1010

June 1976 The Journal o[ P E D I A T R I C S

Effect of premature delivery on the maturation of the Hering-Breuer inspiratory inhibitory reflex in human infants The Hering-Breuer inspiratory inhibitory reflex was studied serially in a group of premature infants and in a group of term infants in the immediate postnatal period. The premature infants had a stronger inspiratory inhib(tory reflex than did the term infants at birth," this reflex decreased with maturation of the premature. Development in the extrauterine environment significantly delayed the rate of disappearance of this reflex. This may indicate that premature delivery retards the neurologie maturation of the huma n infant. The term infant showed no change in the activity of the inspiratory inhibitory reflex in the first five days of life.

S. M. L. Kirkpatrick, M.D., A. Olinsky, M.B., M. H. Bryan, M.D.~ and A. C. Bryan, M.B.,* Toronto, Ont., C a n a d a

IN 1868 HERING AND BREUER showed that sustained lung inflation in animals inhibited inspiration and that this reflex was abolished by vagotomy? In addition they showed that by occluding the airway at the end of expiration, the next inspiratory effort was prolonged and more forceful and that this effect was abolished by vagotomy. Although awake adult man has a weak or absent Hering-Breuer reflex, ~ Cross and associates3 showed, using the inflation technique, that the HeringBreuer reflex is present in term newborn infants and that its activity decreased during the first five days of life. Olinsky and associates4 demonstrated, using the end expiratory occlusion technique, that premature infants have a marked dependence on the inspiratory inhibitory reflex. We have studied a group of term normal infants (in the first two weeks of life) and a group of healthy premature infants of varying gestational ages. We have compared the Hering-Breuer inspiratory inhibitory reflex immediately postnatally in these infants to the activity of From The Research Institute, Hospital for Sick Children. Supported by the Medical Research Council Grant No. MA 4750, and the National Institute of Health Grant No. 5RO1-HDO 7826-02. *Reprint address: Suite 4531, Hospitalfor Sick Children. 555 University Ave., Toronto, Ontario M5G 1X8.

Vol. 88, No. 6, pp. 1010-1014

this reflex in the series of premature infants followed postnatally by Olinsky and associates. This comparison enabled us to ascertain if the decreasing activity of the Hering-Breuer reflex, seen in the prematurely born infant. was influenced by birth and subsequent extrauterine developments, as compared to infants of similar conceptional age who had "enjoyed an intrauterine environment" for a longer period of time. In addition we have studied the Hering-Breuer reflex activity in term infants within the first 24 hours of life and four to six days postnatally, to try and confirm Cross and associates' results, by using the end expiratory occlusion technique.

METHODS The initial part of the study was carried out on two groups of infants. The first group consisted of 35 term infants and 24 premature infants (gestational age 29 to 36 weeks) studied within the first two weeks of life. The second group was made up of 16 premature infants (mean gestational age 30 weeks) who were tested serially for up to 40 weeks after birth. In the second phase of the study, 23 term infants were studied within the 24 hours after birth and again four to six days postnatally to determine the change in the strength of the inspiratory inhibitory reflex immediately postnatally by the end expiratory occlusion method.

Volume 88 Number 6

Hering-Breuer inspiratory inhibitory reflex

10 1 1

VT

PREMATURE

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Fig. 1. Recordings of mask pressure (PM) and tidal volume (Vr) in a premature infant and a term infant. Arrows mark the point at which the airway was occluded. Prolongation of the inspiratory effort, measured from a negative mouth pressure, is much greater in the premature infant.

Fig, 2. Plot of tidal volume versus reciprocal of inspiratory time, to illustrate that changing tidal volume may not change the percentage slowing ofinspiratory rate, (1/Ti) but affects the slope (m).

