Vulnerability to Hypoxemia in the Newborn

Transcription

1 Sleep, 3(3/4): Raven Press, New York Vulnerability to Hypoxemia in the Newborn D. J. Henderson-Smart Department of Perinatal Medicine, King George V Memorial Hospital, Sydney, Australia The purposes of this paper are (1) to review the factors which lead to rapid O2 de saturation when breathing is interrupted in the newborn and (2) to examine the various responses to hypoxemia in the newborn, with particular emphasis on the ventilatory component and its state dependence. Many of the concepts expressed in this paper were developed in conjunction with David Read. RAPID OXYGEN DESATURA TION IN THE NEWBORN During apnea in anesthetized newborn puppies, it has been shown that the O 2 saturation decreases more rapidly than in the adult (James, 196). Our observations in babies support this. During studies of both term and preterm babies using an ear oximeter (Waters), rapid rates of desaturation have been observed during even brief pauses in breathing (Henderson-Smart, 1978). This is most marked in preterm babies during both obstructive and central apneas (Fig. 1). No quantitative study has been made comparing newborns and adults. However, if the rate of de saturation is compared with those iii adults with obstructive sleep apnea (Sullivan and Guilleminault, this volume), those in preterm babies are much greater. In adults, Farhi (1964) showed that the factors that determine the arterial O 2 levels during apnea are the O 2 store of the body and the rate of metabolic O 2 consumption. Qualitatively, the most important store of O 2 is in the lungs. The importance of these factors is illustrated by the example shown in Fig. 2, in which an adult has carried out voluntary breath holds at different lung volumes, with and without exercise. There is a need for quantitative data in newborns of different species and at various postnatal ages. Our observations in human neonates suggest that the arterial O 2 levels fluctuate rapidly and resemble those observed in the adult with a reduced lung volume, during exercise or at high altitude. In babies a number of factors might contribute to the increased rate of O 2 de saturation during apnea. Like adults at high altitude, they may start at a lower saturation and thus be on the steep part ofthe oxyhemoglobin dissociation curve. Furthermore, they have small lung oxygen stores (end-expiratory lung volumes) in relation to their rate of O 2 consumption (Cook et al., 1957). During central apnea, Accepted for publication September 198. Address correspondence and reprint requests to Dr. Henderson-Smart at Department of Perinatal Medicine, King George V Memorial Hospital, Camperdown, NSW 25, Sydney. Australia. 331

2 332 D. J. HENDERSON-SMART a nme '.Klniiimlimiimhimiiql... ~himlinn,mnnnmutmnnli.mnmil,m'imnmn,miim.nmiimii.mnmiiim.. 1 Sao." 9 8 b TIME, cllihiilitiilihhnhuiliiliihihiiluiliiiiiwiliiliihiiiliiiiiui... 1li1ii1ii 1.1/11 l Sao." 9t FIG. 1. Recordings of diaphragm movements recorded with an abdominal strain gauge (ABDIDI) and O. saturation (Sao.) in a preterm baby breathing 3%. Top: A central apnea of 45 sec duration results in a marked fall in Sao. despite prior O. supplementation. Bottom: The apnea is initially central and then obstructive (falling Sao. despite increased breathing efforts). Note that the paper speed has been halved in the middle section of the upper trace. Sao,... loof-f I 9 I 8 full INSPIRATION END ElPIRAflON Rf$IDUAL VOlUME :::fw. :>J ~ 14 cond. I 1\ ( AT ~ -t r EXERCISE V REST FIG. 2. The effects on oxygen saturation (Sao.) of breath holds at different lung volumes and increased O. consumption (light exercise) in an adult. The lower the lung volume (. store), the more rapid the fall in Sao. (time taken to reach 9O'Yo recorded). Exercise increases the rate of fall in Sao. at all levels of lung volume. Over the same range of Sao., the rate of fall in the baby during apnea is similar to that observed in the adult at low lung volumes or at resting lung volume during light exercise. Sleep, Vol. 3, No. 314, 198

