Background and objectives Delivery of inadvertent high tidal volume (VT) during positive pressure ventilation (PPV) in the delivery room is common. High VT delivery during PPV has been associated with haemodynamic brain injury in animal models. We examined if VT delivery during PPV at birth is associated with brain injury in preterm infants <29 weeks’ gestation.
Methods A flow-sensor was placed between the mask and the ventilation device. VT values were compared with recently described reference ranges for VT in spontaneously breathing preterm infants at birth. Infants were divided into two groups: VT<6 mL/kg or VT>6 mL/kg (normal and high VT, respectively). Brain injury (eg, intraventricular haemorrhage (IVH)) was assessed using routine ultrasound imaging within the first days after birth.
Results A total of 165 preterm infants were included, 124 (75%) had high VT and 41 (25%) normal VT. The mean (SD) gestational age and birth weight in high and normal VT group was similar, 26 (2) and 26 (1) weeks, 858 (251) g and 915 (250) g, respectively. IVH in the high VT group was diagnosed in 63 (51%) infants compared with 5 (13%) infants in the normal VT group (P=0.008).
Severe IVH (grade III or IV) developed in 33/124 (27%) infants in the high VT group and 2/41 (6%) in the normal VT group (P=0.01).
Conclusions High VT delivery during mask PPV at birth was associated with brain injury. Strategies to limit VT delivery during mask PPV should be used to prevent high VT delivery.
- delivery room
- neonatal resuscitation
- brain injury
- respiratory functions tests
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What is already known on this topic?
Delivery of inadvertent high tidal volume during mask ventilation in the delivery room is common.
Delivery of high tidal volumes during mask ventilation has been associated with haemodynamic brain injury in animal models.
What this study adds?
Delivery of high tidal volumes during mask ventilation at birth was associated with brain injury.
Strategies to limit delivery of high tidal volume during mask ventilation are needed to reduce potential brain injury.
If infants fail to initiate breathing at birth, positive pressure ventilation (PPV) is recommended to ensure a successful transition to newborn life.1 The purpose of PPV is to establish a functional residual capacity, deliver an adequate tidal volume (VT), initiate spontaneous breathing and facilitate gas exchange, while minimising lung injury.2 During PPV, a fixed pressure is chosen with the assumption this will deliver an adequate VT.3 4 However, the VT is rarely measured and high VTs are often delivered.3 5–7 Several animal studies have demonstrated that PPV with VTs>8 mL/kg causes lung inflammation and lung injury.8–11 Although this has been recognised by an increased use of volume-targeted ventilation in the neonatal intensive care units (NICU),12 13 the same emphasis has not been employed in the delivery room.14–17 Several observational delivery room studies have reported that high VTs are frequently delivered during mask PPV,3–6 which can be limited when a respiratory function monitor is used.7 The delivery of excessive VTs potentially causes hypocarbia,18 which is associated with white matter injury including periventricular leukomalacia (PVL).19 Furthermore, several animal studies have demonstrated that excessive VT delivery during PPV in the delivery room causes brain inflammation and injury.20–23 The pathways by which PPV causes brain inflammation and brain injury include (1) altered pulmonary venous return and left ventricular output resulting in rapid abnormal fluctuations to cerebral blood flow, (2) fluctuations in blood pressure due to variable VT during PPV,24 (3) initiation of pulmonary inflammation, which initiates a systemic and subsequent cerebral inflammatory cascade and (4) a sudden rather than gradual increase in oxygen delivery causing a vascular response in the brain.22 Animal studies using premature lambs by Polglase et al 20 22 and Skiӧld et al 21 demonstrate that VTs>8 mL/kg cause brain inflammation and brain injury which is evident within 90 min after initiation of PPV. However, no study has examined the association between VT and brain injury in preterm infants.
We recently described that the 50th percentile for spontaneous VT in preterm infants during mask Continuous positive airway pressure (CPAP) ranged from 4.2 to 5.8 mL/kg immediately after birth.25 We aimed to examine if preterm infants <29 weeks’ gestation receiving PPV in the delivery room with high VTs at birth have a higher incidence of brain injury compared with those receiving lower VT. We hypothesised that preterm infants <29 weeks’ gestation at birth who receive PPV with VT>6 mL/kg have higher rates of brain injury compared with PPV with VT<6 mL/kg.25
Patients and methods
Patients and setting
This observational study was carried out between July 2013 and June 2015 at The Royal Alexandra Hospital, Edmonton, Canada, a tertiary perinatal centre admitting ~350 infants with a birth weight of <1500 g and ~200 infants with a <29 weeks gestation to the neonatal nursery. Written deferred parental consent was obtained for chart abstraction after delivery. During the study, the research team attended deliveries of preterm infants <32 weeks gestation in addition to the Resuscitation-Stabilization-Triage team (usually a neonatal nurse, neonatal respiratory therapist, neonatal nurse practitioner or neonatal fellow and a neonatal consultant). The research team was not involved in the clinical care of the infants.
