Objectives To test the hypothesis that the ventilatory response to a carbon dioxide (CO2) challenge would be lower in the prone compared to the supine position in prematurely born infants studied post-term. To determine whether there were postural-related differences in respiratory drive, respiratory muscle strength, thoracoabdominal synchrony and/or lung volume.
Design Prospective cohort study.
Setting Tertiary neonatal unit.
Patients Eighteen infants (median gestational age 31 (range 22–32) weeks) were studied at a median of 5 (range 2–11) weeks post-term.
Interventions The ventilatory responses to three added carbon dioxide (CO2) levels (0% baseline, 2% and 4%) were assessed in the prone and supine positions.
Main outcome measures The airway pressure change after the first 100 ms of an occluded inspiration (P0.1) (respiratory drive) and the maximum inspiratory pressure during crying with an occluded airway (Pimax) (respiratory muscle strength) were measured. The P0.1/Pimax ratio at each CO2 level and slope of the P0.1/Pimax response were calculated.
Results The mean P0.1 (p<0.05) and P0.1/Pimax (p<0.05) were higher and the functional residual capacity (p=0.031) lower in the supine compared to the prone position. The mean P0.1 and P0.1/Pimax increased independently of position as the percentage CO2 increased (p<0.001). There was no tendency for the differences in P0.1 and P0.1/Pimax between the prone and supine position to vary by CO2 level.
Conclusions Convalescent, prematurely born infants studied post-term have a reduced respiratory drive, but not a lower ventilatory response to a CO2 challenge, in the prone compared to the supine position.
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What is already known
Prematurely born infants are at increased risk of sudden infant death syndrome (SIDS).
Prematurely born infants are particularly at increased risk of SIDS if slept prone rather than supine.
Prematurely born infants have a reduced ability to respond to added dead space in the prone position.
What this study adds
Prematurely born infants studied post-term had reduced respiratory drive in the prone compared to the supine position.
Prematurely born infants studied post-term had higher lung volumes in the prone position.
Prematurely born infants studied post-term did not have lower ventilatory responses to a carbon dioxide challenge in the prone position.
Prematurely born infants compared to those born at term are at increased risk of sudden infant death syndrome (SIDS), particularly if they are slept prone.1 A possible mechanism for the increased risk of SIDS in prematurely born infants sleeping prone could be an impaired ability to respond to respiratory compromise, such as elevated carbon dioxide (CO2) levels. Post-mortem examination studies of chemosensitive brainstem tissue from infants who died of SIDS have demonstrated decreased neuromodulator receptor binding.2 In addition, increased levels of mRNA encoding an Na+/H+ exchange associated with reduced CO2 responsiveness have been found.3 A transgenic mouse model with a functional deficit in serotonin homeostasis, had episodes of autonomic dysregulation, cardiovascular crises and death, resembling SIDS.4 The transgenic mice had reduced responses to a hypercapnic challenge as compared to control litter mates.4 Those findings4 support the hypotheses that the chemosensitivity of midbrain serotonergic neurones may be responsible for arousal responses to life-threatening episodes of hypercapnia and that functional impairment of midbrain serotonergic neurone responses to hypercapnia may contribute to sudden death.4 The serotonergic neurones are located in the arcuate nucleus at the ventral surface of the medulla oblongata.5
We have demonstrated that convalescent prematurely born infants studied post-term had a reduced ability to respond to added dead space (tube breathing) in the prone compared to the supine position.6 The major stimulus during tube breathing is hypercapnia.7 We have also demonstrated that prematurely born infants studied at a median postmenstrual age (PMA) of 36 weeks had a reduced ventilatory response to a carbon dioxide (CO2) challenge in the prone compared to the supine position.8 We therefore hypothesised that prematurely born infants studied post-term would have a reduced ventilatory response to a CO2 challenge in the prone compared to the supine position, the aim of this study was to test that hypothesis. We assessed the response to the CO2 challenge by measuring P0.1 and P0.1/Pimax. P0.1 is influenced by Pimax, which is influenced by posture.9 P0.1 may also be influenced by lung volume which is also influenced by posture, being greater in the prone position.10 ,11 In addition, therefore, we wished to determine whether any difference in the response to the CO2 challenge was associated with postural-related differences in respiratory drive, respiratory muscle strength, thoracoabdominal synchrony and/or lung volume.
Inclusion and exclusion criteria
Infants born prior to 33 weeks of gestation at King's College Hospital NHS Foundation Trust without congenital abnormalities were eligible for recruitment into the study. Parents were approached when their infant was on the neonatal unit. Infants whose parents gave informed written consent were recruited. Infants were not assessed if they were receiving supplementary oxygen. The study was approved by the King's College Research Ethics Committee.
Infants were assessed when they were post-term, but less than 12 weeks corrected age. For each study session, the position (prone or supine) in which infants were first studied was randomised. Measurements in the two positions were performed consecutively on the same day. In each position, lung volume was measured and then the hypercapnic challenge undertaken. Thoracoabdominal synchrony was assessed during the hypercapnic challenge. Oxygen saturation was continuously monitored using a pulse oximeter (Ohmeda Biox 3740; BOC Health Care, Louisville, Colorado, USA).