3 HYPOXEMIA IN THE NEWBORN 333 ~, the lung volume decreases further (Olinsky et al., 1974). In normal term babies, lung volume decreases by an average of 3% (Henderson-Smart and Read, 1979) during active sleep at a time when metabolic O 2 consumption is increased and apneas are more frequently observed. I, t\':' RESPONSES TO HYPOXEMIA IN THE NEWBORN Physiological defenses in the presence of rapidly falling arterial O 2 level might include cardiovascular reflexes, metabolic adjustments, and ventilatory responses. In the newborn, there is evidence that all of these may play some part. Cardiovascular reflexes are similar to those seen in diving aquatic mammals (Daly et al., 1979). They include a redistribution of the body's blood flow to favor the heart and brain, as well as a decrease in heart rate and cardiac output. Such responses are a major defense for the fetus, in which there is ventilatory depression in the presence of hypoxia (Boddy et ai., 1974). In apneic newborn human, recordings of bradycardia and peripheral vasoconstriction suggest similar reflexes are active (Storrs, 1977). In the adult human, these reflexes appear to be less active. It is unclear when these reflexes become less active during development. Metabolic changes, including utilization of anaerobic energy-producing pathways, may also account for the newborn's resistance to hypoxic cellular damage. During hypoxia in newborn babies, a decrease in O 2 consumption has been observed, and it has been suggested that this represents a switch to anaerobic metabolism (Cross and Warner, 1951). In the fetal, newborn and adult sheep, myocardial glycogen stores appear to be critical determinants of hypoxic survival and account for the sustained circulatory response and resistance to hypoxia seen in the mature fetus and newborn (Dawes, 1968). VENTILATORY RESPONSE TO HYPOXIA The carotid bodies appear to be the main O 2 sensors influencing breathing. In newborn lambs the discharge of carotid chemoreceptor afferents increases with hypoxemia and decreases with elevation of Pao 2 (Biscoe and Purves, 1967). However, the absolute firing rate of these afferents at any given level of oxygenation is less in newborn kittens than in the adult cat (Schwieler, 1968). Hyperoxia produces an immediate fall in ventilation in both term and preterm babies (Cross and Warner, 1951; Rigatto et ai., 1975a). This suggests that the carotid body reflexes are active and that resting hypoxic drive is considerable. That is consistent with the findings of lower resting Pao 2 in newborn babies. However, after this initial fall, over the first minute of hyperoxia, ventilation rises above the control values. This may reflect hyperoxic cerebral vasoconstriction with accumulation of brain tissue CO 2 and consequent increased drive to breathe as postulated for adult man (Lambertsen, 1965). This could be greater in the newborn, since hyperoxic vasoconstriction is more intense in newborn puppies (Kennedy et ai., 1971). Administration of low O 2 mixtures (12-18%) results in a biphasic ventilatory response peculiar to the newborn (Cross and Warner, 1951; Rigatto et ai., 1975a). There is an initial increase in ventilation lasting 1-2 minutes followed by a sus- Sleep, Vol. 3, No. 314, 198

4 334 D. J. HENDERSON-SMART tained fall below resting levels. This fall occurs even if the Paco2 is prevented from decreasing during the initial hyperventilation. In a coid environment the controi levels of ventilation are increased, and during administration of hypoxic gases only ventilatory depression is observed (Ceruti, 1966). The maturation of hypoxic responses is poorly documented. Studies in a few infants suggest a sustained increase in ventilation after the first week oflife in term babies (Ceruti, 1966) and after 18 days in those born before term (Rigatto et ai., 1975a). Various mechanisms for this poorly sustained hypoxic ventilatory response in the newborn have been suggested. The usual explanation is direct medullary hypoxic depression (Rigatto et ai., 1975a). However, studies of anesthetized newborn animals indicate that hypoxic depression occurs at P2 levels well below those likely to occur in the babies while breathing 12-18% O2, That the carotid sensors are still active and influencing breathing during the phase of ventilatory depression is indicated by an immediate further fall in ventilation on returning to air or an 2-rich mixture. This is also supported by studies in decerebrate newborn kittens with similar biphasic ventilatory responses, in which carotid nerve recordings indicate continued firing during ventilatory depression (Schwieler, 1968). An increase of cerebral blood flow in response to the hypoxemia could account for the decreased drive to breathe by lowering brain tissue Pco2. A vigorous cerebral blood flow response to altered O2 levels might also explain the reversal of the COJ2 interaction in the newborn baby compared with the adult. If the arterial O2 level falls in the newborn, the ventilatory response to CO2 is depressed, while with raised O2 levels it is increased (Rigatto et ai., 1975b). Thus, there appear to be three types ofresponse to hypoxemia during development: (1) ventilatory depression in utero; (2) an initial increase in ventilation, then depression in some newborn species; and (3) a sustained increase in ventilation in older infants and adults. VENTILATORY RESPONSES TO HYPOXEMIA AND SLEEP STATES Hyperoxic Tests In newborn babies the resting hypoxic drive is similar in quiet or active sleep as measured by observing the fall in minute ventilation while breathing 1% O2 (Bolton and Herman, 1974; Fagenholz et ai., 1976). These results do not indicate whether the baby is able to increase its level of ventilation during hypoxemia. Hypoxic Tests The author and David Read have studied ventilatory responses to rapidly developing hypoxemia during natural sleep in newborn lambs and puppies. Details of the methods and results have been reported elsewhere (Henderson-Smart and Read, 1979). Briefly, ventilation was derived from integration of the airflow measured at the nose in the lambs and at a chronic tracheostomy in the puppies. This was related to the arterial O2 saturation measured directly with a polarographic Sleep, Vol. 3, No. 314, 198