The end expiratory occlusion technique was carried out by measuring resting tidal volume (Vr) and respiratory frequency (f) by using a pneumotachograph attached to a snugly fitting face mask. At the end of expiration the airway was closed by occluding the ope n end of the pneumotachograph (Fig. 1). T h e duration of the next inspiratory effort was monitored by a pressure transducer attached to the mask, which recorded the magnitude and duration of the negative pressure generated in the mask during the occluded inspiratory effort. The inspiratory duration (T~o~) of the occluded breath inegative mask pressure) was measured. The end expiratorY occlusion technique allows the demonstration of the inspiratory inhibitory reflex with a minimum of physiologic disturbance. If the respiratory control system requires stretch receptor information to terminate inspiration, then the occluded breath will be more prolonged than the unoccluded breath, as the tidal volume on occlusion is zero (apart from a small decompression volume) and the stretch receptors will not be stimulated to terminate inspiration. If the respiratory system is independent of stretch receptors, the occluded !nspiratory effort will have the same duration as the previous unoccluded breath (Fig. 1). Thus the prolongation of inspiratory time on occlusion is proportional to the strength of the inflation reflex. Since the inspiratory duration (Ti) is inversely related to inspiratory frequency, (f0:

then the slowing of respiratory frequency (as T~ 4. f~ +) on occlusion is also proportional tO the strength of the inflation reflex. Olinsky expressed this change of respiratory rate as percent prolongation of Tt: T,

f,e~ ]/T~

(l- ~

)x

100.

(~

This method of expressing the data does not take into account changes in tidal volume that occur with growth in the neonatal period. The problem is illustrated in Fig. 2. Two infants with different tidal volumes (or the same infant during growth) in this figure have exactly the same percentage prolongation. Grunstein and associates ~ used the slope (m) of the line AC and BC to assess the strength of the inspiratory inhibitory ratio. He used the equation: l / T i - 1/T~oc~ 1/m = v; (2) This equation does contain tidal volume (V,~), thus allowing one to compare infants of different size. The relationship between percent prolongation and the slope is given in the appendix. RESULTS Using 1/m as a measure of the activity of the inspiratory inhibitory reflex we have found that the reflex persists for a considerable period of time after birth in the premature infants. The rate of decrease in activity pf the reflex varied a great deal between infants, but many of the premature infants still have a significantly (p < 0.01)

10 12

Kirkpatrick et aL

The Journal ofPediatrics June 1976

0.2800

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CONCEPTIONAL AGE, WEEKS

Fig. 3. Plot of l / m (proportional to the strength of the inspiratory inhibitory inflation reflex) versus conceptional age. The two regression lines show the rate of disappearance of the reflex in two groups of infants: (1) Premature born infants (solid line) that were studied sequentially as they developed in an extrauterine environment. (Regression line calculated from all examinations.) y = 0.4391 -0.0102 x R = 0.7235, T = 7.9137, n = 59; (2) Infants who developed in an intrauterine environment (broken line ) and were studied within two weeks of birth. (One examination for each infant.) y = 0.2704-0.0045 x R = 0.7049, T = 6.2065, n = 41. The slopes of the two:lines are significantly different (p < .001). Units of 1/m are sec-1 m1-1.

were obliged to mature

Table I

Term infants Premature

I

--~at 40 weeks conceptual age I No. 0.0308 • 0.0284 0.0887 • 0.0350

36 8

Significant with p < 0.0l.

outside the confines of the

uterus. T e r m normal infants were studied, using the end expiratory occlusion technique, within 24 hours of birth, and again at four to six days of age. The activity is expressed as 1/m from equation 2 (Table II). No statistical difference was observed in the inspiratory inhibitory reflex on these two occasions.

Table II

DISCUSSION

Age

--~of term infants

No.