Measurements were commenced in each position after the infants had been fed and had been in quiet sleep for at least 20 min. The infants were only assessed when in quiet sleep. Sleep state was assessed using behavioural indicators; quiet sleep state was indicated by the infant’s eyes being closed, a regular respiratory pattern and minimal spontaneous movements. If the infant aroused from sleep, other than during the assessment of respiratory muscle strength, the assessment was discontinued and only restarted when the infant returned to quiet sleep.
Hypercapnic challenge and assessment of respiratory drive (P0.1) and respiratory muscle strength (Pimax)
The hypercapnic challenge was delivered via a facemask and pneumotachograph using an open circuit system containing a two way non-rebreathing valve to which the distal end of the pneumotachograph was attached. The open circuit had individually adjustable flows of carbon dioxide (CO2) and air as previously described.8 A constant flow of medical air through the open circuit could be enriched with a variable concentration of carbon dioxide (CO2) from a cylinder, the flow being controlled by a rotameter. The inspiratory line of the open circuit could be clamped and released in order to produce the occlusion necessary for P0.1 and Pimax measurements.
Respiratory flow was measured using the pneumotachograph (GM Engineering, Kilwinning, UK), which was attached to a differential pressure transducer (MP45, Validyne Corporation, Northridge, California, USA). Airway pressure was measured from a side port on the pneumotachograph using a differential pressure transducer (MP45, Validyne Corporation). Flow and pressure signals were amplified (Validyne CD 280, Validyne, Northridge, California, USA). Inspired and expired gases were measured continuously using a capnograph (CO2SMO capnograph (Respironics UK, Chichester, UK) which sampled gas using a fine bore catheter inserted into the facemask. Flow, pressure and CO2 concentration data were acquired on a computer running Spectra software (Grove Medical, London, UK) with 100 Hz analogue to digital sampling. Flow was digitally integrated to give tidal volume and minute volume calculated from the respiratory rate and tidal volume. The inspired and end tidal CO2 (ETCO2) were measured continuously using the capnograph and displayed throughout the study. In each sleeping position, assessments were made at three levels of added CO2 (0% (baseline), 2% and 4%). Each mixture of CO2 was titrated and a stable inspiratory CO2 concentration achieved before the infant was connected to the breathing circuit. The infant breathed the air/CO2 mixture for at least 5 min to allow ventilation and ETCO2 to reach steady state. P0.1 (the airway pressure change after the first 100 ms of an airway occlusion) and Pimax (the maximum inspiratory pressure during crying with an occluded airway) were assessed at baseline and at the end of each period of hypercapnia. Five sets of airway occlusions at end expiration were performed and the mean P0.1 calculated. During the fifth occlusion, the line remained occluded for 5–7 breaths once the infant started to cry. From those occluded breaths, Pimax was determined. Once the series of occlusions at a CO2 level had been made, the infant was only studied at the next CO2 level once they had returned to quiet sleep. The measurements were repeated at each inspired CO2 concentration and in both positions. P0.1/Pimax ratios were calculated at each inspired CO2 level and the slope of the P0.1/Pimax calculated. For each position, the subject’s respiratory rate, tidal volume and minute ventilation were calculated for each CO2 level.
Thoracoabdominal synchrony was assessed using uncalibrated respiratory inductance plethysmography (Respitrace model 10.9230; Ambulatory Monitoring, New York, USA) in AC-coupled mode as previously described.4 Thoracoabdominal asynchrony was determined in each position from five breaths after stabilisation of ETCO2. For each breath, the chest and abdominal wall movements were derived from the recording software. A Lissajous figure was plotted and the phase angle determined according to the method described by Allen et al.12 For each position, the mean phase angle from the five breaths was used for analysis.
Lung volume was assessed by measurement of functional residual capacity (FRC) using a helium gas dilution technique as previously described.10 During the measurement, if there was no change in the helium concentration over a 15 s period, equilibration was deemed to have occurred. The initial and equilibration helium concentrations were used in the calculation of FRC, which was corrected for oxygen consumption (assumed to be 7 mL/kg/min13) and to body temperature, pressure and water vapour-saturated conditions. FRC was measured twice in each position and the results of the paired measurements were averaged and related to body weight. The mean intrasubject coefficient of variation of the measurement of FRC was 5.8%.
Recruitment of 18 infants allowed us to detect, with high power (>99%) at the 5% level, a difference of 4.5 SDs in the response to the CO2 challenge between positions; such a difference was found when using inductance plethysmography to assess the difference in the response to hypercapnia between positions in healthy preterm infants.14
Summary statistics are presented by position and by percentage CO2. Generalised estimating equations (GEEs) with an exchangeable correlation structure were used to analyse the effect of the CO2 challenge in the prone and supine position. Main effects models were fitted first, that is position (prone and supine) and percentage CO2 (0, 2, 4%). Where either or both position or percentage CO2 were statistically significant, an interaction term was added to the model and tested for significance. If the interaction was not significant, this term was removed and the main effects model presented. Transformations were used where appropriate to correct skewness in the results: square root for phase angle and P0.1/Pimax and logarithm for P0.1.