5 . HYPOXEMIA IN THE NEWBORN 335 curette oximeter in the lambs and derived from the end-tidal O2 tension measured with a mass spectrometer in the puppies. In each animal, rapidly developing hypoxemia was induced by rebreathing from a small bag ofn2. The volume ofthis bag was previously determined in trial runs to prevent hypocapnia during any ventilatory responses. Consistency of the end-tidal Pc2 was ensured by measurements during each test. Sleep state was scored as active (REM) and quiet (non-rem) from the electroencephalogram, eye movements, and behavioral observations. To examine the rib cage motion and intercostal muscle activity in quiet and active sleep, 3 additiional puppies with intact upper airways were also studied. The lambs showed depressed ventilatory responses to rapidly developing hypoxemia in active sleep (AS) compared with quiet sleep (QS). During each episode of AS in the lambs, the rib cage moved paradoxically by collapsing during each inspiration. Typical records for a lamb are shown in Fig. 3. This depicts the usual prompt ventilatory response to a falling arterial O2 saturation (Sa 2 ) and arousal at a Sa2 QUIET SLEEP ACTIVE SLEEP 1-'~"...J.I""""... j_..._a.i..-i.-j 1 [......,."""""I.4-...'IWI,.,.".1'/w- EEG "'I'''l'1''rvl... r~...,... ~v EOG RI8CAGEi~ VENT O[ I I _ I/min -~ o L...I S-. FIG. 3. Typical records of hypoxic tests in a lamb. showing in quiet sleep a prompt ventilatory response and arousal at an O2 saturation (Sao2) of 72%; in active sleep. a depressed ventilatory response and no arousal despite a fall of the Sao2 to 5%. In active sleep the diaphragm electromyogram (EMG) activity increased only at the lowest Sao2levels. and at this time rib cage paradox became more obvious and there was no ventilatory response. (Reproduced with permission from Henderson Smart and Read ) Sleep. Vol. 3. No. 3/4. /98