< 24 hr 6 _+ 1.53 days

0.0341 _+ 0.0205 0.0259 • 0.0102

19 19

No significant difference (0.5 < p < 0.2). more active reflex at 40 weeks post conceptional age, than the m e a n activity found in term infants (Table I). The term and premature infants studied within the first two weeks of life had a less active inspiratory inhibitory reflex than the premature infant of similar post conceptional age (conceptional age = gestational age + postnatal age), who were studied sequentially after birth (Fig. 3). That is, the reflex activity decreased significantly more rapidly (p < 0.001) in infants who had the benefit o f an intrauterine environment for a longer period of time, as compared to the prematurely born infants who

W e have shown that premature infants have a strong inspiratory inhibitory reflex and that the term infant has a much less active reflex than the prematurely born infant. In contrast to Cross and associates' observation, we found no change in the inspiratory inhibitory reflex in the first five days of life in normal term newborn infants. This discrepancy may be due to Cross and associates' actual data which had a wide scatter and included only two follow-up studies. In addition, Younes and associates ~ has recently shown that the duration o f apnea following inflation of the lungs is the result of interaction between declining vagal inspiratory inhibitory activity and rising inspiratory excitatory influence (e.g., increasing arterial CO~ resulting from breath holding). Cross and associates' results may have demonstrated a change in these inspiratory excitatory influences during the first week o f life, i.e., a change in

Volume 88 Number 6

inspiratory chemical drive, rather than a change in vagal influences during the immediate postnatal period. Speculation has arisen as to why man, even as the term newborn infant, has abandoned a method for normal respiratory control that works so well for animals. This might be related to the development of higher evolutionary functions which require the use of "respiratory muscles" to assist in vocalization and complex behavioral acts all of which are incompatible with the inspiratory inhibitory reflex. The integration of these higher functions would thus supercede this simple method for respiratory control. We have demonstrated, with our.sequential studies, a decrease in inspiratory inhibitory reflex with maturation in prematurely born infants, which is in contrast to Bodegard and associates'7 results which included only one infant that was studied sequentially. We have noted a rather large scatter in our data but when we take each individual infant studied sequentially, there is a consistent decrease in the activity of the reflex with age when the change in tidal volume with growth was taken into account. Recently Thach and associates~ have stated that there are no major trends in the lung volume related reflex from 29 weeks' gestation to term. Here again no allowance was made for increasing lung volume: If this increase in lung volume (and decrease in respiratory frequency) that occurs from 29 weeks to 40 weeks are applied to these results for percent change in T~, as used by Thach, then there is a progressive decrease in activity of the inspiratory inhibitory reflex, as expressed by l/m, with increasing gestational age (see Appendix). The decrease in activity of this reflex with maturation of the prematurely born infant depends on whether the development of the infant is intrauterine or extrauterinethe activity of the reflex decreases much more rapidly while the fetus remains in utero. The infant born at 35 weeks' gestational age has a much more active inspiratory inhibitory reflex than the term infant, and even after five weeks of extrauterine development, the infant born at 35 weeks still has a more active reflex than the term infant at birth (both 40 weeks' postconceptional age). The activity of the reflex in the prematurely born infant may not decrease to that of the immediate postnatal term infant until 60 weeks' postconceptional age, demonstrating a detrimental effect of the extrauterine environment on the maturation of this reflex. Although growth velocity in prematurely born infants beyond term follows that of infants born at term, it is as yet unclear whether the neurotogic development of the prematurely born infant after term is the same, with

Hering-Breuer inspiratory inhibitory reflex

10 13

respect to rate and sequence, as the infant born at term. The quantitation of neurologic development has been attempted in recent years, and depending on the neurologic function being studied, this development has been reported to be accelerated, similar or delayed in the prematurely born infant, when compared to the term infant. The delay in maturation of this reflex in prematurely born infants is in contrast to the rate of maturation of some of their other neurologic features, such as electroencephalogram? nerve conduction velocity, 1~ cortical evoked responses/ .... and sleep state. 1:~ 1.~ We have previously suggested that this reflex may help to maintain lung volume in these small preterm infants who are constantly at risk of pulmonary collapse due to the instability of the lungs and pliability of their chest walls. But one might also suggest that the persistence of this simple mechanical mechanism for respiratory control may indicate that the central integration of the more evolutionary advanced inputs into the respiratory control is incomplete. In other words, the persistence of the inspiratory inhibitory reflex may be an index of a more widespread neurologic immaturity. In spite of the fact that some studies on other features of maturation would suggest that the prematurely born infant at term is similar to the term one at birth, this may simply be due to the techniques u s e d - a s suggested by Schulte 1" in connection with EEG studies: "It is quite possible that present-day methods are simply not sensitive enough to detect and quantify all minor differences between infants of equal conceptional ages but different gestational ages." This method of assessing a mechanism for respiratory control has been shown to be sensitive enough to demonstrate that the preterm infant at term still has a much more active inspiratory inhibitory reflex than the term infant at birth; however, the range of activity at any one conceptional age makes the test inapplicable as a measure of maturity.

