Healthy preterm (< 37 wk gestation) and term infants were recruited shortly after birth from the special care unit and maternity wards of the Homerton Hospital, London. Infants with major congenital abnor malities were ineligible, as were those requiring more than 4 h of as sisted ventilation or more than 24 h of oxygen therapy during the neo natal period. Written informed consent was obtained from one or both parents, who were commonly present when measurements were per formed. The study was approved by the City and Hackney Local Re search Ethics Committee.
Respiratory Function Measurements
Serial measurements of respiratory mechanics and HBIR activity (23, 28,29) were obtained in the preterm infants on four occasions: namely, within the first 2 wk after birth (PI); at the expected date of delivery (P2), ÎÆ., between 37 and 41 wk postconceptional age (PCA), where PCA equals gestational age (GA) at birth plus postnatal age (PNA); at 12 to 20 wk PNA (P3); and at approximately 52 to 60 wk PCA (P4), i^., at a corrected PNA of 12 to 20 wk. Full-term infants were studied on two occasions only, since during the first week of postnatal life (Tl) their PCA would be approximately 40 wk, whereas at 12 to 20 wk PNA (12), they would have a PCA of 52 to 60 wk. Follow-up measurements were not performed within 3 wk of an upper respiratory tract infection (30). All infants were measured following a feed and while asleep. This was usually during natural sleep but prior sedation with triclofos so dium, 50 mg/kg given orally (equivalent to 30 mg/kg chloral hydrate), was sometimes required when measurements were made above 44 wk PCA. We have previously shown that this dose of sedation does not in fluence the strength of the HBIR in infants (31). All measurements were performed in a research room with ambient temperature maintained at 22 to 25® C using a servo-controlled air conditioning unit. Most infants were measured in the supine position, although some would only settle in the lateral position. Data collection was confined to periods of be- haviorally determined quiet sleep when posture was stable, respiration regular and no eye movements were seen (30).
End Inspiratory Occlusion V olum e 10ml 1 kPa ao I I i ■+T-+ T r T im e ( s e c o n d s )
Figure 1. Time-based trace from a 7-wk-old infant, born at 33 wk gesta tion, showing calculation of the strength of the Hering-Breuer infla tion reflex. Pao = pressure at the airway opening. In this example, mean expiratory time (ta) from 5 preceding breaths was 0.75 s and expiratory time during occlusion (teocc) was 2.10 s, representing an increase in expiratory time during occlusion (i.e., strength of the HBIR) of 180%.
28). Airflow and airway pressures were digitized at a sampling rate of 100 Hz. Data display, recording, and analysis were performed using the Respiratory Analysis Program (RASP; Physiologic Ltd., Berkshire, UK) previously validated in our department (32).
Tidal breathing was recorded for a minimum of 5 min during quiet sleep. The strength of the HBIR was measured by recording at least 10 regular breaths with a stable end-expiratory level and then briefly clos ing the shutter at the end of an inspiration. This occlusion was main tained until the infant made at least one complete respiratory effort against the shutter (Figure I). At least 1 min was allowed between suc cessive occlusions. Five occlusions were performed in each infant (23). j Respiratory system compliance (Crs) was measured using the Multiple ' < Occlusion Technique (MOT) (28). A series of 15 brief airway occlusions were performed at different volumes within the first two-thirds of expi ration. Each occlusion was held until a relaxed pressure plateau was achieved according to previously established criteria (24, 28, 29).
Mean respiratory rate (RR) and tidal volume (Vt) were calculated from five epochs of 5 to 10 breaths selected over at least 5 min of quiet regular breathing (33). The activity of the HBIR was measured from the percentage change in expiratory time during occlusion (te.occ) rela tive to that recorded during spontaneous breathing (tg) from the 5 breaths immediately preceding the occlusion as described previously (23) (i e., HBIR % = l(tE,occ - tE)/tE] X 100). The strength of the HBIR in each infant was calculated as the mean percentage change from five end-inspiratory occlusions. For each infant, Crs was calculated from least squares linear regression analysis of the volume-pressure data (28). Crown- heel length was measured to the nearest 0.1 cm by two adults using an infant stadiometer, and body weight measured to the nearest 100 g using digital scales (30).
Background Data
Details of the current pregnancy and labor were obtained from the mother’s medical records. Information on maternal smoking during preg- ' nancy was obtained from the mother at entry to the study. Details of maternal smoking postnatally and method of infant feeding were recorded at each subsequent visit. All data were entered on Epi-info (version 5.01a; Centers for Disease Control, Epidemiology Program Office, Atlanta, GA) and validated using double entry.