6 336 D. 1. HENDERSON~SMARq:"... C) I- '" 15 1 z C) 14 u ~t >I' 13. z... C).. :s I- 12 a OS LAMB I ;:: z 11 AS... ~ >... bcp ~ I- => 1..-, "". z.~ FIG. 4. Repeated hypoxic tests in quiet sleep i (filled symbols) and active sleep (open symbols) 9 i i i i in a lamb. The upper panel shows that minute ventilation increased promptly and consistently in quiet sleep, whereas this response was de pressed in each test during active sleep. In the C) lower panel, the breathing rate is shown to in- I- '" z 14 crease in both states over the same range of C) u Sao2' (Reproduced with permission from. Henderson-Smart and Read, 1979.) >I' ~ I- ~o 12. < - < :. '" >- '" 11. C) '" e. o "- 1 u.tj5 '"... '" 9. i i OXYGEN SATURATION '" of 72% in QS; in contrast, during AS there was no ventilatory response and no arousal despite a fau of Sao2 to 5%. Graphs relating the ventilatory responses to Sao2 during each sleep state in this lamb are shown in the upper panel of Fig. 4. Despite the depressed ventilatory response, the respiratory rate increased significantly in response to hypoxemia in AS. Depression of the ventilatory response during AS was associated with failure to augment tidal volume. Arousal occurred more frequently and at a higher Sao2 in QS than in AS in the lambs. During QS, arousal occurred in 6 ofthe 8 tests at Sao2levels of between 83 and 71%. In contrast, during AS arousal occurred in only 2 of 8 tests at 45 and 48%, despite the lower levels reached (45-58%). In contrast to the lambs, puppies increased their ventilation in response to hypoxemia in both sleep states. For each ofthe 4 puppies, the slope of the linear regression obtained when minute ventilation as a percentage of control was related to log end-tidal P2 or to the derived Sao2 was not significantly different in the two sleep states. During AS, the ventilatory response was more irregular breath by breath. A typical result for 1 of the puppies is shown in Fig. 5. Sleep, Vol. 3, No. 3/4, 198

7 HYPOXEMIA IN THE NEWBORN PUppy Z '" 3 (.) 26 '" 22 Z ~ -..: ;:: Z... > ::> z 1 i..... c c ".J,,L, c ~_. a ~ ~oo t. '( FIG. 5. Typical ventilatory responses to hypoxemia in a puppy. Minute ventilation increased in both quiet (filled symbols) and active (open symbols) sleep. Each symbol represents a different test, there being three in each sleep state. During active sleep the ventilatory responses are more irregular breath by breath. (Reproduced with permission from Henderson-Smart and Read, 1979.) 8 i 1 i 9 i 8 i 7 i 6 OXYGEN SATURATION ~ I 5 No puppy developed inspiratory rib cage collapse during any episode of actiw sleep. In the 3 additional puppies with intact upper airways, inspiratory rib cage inflation also persisted during each episode of active sleep, despite depression of lateral intercostal muscle activity (Fig. 6). Inspiratory activity in the anterior (interchondral) muscles, like that of the diaphragm, usually increased in active sleep, although there was marked breath-by-breath variability. GENERAL DISCUSSION It is possible that previous studies showing depressed ventilatory responses to hypoxemia during undefined states in newborn babies may have been performed QUIET SLEEP Rct~ '11' 1" 1 EOG"-" sec ACTIVE SLEEP ~ III 11.1' t". I tlil,1. 'I I tn I ' ill. 1 I. HIIIIIIIIII""" "~ FIG. 6. Recordings ofa 1-week-old puppy with intact upper airway. From top down, rib cage motion (RC), with inflation upwards; diaphragm EMG (OI); anterior interchondral EMG (A IC); posterior intercostal EMG (P IC), and eye movements (EOG). Inspiratory rib cage inflation is present in both sleep states despite depression of intercostal muscle activity. (Reproduced with permission from Henderson-Smart and Read, 1979.) Sleep, Vol. 3. No. 3/4, 198