The study was limited to preterm infants <29 weeks’ gestational age who received PPV at birth for a duration of at least 120 s. Preterm infants who received only continuous positive airway pressure, PPV for <120 s, chest compressions or epinephrine during delivery room stabilisation were excluded.
Delivery room stabilisation
At the Royal Alexandra Hospital, all preterm infants receive delayed cord clamping for 60 s if deemed appropriate by the obstetric team.26 Furthermore, preterm infants received antenatal steroids by the obstetric team if time permits (eg, no antenatal steroids if emergency caesarean section due to maternal or fetal compromise). Immediately after delivery, infants were placed (without drying) in a polyethylene bag under a radiant heat. Respiratory support was started with 30% oxygen and titrated to target reference SpO2 according to the 2010 neonatal resuscitation guidelines.27 If PPV was required, a round silicone facemask (Fisher & Paykel Healthcare, Auckland, New Zealand) was used. PPV was provided with a T-piece device (Giraffe Warmer, GE Health care, Burnaby, Canada), which is a continuous flow, pressure-limited device with a built-in manometer and a positive end expiratory pressure valve. The default settings used were a gas flow of 8 L/min, peak inflation pressure of 24 cm H2O and positive end-expiratory pressure of 6 cm H2O. Staff members attending deliveries (Resuscitation-Stabilization-Triage team) were trained to use the devices.28
A respiratory profile monitor (NM3, Philips Healthcare, Electronics, Markham, Ontario, Canada) was used to continuously measure VT, airway pressures, gas flow and expired CO2. Airway pressure and gas flow were measured using fixed orifice differential pressure pneumotachometer. VT was calculated by integrating the flow signal. Expired CO2 was measured using non-dispersive infrared absorption technique.29 30 According to the manufacturer, the accuracy for the gas flow is ±0.125 L/min and for exhaled CO2 ±2 mm Hg. In the delivery room, the respiratory profile monitor was visible to the resuscitation team.
IntelliVue MP50 (Philips Healthcare) was used to continuously measure heart rate, oxygen saturation and blood pressure. A Masimo Radical pulse oximeter probe (Masimo, Irvine, California, USA), set at maximum sensitivity and two second averaging, was placed around the infant’s right wrist to measure oxygen saturation. Heart rate was measured using three Micro-Premie Leads (Vermed, Bellows Falls, Vermont, USA) and blood pressure using a non-invasive blood pressure cuff of appropriate size on the left upper arm. The left upper arm was chosen to avoid interference with the pulse oximetery measurements.
An Invos Cerebral/Somatic Oximeter Monitor (Invos 5100, Somanetics, Troy, Michigan, USA) with the neonatal sensor was used to measure cerebral tissue oxygen saturation. A transducer contains a light emitting diode and two sensors using two light paths to confirm readings. The Invos Cerebral/Somatic Oximeter Monitor calculates the cerebral tissue oxygen saturation, which is expressed as the percentage of oxygenated haemorrhage (oxygenated haemorrhage/total haemorrhage). The transducer was positioned on the left frontoparietal forehead in each infant regardless of mode of delivery. The sensor on the forehead was secured with a wrap.
All variables were stored continuously in a multichannel system ‘alpha-trace digital MM’ (B.E.S.T. Medical Systems, Austria) for subsequent analysis. Values of gas flow, VT and airway pressure were recorded at 200 Hz; arterial and cerebral tissue oxygen saturation and heart rate were stored every second and the sample rate of cerebral tissue oxygen saturation was 8 s (0.13 Hz). Blood pressure was measured every minute. Outcome data were collected on a case report form. Intraventricular haemorrhage (IVH) was defined according to Papile scoring system31 and divided into grade I (subependymal, germinal matrix haemorrhage), grade II (IVH without ventricle dilatation), grade III (IVH with ventricle dilatation) and grade IV (IVH with parenchymal extension). Hydrocephalus following IVH was defined as either communicating or non-communicating.
