Objectives To assess the work of breathing at different levels of volume targeting in prematurely born infants with evolving or established bronchopulmonary dysplasia (BPD).
Design Randomised crossover study.
Setting Tertiary neonatal intensive care unit.
Patients Eighteen infants born at <32 weeks gestation who remained ventilated at or beyond 1 week after birth, that is, they had evolving or established BPD.
Interventions Infants received ventilation at volume targeting levels of 4, 5, 6 and 7 mL/kg each for 20 minutes, the levels were delivered in random order. Baseline ventilation (without volume targeting) was delivered for 20 minutes between each epoch of volume-targeting.
Main outcome measures Pressure-time product of the diaphragm (PTPdi), a measure of the work of breathing, at different levels of volume targeting.
Results The 18 infants had a median gestational age of 26 (range 24–30) weeks and were studied at a median of 18 (range 7–60) days. The mean PTPdi was higher at 4 mL/kg than at baseline, 5 mL/kg, 6 mL/kg and 7 mL/kg (all P≤0.001). The mean PTPdi was higher at 5 mL/kg than at 6 mL/kg (P=0.008) and 7 mL/kg (P<0.001) and higher at 6 mL/kg than 7 mL/kg (P=0.003). Only at 7 mL/kg was the PTPdi significantly lower than at baseline (P=0.001).
Conclusions Only a tidal volume target of 7 mL/kg reduced the work of breathing below the baseline and may be more appropriate for infants with evolving or established BPD who remained ventilator dependent at or beyond 7 days of age.
- volume targeted ventilation
- bronchopulmonary dysplasia
- work of breathing
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What is already known on this topic?
Volume-targeted ventilation compared with pressure-limited ventilation improves outcomes in prematurely born infants.
Target tidal volumes of 6 mL/kg compared with lower levels reduced the work of breathing in preterm infants with respiratory distress or during weaning.
Prematurely born infants undergoing prolonged ventilation may need higher tidal volumes despite permissive hypercapnia.
What this study adds?
The work of breathing in infants with evolving or established bronchopulmonary dysplasia (BPD) was assessed at different levels of volume targeting and no volume targeting.
A volume target of 7 mL/kg compared with 4, 5, 6 and no volume-targeting reduced the work of breathing in infants with evolving or established BPD.
As the volume target level was increased the spontaneous respiratory rate decreased, hence there were no significant differences in minute volume.
In prematurely born infants, volume-targeted, as compared with pressure-limited, ventilation has been shown in systematic reviews to result in reduction in death or BPD, fewer episodes of hypocarbia and reductions in pneumothorax and intracranial haemorrhage.1 2 The level of volume targeting varied in the studies included in the systematic reviews. It has been shown that in prematurely born infants with acute respiratory distress, ventilation with low tidal volumes of 3 mL/kg as compared with 5 mL/kg increased the level of pro-inflammatory cytokines in tracheal aspirates and prolonged the duration of ventilation.3 Furthermore, in prematurely born infants with acute respiratory distress,4 those weaning from ventilation at <1 week of age5 and in infants born at or near term,6 volumes of 6 mL/kg compared with lower volume-targeted levels reduced the work of breathing (WOB). There are, however, no such studies in infants undergoing prolonged ventilation with developing or established bronchopulmonary dysplasia (BPD). Among prematurely born infants ventilated during the first 4 weeks after birth, tidal volumes increased despite permissive hypercapnia,7 8 suggesting infants with evolving or established BPD may require larger volume target levels to reduce their WOB than those with acute or resolving RDS. The aim of this study was to test that hypothesis.
Infants were eligible for inclusion in the study if they were born at <32 weeks of gestation and remained ventilated at or beyond 1 week after birth. We have previously demonstrated all infants who remained ventilator dependent at a week of age developed BPD. In addition, all included infants were to be making spontaneous respiratory efforts during ventilation. Written, informed parental consent was obtained.
Infants were ventilated using the SLE 5000 or 6000 ventilator (SLE, Croydon, UK) with shouldered endotracheal tubes (Smith’s Medical, Kent, UK). They each received 20 min of volume-targeted ventilation at 4, 5, 6 and 7 mL/kg, the order of delivery randomised between infants. They received an initial 20 min period of baseline ventilation (without volume targeting) and 20 m i n periods of baseline ventilation between each epoch of volume targeted ventilation (VTV). The WOB was recorded for 5 min at the end of each 20 min period. The positive end-expiratory pressure level and the back-up respiratory rate set on the ventilator were kept the same throughout the study. The fraction of inspired oxygen concentration (FiO2) was adjusted to maintain oxygen saturations between 92% and 96%.