8 338 D. J. HENDERSON-SMART predominantly in AS. This particularly likely in preterm babies, who spend a great deal of time in that state. Lambs develop inspiratory rib cage collapse in AS and have depressed ventilatory responses to rapidly developing hypoxemia in that sleep state. In marked contrast, the puppies do not develop inspiratory rib cage collapse and have similar responses to hypoxemia in both AS and QS. Arousals at low Sa2 as seen in the lambs during AS is similar to that observed in adult dogs (Phillipson et ai., 1978). Despite depressed arousal, adult dogs have intact ventilatory responses to hypoxemia in AS, which is similar to the observation in puppies. Possible Reasons for Difference Between States and Between Species A number of factors might explain the difference between the ventilatory responses of lambs and puppies. The first is that during AS in the lamb, the ventilatory response is depressed because of the presence of inspiratory rib cage collapse. Under these circumstances any increased drive to breathe could be dissipated partially in further rib cage distortion. This concept is supported by the correlation of synchronous rib cage movements and intact responses to hypoxemia in the puppies. Furthermore, recent observations by Jeffrey and Read (198) show that full-term newborn calves also have both inspiratory rib cage collapse and depressed ventilatory responses to hypoxemia during AS. A second possibility is that the phasic collapse of the chest wall sets up inhibitory reflexes; this has been postulated in babies and related to rib cage distortion (Knill and Bryan, 1976). The inhibition might be expected to increase progressively with increased central drive and could be a factor limiting the peak diaphragm electromyogram (EMG) activity. Such EMG inhibition has been observed in anesthetized cats during manual distortion of the rib cage (Remmers, 197). There is evidence that the diaphragm is already under increased drive during AS in the newborn, and it is possible that a larger chemoreceptor stimulus may be necessary to further increase its activity at that time. During AS in babies, an increase in the descent of the diaphragm occurs, and this may indicate increased shortening (Knill et ai., 1976; Henderson-Smart and Read, 1979). In lambs during that sleep phase, the diaphragm is the main active respiratory muscle and often shows increased EMG activity (Henderson-Smart and Read, 1978). However, in lambs much ofthis activity may be due to sleep-related events in AS, as opposed to chemoreceptor drive as in QS (Henderson-Smart et al., in press). It has recently been suggested that diaphragm muscle fatigue develops during AS in babies due to the increased work load imposed by rib cage collapse (Muller et al ). This is based on the patterns obtained by spectral analysis of surface recordings of diaphragm EMGs. If these patterns do indicate muscle fatigue, this could contribute to the diminished response to increased drive, such as during hypoxemia. However, there is some doubt as to whether surface recordings reliably reflect only diaphragmatic activity. Even direct recordings of the lateral diaphragm are contaminated with activity from adjacent intercostal and abdominal muscles (Harding et ai., 1979). Sleep, Vol. 3, No. 314, 198

9 HYPOXEMIA IN THE NEWBORN 339 In puppies, upper airway resistance to airflow was bypassed by tracheostomy. This could theoretically have lead to an unloading of the respiratory pump, absence of inspiratory rib cage collapse, and an ability to produce a ventilatory response to the hypoxic stimulus during sleep. We do not have measurements of airway resistance in the puppies or lambs. The present observations that puppies with intact upper airways still do not develop inspiratory rib cage collapse in AS despite depression of intercostal muscle activity suggest that there is some difference between the intrinsic rib cage stability of puppies and that of lambs. There are no other studies of rib cage motion during different sleep states in puppies. Agostoni (1959) has shown that the rib cage of the newborn puppy is more compliant than in adults, although no comparisons between puppies and lambs have been made. We have made a preliminary post-mortem study ofthe rib cage oflambs and puppies (unpublished) and observed that the chondral portion is short in the lamb, whereas it is more extensive in the puppy (Fig. 7). Muscles in this region are more resistant to the spinal inhibition of AS and may provide a wider area of stability in the puppy. Differences in the shape of the rib cage or the orientation of the ribs may also contribute. ' Possible Clinical Implications The finding of depressed ventilatory responses in association with rib cage paradox in the lamb could have implications for babies, who have been shown to have similar rib cage movements during AS for at least the first 3 months oflife or longer (Henderson-Smart and Read, ). While these rib cage movements are part of normal development, under circumstances of increased load due to airway obstruction or noncompliant lungs, the mechanical handicap or rib cage paradox may result in markedly different ventilatory responses to propioceptive LAMB costochondral rost junction PUppy post FIG. 7. Diagrams of the rib cages of a lamb and a puppy. traced from photographs. Note the more extensive interchondral segment in the puppy. rost costochondral junction post Sleep, Vol. 3, No. 3/4, 198

