Article Text
Abstract
Objective T-piece resuscitation systems are pressure unstable and have high imposed work of breathing (iWOB). Pressure stable respiratory support with low iWOB might improve outcome. We have developed a new resuscitation system that can be used with nasal prongs or face mask. The aim of the study was to describe the in vitro performance of the new system and to perform a clinical feasibility trial of initial stabilisation of preterm infants.
Method A mechanical lung model was used to determine iWOB at increasing levels of continuous positive airway pressure (CPAP). The feasibility trial included 36 infants (27–34 weeks of gestation), who were randomised into three groups (T-piece, new system with face mask or new system with prongs). Collected data included problems with usage, safety, time to stable breathing, need for positive pressure ventilation and intubation.
Results In the mechanical lung model, the new system reduced iWOB with 91.5% (mask) and 86.6% (medium prongs) compared with Neopuff (4 cm CPAP, p<0.001). Informed consent was obtained from 45 patients, 39 were randomised and 36 needed support. Randomisation resulted in an imbalance: The group of new system infants had lower gestational age compared with the T-piece group. Thirteen patients needed positive pressure ventilation (median 20 cm H2O). One infant was intubated. The study did not reveal problems with the equipment or safety.
Conclusions Compared with T-piece systems, the new system had a marked reduction in iWOB in bench tests. The feasibility trial did not reveal problems with usability or safety.
- Resuscitation
- Continuous positive airway pressure
- Infant, premature
- Positive pressure ventilation
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What is already known on this topic?
Continuous positive airway pressure delivered with T-piece systems is not pressure stable and has high imposed work of breathing (iWOB).
The International Liaison Committee on Resuscitation 2010 consensus document states that prongs may be a more effective interface than face mask.
There are few alternatives to T-piece systems and the clinical importance of pressure stability is not known.
What this study adds?
The new system is pressure stable and can be used with prongs or face mask.
A clinical feasibility trial revealed no problems with usage.
Trials on the clinical effect of iWOB and type of interface are now possible.
Introduction
The initial management of premature infants has evolved towards less invasive management.1 The benefit of non-invasive management was first noted in observational studies2 ,3 and then in a randomised trial, the COIN trial.4 Less invasive care has been further studied in trials such as the VON, CURPAP and SUPPORT.5 The International Liaison Committee on Resuscitation (ILCOR) consensus document and the European Guidelines for the treatment of respiratory distress syndrome (RDS) recommend using continuous positive airway pressure (CPAP) rather than intubation and mechanical ventilation for initial stabilisation of spontaneously breathing preterm infants with respiratory distress.6 ,7
The ILCOR consensus document from 2010 gives several options for respiratory support after delivery.8 The algorithm aims at establishing stable spontaneous breathing and includes positive pressure ventilation (PPV), if the infant is not breathing and the option to use CPAP to facilitate breathing or ventilation. The document also discusses use of nasal prongs instead of a facemask as the patient interface. The effect of different CPAP systems, the CPAP level and the effect of using different patient interfaces has been insufficiently studied.9
CPAP during resuscitation has been suggested to be beneficial and has been tested in several clinical trials.8 However, when supporting a breathing infant with CPAP, the infant will be challenged with the additional workload that is needed to breathe through the support system. The extra work, imposed work of breathing (iWOB), can be measured by calculating the area within the pressure-volume (work) loop of a spontaneous breath. A system that can maintain stable CPAP during expiration and inspiration will have small pressure changes, a narrow loop and low iWOB.10
The iWOB has been suggested to be an important factor for treatment failure and subsequent need for intubation.11 In our previous bench study, the system for resuscitation (T-piece) was shown to have high iWOB.12 A method for providing respiratory support with CPAP with lower iWOB might reduce treatment failure and the subsequent need for intubation.
The interface used to provide ventilatory support has been highlighted as an area for research.9 A trial comparing initial stabilisation with nasal prongs or face mask in mostly term infants showed better results for the nasal prong interface.13 In spite of these results and the ILCOR 2010 consensus document statement, that nasal prong ventilation during initial stabilisation is an option, the standard of care has remained using a face mask. Two randomised trials have investigated interfaces for T-piece systems.14 ,15 They could not find differences when comparing a face mask interface and a single cut endotracheal tube (nasopharyngeal prong) interface. The interventions used in these trials have high iWOB (the cut endotracheal tube interface will add resistance and increase iWOB) and this could have affected the clinical outcome. The updated ILCOR 2015 consensus document does not mention patient interface.6
A new system for respiratory support has been developed in Östersund and at the Karolinska University Hospital, Sweden. The new system is handled in a similar way to the standard care T-piece system with delivery of PPV by occlusion at an aperture on the device (figure 1). The new system was designed to have a marked reduction in iWOB and also to allow the use of short binasal prongs as the patient interface. The aim of the study was to describe the in vitro performance of the new system and to perform a clinical feasibility trial, comparing a T-piece system with face mask, and the new system with face mask or nasal prongs, for initial stabilisation of preterm infants.