Demographics of study infants were recorded. A breath-by-breath analysis of airway pressure, gas flow and VT was performed and the expired VT of all inflations was measured. Mask leak was calculated from the mask by expressing the volume of gas that did not return through the flow sensor during expiration as a percentage of the volume that passed through the flow sensor during inflation.6 PPV with a mask leak >30% was excluded from further analysis as this had the potential to underestimate measured expired VT.32 VT was assessed for the duration of mask ventilation in the delivery room and infants divided into two groups VT<6 mL/kg or VT>6 mL/kg according to our previous study of normal VT ranges in spontaneously preterm infants. Regional cerebral fractional tissue oxygen extraction was calculated for each minute ((oxygen saturation – cerebral tissue oxygen saturation)/oxygen saturation).33 According to our local hospital policy, cranial ultrasounds are performed around day 3 after birth and graded according to the classification of Papile.31 The data are presented as mean (SD) for normally distributed continuous variables and median (IQR) when the distribution was skewed. Data were compared using Student’s t-test for parametric and Mann-Whitney U test for non-parametric comparisons of continuous variables and Fisher’s Exact test for categorical variables. P values are two-sided and P<0.05 was considered statistically significant. Statistical analyses were performed with Stata (Intercooled 10, Stata, Texas, USA) and figures were created using Prism GraphPad (GraphPad Software, La Jolla, USA).
During the study period, a total of 218 deliveries of preterm infants at <29 weeks’ gestation were attended by the research team. A total of 200 preterm infants <29 weeks required mask PPV, while 18 only required continuous positive airway pressure and were excluded from further analysis. From the 200 infants eligible, 10 were excluded because parents declined consent, the recording malfunctioned in 12 infants and PPV was <120 s in 13 infants, which left 165 infants for analysis. Infant demographics are presented in table 1. A total of 86 (52%) of infants were intubated in the delivery room, and none received chest compressions or epinephrine. PPV was started at a median 40 (25–75) s after delayed cord clamping, and a total of 11 264 inflations were analysed and a total of 4167 inflations were excluded because of mask leak >30%.
Overall, 124 (75%) infants were ventilated with a mean VT>6 mL/kg compared with 41 (25%) ventilated with a mean VT<6 mL/kg. The median (range) VT in the VT<6 mL/kg group and in the VT>6 mL/kg group was 5.3 (4.6-5.7) mL/kg and 8.7 (7.3-10.6) mL/kg, respectively (P<0.0001) (figure 1).
Overall, IVH in infants receiving VT>6 mL/kg during PPV was diagnosed in 63 (51%) infants compared with 5 (13%) infants receiving VT<6 mL/kg (P=0.008). IVH rates in the VT>6 mL/kg group were 30/63 IVH grade I, 8/63 IVH grade II, 3/63 IVH grade III and 22/63 IVH grade IV. In comparison, in the VT<6 mL/kg group 2/41 had IVH grade I, 1/41 had IVH grade II and 2/41 had IVH grade IV.
Severe IVH (grade III or IV) developed in 33/124 (27%) infants in the VT>6 mL/kg group and 2/41 (6%) in the VT<6 mL/kg group (P=0.01).
Hydrocephalus as a consequence of IVH developed in 7/49 (14%) and 2/16 (13%) in the >6 mL/kg and <6 mL/kg VT group (P=0.756), respectively.
Delivery room physiological parameter
Values of oxygen saturation, heart rate, cerebral oxygenation, fraction of inspired oxygen and blood pressure are presented in table 2. Oxygen saturation was significantly lower in the VT<6 mL/kg group at 6, 13 and 14 min after birth compared with the VT>6 mL/kg group (P<0.001). Cerebral tissue oxygen saturation was significantly lower in the VT<6 mL/kg group at 7, 8 and 25 min after birth (P<0.001). Conversely, heart rate was significantly lower in the VT>6 mL/kg group at 5, 20 and 25 min after birth (P<0.001). Fraction of inspired oxygen was similar in both groups within the first 30 min. Systolic, diastolic and mean blood pressure was similar between the groups.