REFERENCES

1. Hering E, and Breuer J: Die Selbsteurtmg der Athmung durch den nevus vagus - Sitzber, Deut Akad Wiss Wien 57:672, 1868. 2. Widdicombe JG: Respiratory reflexes in man and other animal species, Clin Sci 21:163, 1961. 3. Cross KW, Klaus M, Tooley WH, and Weisser K: The response of the new born boby to inflation of the lungs, J Physiol (London) 151:551, 1960. 4. Olinsky A, Bryan MH, and Bryan AC: Influence of lung inflation on respiratory control in neonates, J Appl Physiol 36:426, 1974. 5. Grunstein MM, Younes M, and Milic-Emili J: Control of

10 14

6.

7.

8.

9.

10.

11.

12.

13.

Kirkpatrick et al.

tidal volume respiratory frequency in unanesthetized cats, J Appl Physiol 35:463, 1973. Younes M, Vaillancourt P, and Milic-Emili J: Interaction between chemical factors and duration of apnea following lung inflation, J Appl Physiol 36:190, 1974. Bodegard G, Schwieler GH, Skoglund S, and Zetterstrom R: Control of respiration in newborn babies, Acta Paediatr Scand 58:567, 1969. Thach BT, Frantz ID, Adler SM, Taeusch HW, and Avery MA: Vagal influence on inspiratory duration in premature infants as a function of postnatal and gestational age, Fed Proc 34:358, 1975. Parmelee AH, Schulte FJ, Akiyama Y, Wenner WM, Schultz MA, and Stern MA: Maturation of EEG activity during sleep in premature infants, EEG Clin Neurophysiol 24:319, 1968. Dubowitz V, W.hittaker GF, Brown BH, and Robinson A: Nerve conduction velocity-an index of neurological maturity of the newborn infant, Rev Med Child Neurol 10:741, 1968. Hrbek A, Kaflberg P, and Olsson T: Development of visual and somatosensory evoked responses in pre-term infants, EEG Clin Neurophysiol 34:225, 1973. Akiyama Y, Schulte FJ, Schultz MA, and Parmelee AH: Acoustically evoked responses in premature and full term infants, EEG Clin Neurophysiol 26:371, 1969. Parmelee AH, Wenner WN, Akiyama Y, Schultz M, and Stern E: Sleep states in premature infants, Rev Med Child Neurol 9:70, 1967.

The Journal of Pediatrics June 1976

14.

Dreyfus-Brisac C: Ontogenesis of sleep in human prelnatur~s after 32 weeks of conceptional age. Dev Physchobiol 3:91, 1970. 15. Schulte FJ: The neurological development of the neonate, in Daves, JA, and Dobbing J, editors: The scientific foundation of paediatrics, London, 1974, William Heinniman, Ltd. APPENDIX

%~T~=(1-

9: 1/T,oo~

1/m

T~ T~or ) X 100

(l)

100 -- :U% ~ T, 100 T~ 1 / T ~ - I/T~o0~ VT

(2)

Substituting for 1/T~o~ 1/m =

% ~T~ 100 • T~ • VT

Therefore, as infant grows, T~ and VT increase and l/m, or inspiratory inhibitory reflex, must decrease.