Methods
The new resuscitation system
The new resuscitation system (figure 1) is driven by two flows. The two flows are adjusted to give a fresh gas flow equal to flows used for T-piece systems and the ratio between the flows controls and the CPAP level. The flow in the thin line (jet flow) drives the CPAP generator. The flow in the bias line (10 mm corrugated tube) is added in front of the CPAP generator and is needed in order to give a total flow that generates acceptable inspiratory rise time during PPV. The pressure in the system is limited by an adjustable pressure limiting (APL) valve connected to the bias line. The system can be used with short binasal prongs (referred to as nasal prongs), as shown in figure 1, or a face mask (15 mm connector replaces the nasal prongs connector). PPV is obtained by occluding the system. In the same way as for T-piece systems, the pressure rises until the APL valve opens. CPAP during spontaneous breathing (and positive end expiratory pressure (PEEP) during PPV) is generated by the same method as used in the nasal CPAP system designed by Moa et al. The new system was optimised for pressure stability and iWOB at fresh gas flows 8–15 L/min and CPAP at 4–5 cm H2O. The performance of the new system and the reduction in iWOB seen at higher CPAP levels was highly dependent on manufacturing quality. The system was designed by Kjell Nilsson (one of the inventors of the original Infant Flow) and Thomas Drevhammar (coauthor). The researchers at the Karolinska University Hospital provided clinical feedback on design and function of prototypes during the development.
Mechanical lung simulations
To simulate spontaneous breathing and perform dynamic measurements, a mechanical lung model (ASL 5000, IngMar Medical, Pittsburg, Pennsylvania, USA) was used. The setup was similar to the one used by Drevhammar et al12 in an earlier study. The mechanical lung model generates flow by a motor-driven piston with an integrated pressure transducer for pressure recording. To simulate spontaneous breathing, a simple non-compliant flow pump mode was used. The accuracy of volumes and pressures recorded by the lung model were evaluated using a fixed volume syringe and a calibrated pressure transducer (VT PLUS HF, Fluke Biomedical, Everett, Washington, USA).
The systems were fitted to a standard 22 mm connector attached to the mechanical lung model. A fresh gas flow of 10 L/min was used (unheated and unhumidified air). Two sinusoidal flow profiles were used (I:E 1:1 and RR 60) with a flow maximum of 3 L/min (16 mL tidal volume (TV)) and 6 L/min (32 mL TV). The two T-piece resuscitator systems tested were Neopuff (Fisher and Paykel, Auckland, NZ) and a T-piece system from GE Healthcare (Little Chalfont, UK). The new system was tested with face mask and with nasal prongs. In simulation with nasal prongs (from Infant Flow, CareFusion, Yorba Linda, California, USA), size medium was used for 16 mL TV and size large for 32 mL TV.
After starting the lung simulator, the CPAP was gradually increased from as low as possible to approximately 10 cm H2O. Pressure stability was measured for individual breaths in the range 2.5–9.5 cm CPAP with data compiled in 1 cm CPAP intervals. iWOB was calculated for each breath from the area within the pressure volume loop (modified ASL V.3.1 software).
Data were compiled using Microsoft Excel 2007 (Microsoft, Redmond, Washington, USA) and analysed in PASW Statistics 23 (IBM, Armonk, New York, USA). Data were presented as means with 95% CI. Comparison of means was analysed with analysis of variance (ANOVA) and post hoc tests corrected for multiple comparisons (α=0.05 before Bonferroni correction). p Values <0.05 were considered to be statistically significant.
Clinical feasibility trial
Patients were recruited at two neonatal units of the Karolinska University Hospital, Sweden (Solna and Danderyd) between June 2012 and April 2015. Mothers who were admitted with threatened preterm labour (gestational age of 27–34 weeks by ultrasound) were approached for consent. Parents who consented to participation were randomised to one of three treatments (T-piece system with face mask, new system with face mask or new system with prongs) by sealed opaque envelopes when birth was imminent. The 36 patients were randomised to 12 patients in each arm (one block of 36) and not stratified. The trial was not designed to estimate treatment effects and no power calculations were performed. If a patient did not need respiratory support, a new identical envelope was used for recycling the assignment note. The envelope was sealed and returned into the pile by a person not involved in the trial.