There were no significant differences between the infants intubated either in the delivery room or within 72 hours of admission the NICU between groups. Within the VT>6 mL/kg a total of 26 infants were intubated in the delivery room and a further 30 infants were intubated within the first 72 hours after admission to the NICU. In the VT<6 mL/kg group, a total of 6 and 8 infants were intubated delivery room and the NICU, respectively. Within the first hour after birth, a blood gas was taken for respiratory assessment. The median (IQR) Pco2 was 55 (46–77) mm Hg and 61 (46–78) mm Hg in the high and normal VT group (P=0.796), receptively. The median (IQR) Po2 was 60 (51–73) mm Hg and 57 (49–67) mm Hg in the high and normal VT group (P=0.592), receptively. A total of 22 (18%) and 8 (19%) in the high and normal VT group received indomethacin prophylaxis (P=1.000), respectively. During their NICU admission, a total of 47 (38%) in the high VT group and 28 (69%) in the normal VT group received circulatory support with volumes boluses (P=0.04). Thirty-six (29%) in the high VT group and 21 (50%) in the normal VT group (P=0.137) received dopamine, 4 in each group received dobutamine and 2 in each group received epinephrine. Number of infants who died during hospital admission was similar between the high and normal VT group 20 (16%) and 8 (19%), respectively.
Moderate-to-severe IVH remains a persistent challenge and is associated with neurological sequelae34; 50%–75% of preterm survivors with parenchymal lesions develop cerebral palsy, mental retardation and/or hydrocephalus.34 35 Several factors have been identified to cause brain injury including (1) cerebral blood flow, (2) cerebral regional oxygenation,36 37 (3) cerebral oxygen extraction,38 39 (4) superior vena cava flow,40 (5) mean arterial blood pressure41 and (6) perfusion index.42 In addition, Oei et al reported that not reaching SpO2 levels of 80% at 5 min is associated with adverse outcomes, including IVH.43 Baik et al 36 reported that preterm infants <32 weeks gestation who developed IVH had significantly lower cerebral tissue oxygen saturation during the immediate transition compared with preterm infants not developing IVH.36 However, in the current study infants with VT>6 mL/kg had higher cerebral tissue oxygen saturation compared with infants with VT<6 mL/kg (table 2). This suggests that cerebral tissue oxygen saturation was not a contributing factor for IVH development in our study. Similar, oxygen saturation was similar between groups. Other studies reported higher cerebral oxygenation extraction40 and correlations of mean arterial blood pressure with cerebral oxygen extraction (ρ=–0.19, P=0.03) as a mechanism for cerebral damage.41 We did not observe any difference in arterial blood pressure, and cerebral oxygenation extraction was higher in the VT>6 mL/kg group. This suggests that neither was a factor for IVH development.
A recent Cochrane review reported that volume-targeted ventilation in the NICU significantly reduces grade 3/4 IVH or PVL when compared with pressure-limited ventilation (relative risk 0.48 (95% CI 0.28 to 0.84), risk difference −0.09 (95% CI −0.15 to −0.02)).34 However, this has not been assessed during neonatal resuscitation in the delivery room. We recently reported that infants who were only supported with CPAP in the delivery room had VT<6 mL/kg and a low rate of IVH.25 In the current study, we observed an association between VT delivery and IVH in preterm infants during mask PPV in the delivery room. We observed significant higher rates of IVH in infants <29 weeks’ gestation who received mask PPV with VT>6 mL/kg.
Polglase et al reported that PPV with high VT (12–15 mL/kg) during initial resuscitation alters cerebral haemodynamics and increases brain inflammation, oxidative stress and vascular extravasation compared with using a protective tidal volume strategy.20 Vascular extravasation is an early indicator of cerebrovascular break-down and a marker of haemorrhage. Using MRI Skiöld et al reported acute changes in diffusion measures and metabolite peak-area ratios in preterm lambs ventilated with an injuriously protocol (VT~12 mL/kg and no Positive end-expiratory pressure (PEEP) compared with a protective ventilation strategy.21 These pathologies were evident within 90 min after initiation of PPV and are likely to contribute to permanent brain injury.20 21 In our cohort, 51% of infants who received mask PPV with VT>6 mL/kg showed signs of brain injury on ultrasound, while these signs were only identified in 13% of infants receiving VT<6 mL/kg group. These findings are consistent with that of animal studies showing that high VTs in the DR can cause cerebrovascular injury resulting in increased incidence and severity of injury. Indeed, IVH grade III or IV were observed in 27% and 6% of infants in the >6 mL/kg and <6 mL/kg VT group, respectively.