10 34 D. J. HENDERSON-SMART or chemoreceptive drives. Even in normal babies there is evidence that ventilation ~.., l.o.c'c' 'n1..f::!o,l ~_.n;_.o.a An"";...,.,...o.co;cot;uo 11>I1... noll 1'7h\ r:::t.nrl olr:::t.c't"ro (V";l1 ot o:l.l I,;).1"""" ",-,1.1 J.J.IQl.l1Il.a.ll1'-'U UUJ.J.J..l5.",.,....,LJ.Y,,",,"'''''.1.,,",,'''.1.,.1../1"") 1L4.1..I.,.,.... J.U..:H..."" \..&."' _" _.I.., 1976) loads during AS. ACKNOWLEDGMENT This research was performed with Professor David Read in the Department of Physiology at the University of Sydney. It was supported by the National Health and Medical Research Council of Australia, the Asthma Foundation of New South Wales, and the Copple son Postgraduate Medical Foundation at the University of Sydney. Equipment was provided by generous donations from the Ramaciotti Foundations (Australia) and the Sunley Foundation (England). D. J. Henderson Smart was supported by a N.H. & M.R.C. Studentship. Thanks go to Dr. George Alexander, Division of Animal Production, C.S.I.R.O. Prospect, for supplying the lambs used in this study. REFERENCES Agostoni E. Volume-pressure relationships of the thorax and lung in the newborn. J Appl Physiol 14:99-913, Biscoe TJ and Purves MJ. Carotid body chemoreceptor activity in the newborn lamb. J Physiol 19: , Boddy K, Dawes OS, Fisher R, Pinter S, and Robinson J. Foetal respiratory movements, electrocortical and cardiovascular responses to hypoxaemia and hypercapnia in sheep. J PhysioI243: , Bolton EPG and Herman S. Ventilation and sleep state in the newborn. J Physiol 24:67-77, Ceruti E. Chemoreceptor reflexes in the newborn infant: Effect of cooling on the response to hypoxia. Pediatrics 37: , Cook CD, Cherry RB, O'Brien D, et al. Studies of respiratory physiology in the newborn infant. 1. Observation of normal premature and full-term infants. J Clin Invest 34: , Cross KW and Warner P. The effect of inhalation of high and low concentrations of oxygen on the respiration of the newborn infant. J Physiol 114: , Daly M De B., Angell-James JE, and Elsner R. Role of carotid body chemoreceptors and their reflex interactions in bradycardia and cardiac arrest. Lancet 1: , Dawes OS. Foetal and Neonatal Physiology. Chicago, Year Book Medical, Fagenholz SA, O'Connel K, Shannon DC. Chemoreceptor function and sleep state in apnoea. Pediatrics 58:31-36, Farhi LE. Gas stores of the body. In: WD Fenn and H Rahn (Eds), Handbook of Physiology, Vol I, Respiration, American Physiological Society, Washington, DC, 1964, pp Harding R, Henderson-Smart DJ, McClelland ME, and Johnson P. Posturally related tonic activity recorded from the peripheral diaphragm in awake and sleeping lambs. J Physiol 292:57, Henderson-Smart DJ and Read DJC. Depression of respiratory muscles and defective responses to nasal obstruction during active sleep in the newborn. Aust Pediatr J 12: , Henderson-Smart DJ and Read DJC. Depression of intercostal and abdominal muscle activity and vulnerability to asphyxia during active sleep in the newborn. In: C Gu'illeminault and WC Dement (Eds): Sleep Apnea Syndromes, Alan R Liss, New York, 1978, pp Henderson-Smart DJ and Read DJC. Reduced lung volume during behavioral active sleep in newborn babies. J Appl Physiol 46: , Henderson-Smart DJ, Johnson P, and McClelland ME. The abolition of spontaneous breathing during quiet sleep by eupneic positive pressure ventilation in lambs. J Physiol (in press). James LS. Acidosis of the newborn and its relation to birth asphyxia. Acta Paediatr Scand Suppl 122:17-28,196. Jeffrey HE and Read DJC. Ventilatory responses of newborn calves to progressive hypoxia in quiet and active sleep. J Appl Physiol 48: , 198. Kennedy D, Grave GD, and Jehle JW. Effects of hype roxi a on the cerebral circulation of the newborn puppy. Pediatr Res 5: , Sleep, Vol. 3, No. 3/4, 198