Statistical Methods
Infants in whom full serial measurements were obtained were compared with those lost to follow-up. To investigate the effects of gestational age on HBIR activity shortly after birth, values obtained during the first
Stocks, Dezateux, Hoo, et al.: HBIR Activity In Preterm Infants 1413
TABLE 1
CHARACTERISTICS OF PRETERM AND FULL-TERM INFANTS WITH INCOMPLETE AND COMPLETE SERIAL MEASUREMENTS*
Preterm Term
Incomplete Complete Incomplete Complete
Number 19 25 17 27 Birthweight, kg 1.9 ±0.3 2.0 ± 0 .4 3.1 ±0.5 3.4 ±0.6 Gestation, wk 32.5 ± 1 .9 33.5 ± 1 .6 39.3 ± 1.5 40.1 ± 1.2 Mothers smoking 59 40 53 33 during pregnancy, % Males, % 53 40 47 48 Caucasian, % 47 56 53 67
Details on first m easurement occasion
PNA, wk 0.5 ± 0.4 1.4 ± 0 .6 0.2 ±0.2 0.3 ±0.2
PCA wk 33.0 ± 1.9 34.9 ± 1 .6 39.5 ±1.2 40.3 ± U
Body weight, kg 1.9 ±0.3 2.0 ± 0 .4 3.1 ±0.5 3.4 ±0.6
Body length, cm 44.3 ± 2 .0 44.5 ± 2.8 49.7 ± 2.1 50.9 ± 2.8
HBIR, % 96.0 ± 45.0 105.3 ±4 1 .0 108.6 ±35.8 96.3 ± 32.5
Combined data from first occasiont All Preterm HBIR, % 101.2 ±42.4 RR, bpm 61.1 ±11.4 Vt, ml/kg 7.2 ± 1.5 Crs, ml/kPa/kg 14.3 ±4.1 All Term 101.0 ±33.9 55.3 ±13.1 7.0 ±1.1 n .4 ± 2 .3
Definition o f abbreviations: PNA = p o s tn a ta l a g e ; PCA = p o s tc o n c e p tio n a l a g e; HBIR * H ering-Breuer inflation reflex; RR = resp ira to ry rate ; Vr = tid al volum e, co rre c te d for w eig h t; Crs ■ to ta l resp ira to ry co m p lian c e , c o rre c te d for w e ig h t.
* Values a re ex p re sse d as m e a n 1 SD.
t All d a ta from first m e a s u re m e n t o ccasion; n » 44 fo r b o th p re te rm a n d full-term infants.
pie regression models by imposing a linear form on the decline. In addi tion, the respiratory indices of preterm and full-term infants were com pared at matched PNA and PCAs. All available data were used for these cross-sectional comparisons. Consequently sample size was larger when term infants were compared with the preterm group at birth or at term equivalent (i.e., Tl versus PI or P2) than when comparisons were made in older infants (i.e., T2 versus P3 or P4). 95% confidence intervals of the differences (95% Cl) are presented where appropriate.
Sample Size
Sample size was calculated to allow detection of a 30% difference in the absolute strength of HBIR activity between preterm and term in fants at any given PNA or PCA, with a significance of 5% and a power of 90%, allowing for multiple comparisons and investigation of matura- tional changes with age. Since a 30% difference would be equivalent to the standard deviation of HBIR among healthy infants (23), results from 25 preterm and 25 full-term infants would meet these requirements.
wk), but were otherwise similar with respect to population char acteristics and the strength of the HBIR.
Infants born at term were naturally of higher gestation and birth weight than those delivered prematurely, but did not other wise differ with respect to sex, ethnic group, or maternal smok ing during pregnancy (Table I). To ensure that the groups were similar with respect to maternal smoking, term infants of smok ing mothers were selectively recruited toward the end of the study. Of the mothers who smoked during pregnancy, all but two con tinued to do so after delivery, whereas only one mother who did not smoke during pregnancy did so postnatally. Results from all infants studied in the first 2 wk of life are shown in Figure 2, where it can be seen that, despite wide intersubject variability, a positive HBIR (as indicated by an increase of expiratory time by at least 25% during end-inspiratory occlusion) was present in all but one infant. Furthermore, over the range studied (i.e., 29 to 42 wk GA), gestational age did not appear to have any influence on HBIR activity in healthy infants when measured shortly after birth.
Age, body size, and respiratory function on each test occa sion for infants with complete serial measurements are summa rized in Table 2, The preterm infants were on average just over I wk older than the term infants at the time of initial measure ments (95% Cl of difference PI -Tl: 0.9; 1.3 wk). There was, however, no significant difference in PNA between the two groups at approximately 15 wk (95% Cl of difference P3-T2; -2.6; 0.7 wk). At term equivalent (P2 and Tl), preterm and full-term infants were similar with respect to body weight, length, and PCA. At final measurements (P4 and T2), PCA was an average of 2.6 wk greater in preterm infants (95% Cl of difference P4-T2: 0.6; 4.7 wk), primarily due to postponement of appointments in preterm infants with respiratory infections. However, there were no significant differences in body weight or crown-heel length between the two groups (95% Cl of difference P4-T2: -0.2; 1.0 kg and -0.7; 3.4 cm, respectively) at this stage. All record ings were performed during natural quiet sleep in infants less than 44 wk PCA, whereas light sedation was required in many infants by the time of the final measurements O^ble 2).
Serial measurements for preterm and full-term infants com pleting follow-up are shown in Figures 3 and 4, respectively. HBIR activity increased between birth (PI) and term equivalent (P2) in 18 of the 25 preterm infants (95% Cl of difference P2- Pl: -6.5; 39.3%) (Figure 3) but subsequently decreased by ap proximately 48 wk PCA (95% Cl of difference P3-P2: -53.2;
RESULTS
The strength of the HBIR was assessed on all occasions in 25 preterm and 27 term infants. However, in order to achieve the required sample size, it was necessary to recruit 47 preterm and 48 term infants to the study. Successful measurements were ob tained on the first occasion in all but three preterm and four term infants, who did not remain in quiet sleep for long enough to complete recordings. Subsequent attrition was primarily due to failure to attend one or more of the follow-up appointments. The characteristics of the populations from whom a complete set of measurements were and were not obtained are summarized in Table 1. Although there was a tendency for more infants of Cau casian, nonsmoking mothers to complete follow-up, this did not reach statistical significance. Infants with incomplete measure ments tended to have slightly lower gestational age at birth. On
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