Initiation of ventilation causes brain pathology through the same two mechanistic pathways, which are key to perinatal brain injury: haemodynamic instability and a localised cerebral inflammatory response.44 In the delivery room, pressure-limited ventilation is predominately used resulting in large variable VT deliveries.3–6 Schmölzer et al reported that VT delivery during PPV could vary between 1 and 30 mL/kg4. Large tidal volume delivery during PPV can cause overdistension of the preterm lungs within minutes after birth,9 followed by compression of alveolar capillaries leading to pulmonary haemodynamic instability. This alters pulmonary venous return and cardiac output, which results in large swings in cerebral blood flow.45–47 Furthermore, PPV and PEEP induce variability in intrathoracic pressure, which affects preload, afterload and myocardial contractility causing changes in cerebral hemodynamics.44 Preterm infants <1500 g have impaired autoregulation due to their cerebral immaturity, which can cause hypoxia/ischaemia (if cerebral blood flow is low) or cerebral haemorrhage (if cerebral blood flow is high or rapidly fluctuating between low and high flows).48 Hypoxia has been recently associated with the development IVH in preterm infants.36 37 Unfortunately, our set-up does not allow cerebral blood flow monitoring,49 which is a limitation of the study.
Until now, only one small randomised controlled trial reported on high with lower VT in the delivery room.7 In 49 infants, no difference in IVH was reported; however, the targeted VT was between 4 and 8 mL/kg7, which is considerably higher compared with the cut-off in the current study. Indomethacin has been shown to reduce severe IVH,50 and the percentage of indomethacin prophylaxis was similar in our study and therefore not the cause for the increased rate of IVH.
Using cranial ultrasonography to assess brain injury has some advantages and also some disadvantages, which is a limitation of the current study. Cranial ultrasonography is easy to use at the bedside, has the ability to perform serial studies, is cost effective and is sensitive in detecting IVH (including those with focal parenchymal lesions), ventriculomegaly and focal cystic PVL.51 However, it has a significantly lower sensitivity in detecting white matter injury, especially compared with MRI.51 In addition, identifying inflammation or vascular leakage using cranial ultrasonography is impossible.51 Using MRI to assess the extent of grey and white matter injury would have potentially yielded different results; however, performing MRI immediately after delivery room resuscitation was not feasible in our hospital settings. Also, there were a significantly higher number of infants receiving catecholamines (including dopamine, dobutamine or epinephrine infusion) in the VT>6 mL/kg group. As we do not know the timing of the IVH, the higher catecholamine rates might have contributed to the higher IVH rates in the VT>6 mL/kg group.
Preterm infants ≤29 weeks’ gestation receiving mask PPV with VT>6 mL/kg have a significantly higher incidence of IVH compared with infants receiving mask ventilation with VT<6 mL/kg. Further studies are needed to examine techniques to reduce the incidence of brain injury in these infants.
We would like to thank the parents and infants agreeing to be part of the study. We would like to thank the Resuscitation-Stabilization-Triage team at the Royal Alexandra Hospital for helping and supporting the study. We would also like to thank the public for donation to our funding agencies.
Contributors QM was involved in data collection, analysis and interpretation. He also wrote the first draft and performed revisions of the drafted article and approved the final version of the manuscript for submission. P-YC, MO and GMS were involved in the conception and design of the study. They were also involved in data collection, analysis and interpretation and performed critical revisions of the drafted article and approved the final version of the manuscript for submission. GRP and SKB were involved in the conception and design of the study. They were also involved in data analysis and interpretation and performed critical revisions of the drafted article and approved the final version of the manuscript for submission.
Funding QM was supported by a Summer Studentship of Women’s and Children Research Institute. GRP is supported by a NH&MRC and National Heart Foundation Career Development Fellowship (1105526). SKB is supported by an ARC/NMRC fellowship (1110040). GMS is a recipient of the Heart and Stroke Foundation/University of Alberta Professorship of Neonatal Resuscitation and a Heart and Stroke Foundation Canada and a Heart and Stroke Foundation Alberta New Investigator Award. This research has been facilitated by the Women and Children’s Health Research Institute through the generous support of the Stollery Children’s Hospital Foundation.
Disclaimer The authors have no financial relationships relevant to this article to disclose. No current funding source for this study. The funder had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
Competing interests None declared.
Ethics approval The Neonatal Research Committee, Northern Alberta Neonatal Program and Health Research Ethics Board, University of Alberta approved the study.
Provenance and peer review Not commissioned; externally peer reviewed.
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