Patients received CPAP (4 cm H2O) with the randomised system for until at least 10 min of age and PPV (20 cm H2O peak inspiratory pressure and 4 cm H2O PEEP) when needed. The intervention ended when patients had established stable spontaneous breathing and were transferred to the neonatal intensive care unit (NICU). If patients did not respond to non-invasive PPV they were intubated. If there were problems with the new system during stabilization, the use of backup equipment was allowed (T-piece or self-inflating bag). The mouth was gently closed in infants treated with nasal prongs. The clinicians involved in the trial were six neonatologists and one paediatrician in subspecialty training. Apgar score, time to spontaneous breathing, time to 90% SpO2 and PPV was registered during resuscitation by a nurse or medical doctor. The need for surfactant, respiratory support and development of pneumothoraxes in the first 72 hours was obtained from medical records.
The trial was approved by the regional ethics committee (Stockholm, Sweden 2012/148–31/4).
Data from the clinical trial were analysed in PASW Statistics 23 (IBM). Normal distribution was tested with Shapiro-Wilk test. Normal distributed data were presented as mean (SD) and differences were tested with ANOVA. Non-normal distributed data were presented as median with inter quartile range and differences were tested with Kruskall-Wallis test. Nominal data were tested with Fisher’s exact test. p Values <0.05 were considered to be statistically significant.
Results
Mechanical lung simulations
The pressure stability of the new systems (with prongs and face mask) compared with the T-piece systems are presented as total iWOB in figure 2A (16 mL TV) and 2b (32 mL TV). Examples of pressure volume loops are presented in figure 3. Complete data including pressure swings and total iWOB divided into inspiratory and expiratory iWOB are available as supplemental digital content (see online supplementary tables 1 and 2) including statistical comparisons.
Supplementary tables
The new system had a marked reduction in iWOB and increased pressure stability. For example, at 4 cm H2O CPAP and 16 ml TV, the relative reductions in iWOB compared with Neopuff were 91.5% with face mask and 86.6% with nasal prongs (p<0.001, T-piece Neopuff 4.94 mJ/breath (95% CI 4.82 to 5.06), new system with face mask 0.42 mJ/breath (95% CI 0.41 to 0.42) and with nasal prongs 0.66 mJ/breath (95% CI 0.62 to 0.70)). The effect on iWOB was similar to 32 mL TV with a reduction of 89.0% for new system with face mask and 84.5% with nasal prongs (p<0.001). The differences between T-piece GE and T-piece Neopuff were small (p>0.05 in several comparisons). At higher levels of CPAP, the T-piece systems had increased iWOB and the new system decreased iWOB (figure 2A, B).
Clinical feasibility trial
Informed consent was obtained from 45 patients, 39 were randomised and 36 needed support. Data for the three treatment arms is presented in table 1. The randomisation did not give equal groups with statistical significant difference in gestational age (table 1).
CPAP treatment was delivered with the randomised system to all 36 patients. The level of CPAP was 4.0 cm H2O for 34 patients, 1 patient received 5.0 cm H2O CPAP and 1 patient received 3.4 cm H2O CPAP (both unintentional deviations from protocol). All patients received the randomised system until at least 10 min of age except for the patient who was intubated. There were no differences in outcome or treatment between the groups in the delivery room (table 1). More infants treated with the new system and prongs received surfactant in the first 72 hours.
PPV was used in 13 patients with a set median peak inspiratory pressures of 20 cm H2O (20–23,4 IQR). The peak pressures were increased during PPV in two infants treated with the new system (from 20 to 24 (prongs) and 26 cm H2O (face mask)). One patient randomised to the new system with nasal prongs was difficult to ventilate and at 5 min of age the system was switched to Neopuff. This did not improve ventilation and the infant was intubated at 8 min of age.
Safety
Two pneumothoraxes were detected in two patients with a gestational age of 27 weeks. Both received treatment with the new system with nasal prongs, with 4.0 cm CPAP for 10 min and no PPV. Apgar score was 9-10-10 for both infants. The first infant had subtle radiological signs of RDS at 2 hours of age, but no pneumothorax. He was intubated because of increasing signs of RDS at 24 hours of age, but still had no pneumothorax on X-ray. A small pneumothorax was noted at 48 hours of age, it was not drained and reabsorbed spontaneously within 24 hours. The second infant had no signs of pneumothorax on X-ray at 2 hours of age, but developed a pneumothorax after intubation and surfactant administration at 12 hours of age. There where no other patient safety issues reported and no problems with equipment or usage.
