, SpO2, and HR were recorded from 15 preterm infants every 2 seconds for six hours. Statistical methods of time series and longitudinal data analysis were applied to the data. RESULT: The mean StO2 level was found as 72% (95% confidence interval (CI) 55.5% -85.5%) based on a moving average process with a 5 minute order. Accordingly, longitudinal SpO2 measurements showed a mean level of 91% (95% CI 69% -98%). Generally, compensation strategies to cope with both StO2 and SpO2 desaturations were observed in the studied patients. SpO2 had a significant effect on cerebral oxygenation (p < 0.001), but HR did not, which led to inconclusive results considering different time intervals. CONCLUSION: In infants with intermittent hypoxemia and bradycardia, we found a mean StO2 level of 72% and a strong correlation with SpO2. We observed large differences between individuals in the ability to maintain StO2 at a stable level.

Permissive hypercapnia for severe acute respiratory distress syndrome in immunocompromised children: A single center experience.

BACKGROUND: Controlled hypoventilation while accepting hypercapnia has been advocated to reduce ventilator-induced lung injury. The aim of the study was to analyze outcomes of a cohort of immunocompromised children with acute respiratory distress syndrome (ARDS) ventilated with a strategy of stepwise increasing PCO2 targets up to 140 mm Hg. METHODS: Retrospective analysis of outcomes of a cohort of children with oncologic disease or after stem cell transplantation and severe respiratory failure in comparison with a historical control cohort. RESULTS: Out of 150 episodes of admission to the PICU 88 children underwent invasive mechanical ventilation for >24h (overall survival 75%). In a subgroup of 38 children with high ventilator requirements the PCO2 target ranges were increased stepwise. Fifteen children survived and were discharged from the PICU. Severe pulmonary hypertension was seen in two patients and no case of cerebral edema was observed. Long term outcome was available in 15 patients and 10 of these patients survived without adverse neurological sequelae. With introduction of this strategy survival of immunocompromised children undergoing mechanical ventilation for >24h increased to 48% compared to 32% prior to introduction (historical cohort). CONCLUSIONS: A ventilation strategy incorporating very high carbon dioxide levels to allow for low tidal volumes and limited inspiratory pressures is feasible in children. Even severe hypercapnia may be well tolerated. No severe side effects associated with hypercapnia were observed. This strategy could potentially increase survival in immunocompromised children with severe ARDS.

Reliability of Pulse Oximetry during Progressive Hypoxia, Cardiopulmonary Resuscitation, and Recovery in a Piglet Model of Neonatal Hypoxic Cardiac Arrest.

BACKGROUND: Pulse oximetry is widely used in intensive care and emergency conditions to monitor arterial oxygenation and to guide oxygen therapy. OBJECTIVE: To study the reliability of pulse oximetry in comparison with CO-oximetry in newborn piglets during progressive hypoxia, cardiac arrest, cardiopulmonary resuscitation (CPR), and after return of spontaneous circulation (ROSC). METHODS: Thirty-three newborn piglets were exposed to hypoxia until asystole occurred and then resuscitated until ROSC. Arterial oxygen saturation was monitored continuously by pulse oximetry (SpO2) with one sensor applied to the wrist of the right forelimb (FL) and another to the thigh of the left hind limb (HL). Arterial functional oxygen saturation (SaO2) was measured at baseline and at predefined intervals during each phase of the experiment. SpO2 was compared with coinciding SaO2 values and bias considered whenever the difference (SpO2 - SaO2) was beyond ±5%. RESULTS: Bias values were lower at the baseline measurements (-3.7 ± 2.3% in FL and -4.1 ± 3.4% in HL) as well as after ROSC (1.5 ± 4.2% in FL and 0.2 ± 4.6% in HL) with higher precision and accuracy than during other experiment phases. During hypoxia induction, cardiac arrest, and CPR, there was a marked decrease in precision and accuracy as well as an increase in bias up to 43 ± 26 and 56 ± 27% in FL and HL, respectively, over a range of SaO2 from 13 to 51%. CONCLUSION: Pulse oximetry showed increased bias and decreased accuracy and precision during marked hypoxemia in a model of neonatal hypoxic cardiac arrest.