The WOB was assessed by calculation of the pressure-time product of the diaphragm (PTPdi). Gastric and oesophageal pressures were measured using a dual pressure transducer tipped catheter (Gaeltec, Dunvegan, Scotland). Flow was assessed using a pneumotachograph (Mercury F10L; GM Instruments, Kilwinning, Scotland), which was inserted between the ventilator circuit and the endotracheal tube and connected to a differential pressure transducer (±2 cm H2O; MP45; Validyne, Northridge, California, USA). The pneumotachograph had a side port by which airway pressure was measured, this was connected to a pressure transducer (±100 cm H2O; MP45; Validyne, Northridge, California, USA). Air flow, airway pressure, gastric and oesophageal pressure signals were recorded simultaneously on a personal computer running specially written software (Labview V.5.0, National Instruments, Austin, Texas, USA) with 100 Hz analogue-to-digital sampling (16 bit DAQ card, DAQ 6036E, National Instruments, Austin, Texas, USA). Tidal volume was calculated by digital integration of the flow signal by the software.
Transdiaphragmatic pressure was obtained by subtraction of the gastric pressure from the oesophageal pressure; this was then integrated with time for the inspiratory portion of each breath to give the PTPdi. For each breath, the beginning and end of inspiration was determined from the flow signal, in order to delineate the inspiratory work of breathing. The mean PTPdi of the first 20 artefact-free breaths in the last 5 min of the recording of each 20 min epoch of ventilation was calculated. The WOB results from the five periods of baseline ventilation were averaged. The mean expiratory tidal volume (VTe) was calculated from the 20 breaths in each epoch and the total expiratory minute volume (MVe) was calculated by multiplying the mean VTe by the respiratory rate.
Data were assessed for normality using the Shapiro-Wilk test. A one-way repeated measures analysis of variance was used to assess for differences between the different levels of volume targeting. For some variables, assumptions of sphericity were violated, therefore Greenhouse-Geisser correction was applied where necessary. Bonferroni adjustment was used for post hoc comparisons. Statistical analysis was performed using IBM SPSS Statistcs V.14.
Recruitment of 18 infants allowed detection with 80% power at the 5% significance level, a difference equivalent to 1 SD in the results of PTPdi between the different levels of volume targeting. The SD was derived from results from previous infants with evolving BPD in whom PTPdi had been measured.
Eighteen babies, median gestational age at delivery 26 (range 24–30) weeks and median birth weight 814 (range 438–1190) g were studied at a median of 18 days after birth (range 7–60) days. Fifteen infants had received at least one dose of antenatal steroids and all had received postnatal surfactant. When studied, 2 babies were supported by synchronised intermittent mandatory ventilation and 16 by assist control ventilation. All of the infants were subsequently diagnosed with BPD (oxygen dependency beyond 28 days). Three had mild, six moderate, and eight severe BPD according to the National Institutes of Health consensus definition.9 One infant died before 36 weeks corrected gestational age and hence it was not possible to determine BPD severity.
All babies completed the protocol and had work of breathing assessed at each level of volume targeting. At all levels of volume targeting the infants continued to breathe. The mean PTPdi was higher at 4 mL/kg than at baseline, 5 mL/kg, 6 mL/kg and 7 mL/kg (P<0.001). The mean PTPdi was higher at 5 mL/kg than at 6 mL/kg (P=0.008) and 7 mL/kg (P<0.001) and higher at 6 mL/kg than 7 mL/kg (P=0.003). Only at 7 mL/kg was the PTPdi significantly lower than at baseline (P=0.001) (figure 1).
The mean Vte was significantly lower at 4 mL/kg than at baseline (P<0.001) and higher at 6 and 7 mL/kg than baseline (P=0.026, P<0.001) respectively. The PIP was significantly higher at 7 mL/kg than at baseline (P=0.032) and 6 mL/kg (P=0.044) and at baseline than 4 mL/kg (P=0.001) and 5 mL/kg (P=0.002) (table 1). The spontaneous respiratory rate of the infants was significantly higher at 4 mL/kg than at baseline (P=0.049) and at 4 and 5 mL/kg than at 7 mL/kg (P<0.001, P=0.038), respectively (table 1). There were no significant differences between the MVe or the FiO2 at different levels of volume targeting.