11 HYPOXEMIA IN THE NEWBORN 341 Knill R and Bryan AC. An intercostal-phrenic inhibitory reflex in human newborn infants. J Appl Physiol 4: , Knill R, Andrews W, Bryan AC, and Bryan MH. Respiratory load compensation in infants. J Appl Physiol 4: , Lambertsen OJ. Effects of oxygen at high partial pressure. In: WD Fenn and H Rahn (Eds), Handbook of Physiology, Vo12, Respiration, American Physiological Society, Washington, DC, 1965, P 127. Muller NL, Gulston G, Cade, Whitton J, Bryan MH, and Bryan AC. Diaphragmatic muscle fatigue in the newborn. J App/ Physio/ 46: , Olinsky A, Bryan NH, and Bryan AC. Influence oflung inflation on respiratory control in neonates. J App/ Physio/ 36: , Olin sky A, Bryan MH, and Bryan AC. Response of newborn infant to added respiratory loads. J Appl Physio/ 37: , Phillipson EA. Respiratory adaptations in sleep. Annu Rev PhysioI4O: , Phillipson EA, Sullivan CE, Read DJC, Murphy E, and Kozar LF. Ventilatory and waking responses to hypoxia in sleeping dogs. J App/ Physio/ 44:512-52, Purcell M. Response in the newborn to raised upper airways resistance. Arch Dis Child 51:62-67, Remmers JE. Inhibition of inspiratory activity by intercostal muscle afferents. Resp Physio/ 1: , 197. Rigatto H, Brady JP, and Verduzco RT. Chemoreceptor reflexes in preterm infants: 1. The effects of gestational and postnatal age on the ventilatory response to inhalation of 1% and 15% oxygen. Pediatrics 55:64-613, 1975a. Rigatto H, Torre Verduzco R de la, and Cates DB. Effects of oxygen on the ventilatory response to CO, in preterm infants. J App/ Physio/ 39: , 1975b. Schwieler GH. Respiratory regulation during postnatal development in cats and rabbits and some of its morphological substrate. Acta Physiol Scand Supp/ 34: 1-123, Storrs CN. Cardiovascular effects of apnea in preterm infants. Arch Dis Child 52:534-54, Discussion Dr. Jeffrey said that she and Dr. Read studied the ventilatory response to progressive isocapnic hypoxia in 5 newborn calves and found rib cage paradox and a depressed ventilatory response during active sleep. Unlike the data in lambs, they showed no increase in breathing rate during hypoxia in either quiet or active sleep, which suggests that there is a species difference in the ventilatory response to hypoxia. Dr. Phillipson suggested that another cause of the rapid oxyhemoglobin de saturation in premature newborn infants could be shunting through the ductus arteriosus or foramen ovale in response to hypoxia-induced pulmonary vasoconstriction. Such shunting has been observed in babies with respiratory distress syndrome. Dr. Shannon pointed out that in the studies in which Rigatto had shown a biphasic ventilatory response to hypoxia, the babies' Pco 2 levels did not increase. He said that in his own studies of lambs with denervated carotid bodies, this phenomenon seemed to be associated with a depression in metabolic rate. He wondered if similar observations were made in the lambs and puppies. Dr. Henderson-Smart replied that they kept end-tidal CO 2 constant, but did not measure CO 2 production. Dr. Mouret asked if some of the differences might arise from the fact that lambs utilize the pentose pathway instead of the glycolytic pathway, while suckling. Dr. Bryan also noted that biochemical factors might be important, particularly in relation to respiratory muscle performance. He pointed out that the newborn calf was able to utilize both glucose and lactate for energy production and that newborn mammals appear to be able to switch off oxidative metabolism and conserve O 2, Dr. Shannon outlined work he had done recently with neurological colleagues. While the neurologists did physical examinations of preterm infants weighing under 15 g, his own team did 12 hr cardiorespiratory recordings on the same babies, without prior knowledge of the neurological findings. They found in general that the babies who developed apnea were clearly identified as neurologically abnormal. In more recent work it appears that those Sleep, Vol. 3, No. 3/4, 198

12 342 D. J. HENDERSON-SMART who develop prolonged apnea have computer assisted tomography scan evidence of intraventricular hemorrhage during the tlrst 24 hr. Dr. Henderson-Smart said that in his experience apnea usually began on the first day of life, so it would be difficult to have a neurological examination preceding the onset of apnea. Dr. Schulte said that his own results of over 1 years of examining babies were in strong disagreement with those of Dr. Shannon. When he examined many hundreds of preterm babies consecutively, he could not find a neurological difference between babies with apnea and those without. He also noted that a low blood glucose is common in babies less than 15 g and that he had not been able to find a correlation between blood glucose, the rapidity of fall in blood glucose, and the neurological examination. Sleep, Vol. 3, No. 3/4, 198