Discussion
In vitro tests
The in vitro comparisons of the performance of the new system and T-piece systems show that the new system is more pressure stable. This can be seen in the large reduction of iWOB and pressure swings with the new system. The system was specifically designed to achieve this and the development was initiated by the high iWOB seen for Neopuff in a previous in vitro study.12
The reduction in iWOB gives two opportunities for clinical research. First, the importance of a reduced iWOB during resuscitation or after extubation can be studied. Second, the clinical effects of different levels of CPAP can be investigated without large changes in iWOB. The T-piece systems showed a marked increase in iWOB (figure 2A, B) at higher CPAP levels. Therefore, investigating the effects of increased CPAP levels with these systems will also investigate effects of increased iWOB.
The new system can be used with both nasal prongs and face mask. This gives an opportunity to further investigate differences noted by Capasso et al.13 The difference in iWOB between face mask and nasal prongs for the new system (figure 2A, B) is relatively small, but would have to be considered when designing a study or interpreting the results of interface comparisons.
Limitations
The in vitro tests are limited by the artificial nature and can be criticised for not reflecting clinical use. We are aware of this but used sinusoidal flow pattern that was symmetrical (I:E 1:1) to give equal inspiratory and expiratory flows. The large differences in iWOB were present in both simulations (16 and 32 mL TV) and we believe they would be present if other breath profiles would have been used.
The in vitro tests were performed in a non-compliant model to give reproducible delivery of tidal volumes. Gas compression and tube compliance will give a reduction in delivered volumes in systems with large pressure swings such as T-piece systems. The in vitro tests will thus underestimate the iWOB for T-piece systems. Correcting for this artefact is very complex and was not attempted.
Clinical feasibility trial
The clinical feasibility trial revealed no problems with usage or safety. The small number of patients and the absence of stratification led to imbalanced treatment groups with lower gestational age in the group treated with the new system and nasal prongs. A larger proportion of these more immature infants were treated with surfactant. Two patients (27 weeks of gestation) treated with the new system and nasal prongs had pneumothoraxes diagnosed in the NICU. The initial stabilisations for these patients were unproblematic and PPV was not used. The infants had no signs of pneumothorax on initial chest X-rays and we believe that the pneumothoraxes were unrelated to the system used for initial stabilisation. Both the increased risk for pneumothorax and need for surfactant treatment are well-recognised risks in infants with RDS.
There were several limitations in the feasibility trial. The intervention could not be blinded and the number of investigators involved was few. This could lead to bias. The number of patients was too low to draw definite conclusions on safety or estimations of treatment effect.
Future directions and ILCOR documents
Perlman et al9 identified the following gaps of knowledge in the ILCOR 2010 consensus document: “What is the appropriate interface to effectively ventilate infants…? What is the optimal device for delivering PEEP and CPAP?”.
These questions remain unanswered and the trial by Capasso et al is not mentioned in the updated ILCOR 2015 consensus document.6 ,13 A reason for the slow progress could be lack of equipment suitable to answer these questions. There are currently no resuscitation devices that (1) allow CPAP with low iWOB with an option to deliver PPV if needed and (2) can be used with a nasal prong interface.
The new system has technical properties that allow further research on these potentially important factors for improving neonatal resuscitation.
Conclusions
A new system was developed (1) to reduce work of breathing compared with the T-piece system and (2) to allow patient resuscitation with nasal prongs or face mask. Compared with the T-piece system, the new system had a marked reduction in the iWOB in bench tests. The feasibility trial did not reveal problems with usability or safety. The possible clinical effects of a reduction in iWOB or the use of nasal prongs need to be investigated in a randomised trial.
Acknowledgments
The new system was developed together with Kjell Nilsson, MD.
References
Footnotes
Contributors All authors have actively contributed. SD, TD and BJ planned the study. SD, LT and SK recruited patients, collected and analysed data. SD and TD performed the in vitro experiments. All authors were involved in writing and reviewing the manuscript.
Funding This study was supported by independent grants from The Research and Development Unit, Jämtland County Council and Sällskapet Barnavård, Stockholm.
Competing interests TD is one of the inventors of the new system. He was not involved in patient care or collection of clinical data.
Patient consent Obtained.
Ethics approval Ethical Review Board Karolinska Institutet, Stockholm, Sweden.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement Raw data from the in vitro simulations and anonymous data from the clinical feasibility trial are available on request. Please contact the corresponding author.