We have demonstrated that in infants with evolving or established BPD, only at 7 mL/kg was the work of breathing significantly reduced from that during pressure-limited ventilation. It has been demonstrated that infants that remain ventilated develop higher tidal volume requirements despite permissive hypercapnia.7 This likely reflects that infants undergoing prolonged ventilation have an increased dead space.10 Our findings are important as we have identified a volume-targeted level associated with the lowest level of WOB. In the Cochrane review of pressure-limited versus volume-targeted ventilation, it is stated that currently there is little evidence regarding the appropriate tidal volume target in prematurely born neonates (including those with established BPD).11
There were no significant differences in the minute ventilation between the different levels of volume targeting. As the level of volume targeting increased, the infants’ respiratory rates decreased. Those data suggest that the infants altered their respiratory rates to maintain a relatively constant minute ventilation at different levels of volume targeting to maintain blood gas homeostasis.
In an international survey of volume-targeted ventilation, many units reported reluctance to use tidal volumes >6 mL/kg for babies with established BPD who remained ventilator-dependent.12 It is unclear what this upper limit of target volume is based on. It is perhaps influenced by evidence from adults with acute respiratory distress syndrome in whom ventilation with 6 mL/kg rather than 12 mL/kg was associated with reduction in mortality.13 It should be noted that in preterm infants breathing spontaneously on continuous positive airways pressure after delivery, during crying or grunting the median tidal volume recorded exceeded 7 mL/kg, thus suggesting that such a tidal volume may be within the normal range.14 While it is clear from surveys of practice that infants do cope on lower-targeted tidal volumes, it is likely that they are persistently working harder to breathe and, therefore, growth may be impaired. PTPdi is closely related to the oxygen cost of breathing and it has previously been demonstrated that growth failure in infants with BPD is closely related to oxygen consumption. Thus, an increased WOB may be detrimental in terms of adequate growth.15
At the highest level of volume targeting, the respiratory rate of the infants was a mean of 44 bpm compared with 61 bpm at the lowest level of volume targeting. This indicates that there may have been some suppression of the infants’ respiratory drive. All of the infants continued to breathe at the highest volume-targeted level and thus their respiratory drive was not completely suppressed. Nevertheless, this highlights the importance of identifying the appropriate level of targeted tidal volume for an individual, by assessing their work of breathing by degree of recession and changes in oxygen requirement, and determining whether they are continuing to breathe.
There are strengths and some limitations to our study. All the infants were subsequently diagnosed with BPD. The infants were examined at all of the four tidal volumes and hence acted as their own controls. Each level of VTV was compared with the baseline level (ie, without VTV), which was the average of the four baseline readings. The VTV levels were given in a random order. We used the pressure-time product of the diaphragm as our outcome measure as it is a measure of diaphragmatic metabolic work. Other techniques such as thoracoabdominal asynchrony instead give an indirect measurement of respiratory muscle function. In a future study, it would be useful to also determine the effect of different levels of volume targeting on transcutaneous carbon dioxide levels. This was a crossover study, hence we cannot comment on whether different tidal volumes affected long-term outcome.
In conclusion, we have demonstrated that a volume-targeted level of 7 mL/kg compared with lower volume-targeted levels or no volume targeting reduced the WOB in preterm infants with evolving or established BPD. We have described above that an increased WOB may be detrimental in terms of adequate growth. We would, therefore, recommend a trial of a volume-targeted level of 7 mL/kg in infants with evolving or established BPD.
Contributors AG and KA designed the study, KH collected the data, KH, TD and AG were involved in the analysis of the results. All authors were involved in the production of the manuscript and approved the final version.
Funding KH was supported by the Charles Wolfson Charitable Trust and by SLE. The research was supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy’s and St Thoma’s NHS Foundation Trust and King’s College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the department of health.
Competing interests AG has held grants from various ventilator manufacturers. AG has received honoraria for giving lectures and advising various ventilator manufacturers. AG is currently receiving a non-conditional educational grant from SLE.
Ethics approval The study received approval from the South-East Coast—Surrey NHS Research Ethics Committee. The study was registered on the ISRCTN database, number 17041826.
Provenance and peer review Not commissioned; externally peer reviewed.
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