Neurodevelopmental outcomes of extremely low birthweight infants randomised to different PCO2 targets: the PHELBI follow-up study.

BACKGROUND: Tolerating higher partial pressures of carbon dioxide (PCO2) in mechanically ventilated extremely low birthweight infants to reduce ventilator-induced lung injury may have long-term neurodevelopmental side effects. This study analyses the results of neurodevelopmental follow-up of infants enrolled in a randomised multicentre trial. METHODS: Infants (n=359) between 400 and 1000 g birth weight and 23 0/7-28 6/7 weeks gestational age who required endotracheal intubation and mechanical ventilation within 24 hours of birth were randomly assigned to high PCO2 or to a control group with mildly elevated PCO2 targets. Neurodevelopmental follow-up examinations were available for 85% of enrolled infants using the Bayley Scales of Infant Development II, the Gross Motor Function Classification System (GMFCS) and the Child Development Inventory (CDI). RESULTS: There were no differences in body weight, length and head circumference between the two PCO2 target groups. Median Mental Developmental Index (MDI) values were 82 (60-96, high target) and 84 (58-96, p=0.79). Psychomotor Developmental Index (PDI) values were 84 (57-100) and 84 (65-96, p=0.73), respectively. Moreover, there was no difference in the number of infants with MDI or PDI <70 or <85 and the number of infants with a combined outcome of death or MDI<70 and death or PDI<70. No differences were found between results for GMFCS and CDI. The risk factors for MDI<70 or PDI<70 were intracranial haemorrhage, bronchopulmonary dysplasia, periventricular leukomalacia, necrotising enterocolitis and hydrocortisone treatment. CONCLUSIONS: A higher PCO2 target did not influence neurodevelopmental outcomes in mechanically ventilated extremely preterm infants. Adjusting PCO2 targets to optimise short-term outcomes is a safe option. TRIAL REGISTRATION NUMBER: ISRCTN56143743.

Inflammatory Mediators in Tracheal Aspirates of Preterm Infants Participating in a Randomized Trial of Inhaled Nitric Oxide.

BACKGROUND: Ventilated preterm infants frequently develop bronchopulmonary dysplasia (BPD) which is associated with elevated inflammatory mediators in their tracheal aspirates (TA). In animal models of BPD, inhaled nitric oxide (iNO) has been shown to reduce lung inflammation, but data for human preterm infants is missing. METHODS: Within a European multicenter trial of NO inhalation for preterm infants to prevent BPD (EUNO), TA was collected to determine the effects of iNO on pulmonary inflammation. TA was collected from 43 premature infants randomly assigned to receive either iNO or placebo gas (birth weight 530-1230 g, median 800 g, gestational age 24 to 28 2/7 weeks, median 26 weeks). Interleukin (IL)-1ß, IL-6, IL-8, transforming growth factor (TGF)-ß1, interferon γ-induced protein 10 (IP-10), macrophage inflammatory protein (MIP)-1α, acid sphingomyelinase (ASM), neuropeptide Y and leukotriene B4 were measured in serial TA samples from postnatal day 2 to 14. Furthermore, TA levels of nitrotyrosine and nitrite were determined under iNO therapy. RESULTS: The TA levels of IP-10, IL-6, IL-8, MIP-1α, IL-1ß, ASM and albumin increased with advancing postnatal age in critically ill preterm infants, whereas nitrotyrosine TA levels declined in both, iNO-treated and placebo-treated infants. The iNO treatment generally increased nitrite TA levels, whereas nitrotyrosine TA levels were not affected by iNO treatment. Furthermore, iNO treatment transiently reduced early inflammatory and fibrotic markers associated with BPD development including TGF-ß1, IP-10 and IL-8, but induced a delayed increase of ASM TA levels. CONCLUSION: Treatment with iNO may have played a role in reducing several inflammatory and fibrotic mediators in TA of preterm infants compared to placebo-treated infants. However, survival without BPD was not affected in the main EUNO trial. TRIAL REGISTRATION: NCT00551642.