The 18 infants (10 males) had a median gestational age of 31 (range 23–32) weeks and birth weight of 1440 (range 620–2200) gm. They were studied at a median age post-term of 5 (range 2–11) weeks. None of the infants were receiving medications or supplementary oxygen at the time of study; two of the mothers had smoked during pregnancy.
The mean P0.1 and P0.1/Pimax increased in each position as the percentage CO2 increased (p<0.001) (table 1). The mean levels of P0.1 and P0.1/Pimax were lower in the prone compared to the supine position, regardless of CO2 level (table 1). There were no significant effects of either position or percentage CO2 on Pimax or the phase angle (table 1). The mean FRC was greater in the prone compared to the supine position (p=0.031). There was no significant difference in the P0.1/Pimax slopes between the prone and supine position (p=0.248) (table 1).
There was no tendency for the differences in levels in P0.1 or P0.1/Pimax between prone and supine to vary by CO2 level and the differences between prone and supine were similar as shown by the non-significant interaction terms for P0.1 (p=0.63) and P0.1/Pimax (p=0.47) (table 2).
We have demonstrated the mean P0.1 and P0.1/Pimax increased independently of position as the percentage of CO2 increased in prematurely born infants studied post-term. There was, however, no tendency for differences in the P0.1 or P0.1/Pimax levels between prone and supine to vary by CO2 level, that is the infants did not have a lower ventilatory response to the CO2 challenge in the prone compared to the supine position. This does not contradict our previous results6 as we demonstrated a slower ventilatory response to added dead space in the prone compared to the supine position rather than a difference in the size of the response. Indeed, in both positions, the infants were able to fully compensate for the added dead space, but they did it more slowly in the prone position.6 At 36 weeks PMA, Martin et al14 reported a reduced response to hypercapnia in the supine position, whereas we found the opposite, that is a reduced ventilatory response to the CO2 challenge with a smaller P0.1/Pimax response slope in the prone position.8 Our current finding of no such reduced ventilatory response post-term suggests that from 36 weeks PMA to the first 12 weeks post-term there is maturation of the peripheral and chemoreceptor responses. This is in keeping with previous findings.15–17
We assessed the ventilatory response to a hypercapnic challenge by measuring the P0.1/Pimax ratio as previously reported.8 P0.1 is an indicator of respiratory output but is affected by respiratory muscle strength; hence, we controlled for this by relating the P0.1 to the Pimax results at each added CO2 level. Use of that normalised ratio has been shown in ventilated adults to be a better indicator of respiratory drive and predictor of successful weaning than absolute P0.1 values.18 The ventilatory responses were measured acutely and for a relatively short period, we cannot, therefore, comment on whether prematurely born infants studied post-term have a different sustained response to elevated CO2 according to position. The same challenge, however, was used in the two positions and hence the results we demonstrate with the caveat given above are valid.
In this study, the infants had a significantly lower P0.1 in the prone compared to the supine position, confirming our earlier findings.6 As above, P0.1 is influenced by respiratory muscle strength, but we found no significant differences in the Pimax results between positions. Hence, the lower mean P0.1 in the prone position reflects reduced respiratory drive. We have previously speculated that this may be due to the significantly higher FRC in the prone position,11 which we further demonstrate in these subjects and the stronger Hering-Breuer reflex that has been demonstrated in that position.19 In healthy adults, the strength of the Hering-Breuer reflex is directly proportional to increasing lung volume.20 The significantly higher FRC in the prone position would result in increased feedback from pulmonary stretch receptors which would reduce respiratory drive, hence the lower P0.1.
We studied prematurely born infants post-term up to a corrected age of 12 weeks. It has previously been suggested that prematurely born infants may be at increased risk of SIDS up to 12 weeks post-term.21 Our results then fit well with the triple risk model of vulnerability of SIDS, that is where a vulnerable infant with an underlying susceptibility is faced with an exogenous stress or during a particular period of development,22 as we have demonstrated prematurely born infants studied in the immediate post-term period have poorer respiratory control in the prone position.
In conclusion, we have demonstrated that convalescent prematurely born infants studied post-term had reduced respiratory drive, but not a reduced response to a CO2 challenge in the prone compared to the supine position. To our knowledge, this is the first study assessing prematurely born infants’ response to a CO2 challenge post-term. Our results highlighting that convalescent prematurely born infants have reduced respiratory drive when sleeping in the prone position post-term, support the argument for placing infants supine for sleep to minimise the risk of SIDS.
Contributors AG, ADM and SH designed the study. TS undertook the recruitment and the assessments, advised by GFR. JLP undertook the analysis. All authors were involved in the production of the manuscript.
Funding This research was supported by the National Institute for Health Research (NIHR) Biomedical Research Centre at Guy's and St Thomas’ NHS Foundation Trust and King's College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.
Competing interests TS was supported by a Chadburn Lectureship. AG is an NIHR Senior Clinical Investigator.
Ethics approval King's College Research Ethics Committee.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement We agree to the data sharing statement.