Tidal Volume Delivery and Endotracheal Tube Leak during Cardiopulmonary Resuscitation in Intubated Newborn Piglets with Hypoxic Cardiac Arrest Exposed to Different Modes of Ventilatory Support.

BACKGROUND: There are few data available on the interaction of inflations, chest compressions (CC), and delivery of tidal volumes in newborn infants undergoing resuscitation in the presence of endotracheal tube (ET) leaks. OBJECTIVES: To determine the effects of different respiratory support strategies along with CC on changes in tidal volume and ET leaks in hypoxic newborn piglets with cardiac arrest. METHODS: Asphyxiated newborn piglets, intubated with weight-adapted uncuffed ET, were randomized into three groups and resuscitated according to ILCOR 2010 guidelines: (1) T-piece resuscitator (TPR) group = peak inspiratory pressure (PIP)/positive end-expiratory pressure (PEEP) 25/5 cm H2O, rate 30/min, inflations interposed between CC (3:1 ratio); (2) self- inflating bag (SIB) group = PIP 25 cm H2O without PEEP, rate 30/min, inflations interposed between CC (3:1 ratio), and (3) ventilator group = PIP/PEEP of 25/5 cm H2O, rate 30/min. CC were applied with a rate of 120/min without synchrony to inflations. RESULTS: We observed a significant increase of leak (average increase 11.4%) when CC was added to respiratory support (p = 0.0001). Expired tidal volume was larger in the SIB group than in the two other modes which both applied PEEP. However, tidal volumes caused by CC only were larger in the two groups with PEEP than in the SIB group (without PEEP). CONCLUSIONS: There is interaction between lung inflations and CC affecting leak and delivery of tidal volume, which may be influenced by the mode/device used for respiratory support. Leak is larger in the presence of PEEP. However, CC cause additional tidal volume which is larger in the presence of PEEP.

Mortality and Major Morbidity of Very-Low-Birth-Weight Infants in Germany 2008-2012: A Report Based on Administrative Data.

BACKGROUND: Expectant parents of very preterm infants, physicians, and policy makers require estimates for chances of survival and survival without morbidity. Such estimates should derive from a large, reliable, and contemporary data base of easily available items known at birth. OBJECTIVE: To determine short-term outcome and risk factors in very-low-birth-weight preterm infants based on administrative data. METHODS: Anonymized routine data sets transmitted from hospital administrations to statutory health insurance companies were used to assess survival and survival free of major morbidities in a large cohort of preterm infants in Germany. RESULTS: After exclusion of infants with lethal malformations, there were 13,147 infants with a birth weight below 1,500 g admitted to neonatal care 2008-2012, of whom 1,432 infants (10.9%) died within 180 days. Estimated 180 days survival probabilities were 0.632 (95% confidence interval 0.583-0.677) for infants with 250-499 g birth weight, 0.817 (0.799-0.834) for 500-749 g, 0.931 (0.920-0.940) for 750-999 g, 0.973 (0.967-0.979) for 1,000-1,249 g, and 0.985 (0.981-0.988) for 1,250-1,499 g. Estimated probabilities for survival without major morbidity (surgically treated intraventricular hemorrhage, necrotizing enterocolitis, intestinal perforation, or retinopathy) were 0.433 (0.384-0.481) for 250-499 g, 0.622 (0.600-0.643) for 500-749 g, 0.836 (0.821-0.849) for 750-999 g, 0.938 (0.928-0.946) for 1,000-1,249 g, and 0.969 (0.964-0.974) for 1,250-1,499 g, respectively. Prediction of survival and survival without major morbidities was moderately improved by adding sex, small for gestational age, and severe or moderate congenital malformation, increasing receiver operating characteristic areas under the curve from 0.839 (0.827-0.850) to 0.862 (0.852-0.874) (survival) and from 0.827 (0.822-0.842) to 0.852 (0.846-0.863) (survival without major morbidities), respectively. CONCLUSION: The present analysis encourages attempts to use administrative data to investigate the association between risk factors and outcome in preterm infants.