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Obstructive, mixed, and central apnea in the neonate: Physiologic correlates
FETAL AND NEONATAL MEDICINE
Obstructive, mixed, and central apnea in the neonate' Physiologic correlates Nell N. Finer, MD, Keith J. Barrington, MD, Barbara J. Hayes, RN, a n d Aston Hugh, BSc From the Department of Newborn Medicine, Royal Alexandra Hospital, and the Department of Pediatrics, Universityof Alberta, Edmonton, Alberta, Canada In an attempt to determine physiologic responses to neonatal apnea, we evaluated changes in heart rate and o x y g e n saturation as measured by pulse oximetry during 2082 episodes of a p n e a lasting 15 seconds or more in 47 infants less than 34 weeks of gestational a g e with i d i o p a t h i c apnea of prematurity. Of these episodes, 832 (39.9%) were central, 1032 (49.6%) were mixed, and 218 (10.5%) w e r e obstructive. Oxygen saturation d e c r e a s e d with increasing duration of apnea regardless of type or treatment, and the decrease in saturation was correlated with preapnea saturation. The baseline heart rate was similar for all a p n e a types. Infants receiving d o x a p r a m had a l o w e r b a s e l i n e h e a r t r a t e ( 1 3 7 . 8 _ 10.5 beats/min) than did infants receiving no therapy (142.8 _ 16.6 b e a t s / m i n ) and infants receiving theophylline (149.7 _+ 15.0 beats/min) (p = <0.001). A heart rate fall to less than 100 b e a t s / m i n was seen more frequently with central a p n e a than with mixed or obstructive events, and in infants who were not receiving therapy. Falls in heart rate were significantly less in infants receiving d o x a p r a m ( 2 7 . 8 % ___18.0%) than in infants receiving theophylline (44.5% _+ 19.0%) or no therapy (48.4% _+ 18.3%) (p = <0.001). The most common heart rate pattern o v e r a l l was a gradual decrease interrupted by accelerations, whereas an initial heart rate a c c e l e r a t i o n was the most c o m m o n pattern in obstructive apnea. We c o n c l u d e that heart rate response to neonatal a p n e a is c o m p l e x and is dependent on therapy and on type and duration of apnea. (J PEDIATR1992;121:943-50)
Idiopathic apnea of prematurity is common in low birth weight neonates. Central apnea is usually readily diagnosed by using current monitoring systems and nursing surveillance, but mixed and obstructive events are more difficult to diagnose because the monitoring of chest wall movement is unreliable.1-5 In our experience, 50% of significant idiopathic apnea of prematurity has an obstructive component; approximately 40% of all episodes are mixed events, and 10% are obstructive. I The most commonly employed methods of detecting obstructive apnea have involved the measurement of air flow at the nose with thermistors or the measurement of exhaled
Submitted for publication Nov. 14, 1992; accepted July 17, 1992. Reprint requests: Nell N. Finer, MD, Royal Alexandra Hospital, 10240 Kingsway, Edmonton, Alberta T5H 3V9, Canada. 9/23/41044
carbon dioxide by using end-tidal CO2 devices. 6 None of these devices, however, is currently available for routine monitoring of the low birth weight infant with apnea. Because all of our studies evaluating apnea of prematurity have involved the use of end-tidal CO2 along with measurement of heart rate, impedance pneumography, and pulse oximetry, we thought that it would be useful to evaluate the ANOVA
Analysis of variance
physiologic response of the neonate to the different apnea types. We questioned whether there may be some pattern of abnormalities in the currently monitored measurements that might facilitate the recognition of these events without the use of more cumbersome monitoring. In addition, we wished to evaluate the effects of pharmacologic therapy on the physiologic response to neonatal apnea.
943
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Finer et al.
The Journal of Pediatrics December 1992
5O 45
~-~
Central Mixed ObsLruetive
40 r.~
35 o . ,-q
bO 25 oO
2O 15
r_)
10 5 0 0
<20
:0-30
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50-40
40-50
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(sec)
>50
Fig. I. Falls in oxygen saturation plotted against durations of apnea from less than 20 seconds to more than 50 seconds by apnea type (central, mixed, and obstructive). Increasing apnea length was associated with greater desaturation (r = 0.26; p = 0.0001).
METHODS
We reviewed and analyzed apnea epochs that had been recorded during two previous prospective trials using identical methods to evaluate idiopathic apnea of prematurity. !, v The first trial involved infants receiving theophylline or no therapy, and the second was a randomized, placebocontrolled evaluation of doxapram and theophylline. In both studies, infants were treated if they had more than 0.3 episode of apnea per hour, lasting 15 seconds or more, with either a 5% or greater desaturation or a 20% decrease in heart rate, or both. All infants had normal findings on clinical examination, no evidence of intracranial abnormality by ultrasound examination, no evidence of sepsis or of electrolyte or metabolic disorder, and no evidence of pulmonary parenchymal disorders. Oxygen was administered only to infants whose baseline oxygen saturation was less than 90% to 92%. The infant's sleep state during the recording was not determined. The methods have been described previously. A computerized data acquisition system inolttded a personal computer (Compaq 286 or Compaq 386; Compaq Computer Corp., Houston, Tex.) with an analog to digital conversion device (DT2801, Data Translation Inc., Marlborough, Mass.). The computer was interfaced to the neonates' mon-
itors by using the outputs available from the monitor (model 78833B or 78801A; Hewlett Packard, Federal Republic of Germany) to record heart rate, impedance respiration, and the outputs available from the pulse oximeter (model N-100 or N-200; NeUcor Inc., Hayward, Calif.) and an end-tidal CO2 monitor (Traverse Capnometer, model 2200; Trudell Medical, Saline, Mich.). An acquisition program was written with proprietary software (Asyst, Macmillan Software Co., New York, N.Y.) for the data acquisition and subsequent analysis. After each 12 hot/rs of data acquisition, the computer identified epochs in which there had been a fall to baseline ( + 5%) of the end-tidal CO2 signal, which was associated with either a fall in heart rate of 20% from the previous mean (which was continuously calculated) or a fall in pulse oximetry-measured oxygen saturation of more than 5%. Any event that was thought to be secondary to artifact, either move~nent by the infant or dislodgment of the end-tidal CO2 catheter from the tip of the nares, or secondary to artifactual change in the other measurements was not further considered. Only epochs in which there was evidence of an appropriate end-tidal CO2 signal, both before and after the event, were analyzed to avoid long periods of potential mouth breathing. In addition, to qualify as a significant
Volume 121 Number 6
Obstructive, mixed, and central apnea in the neonate
100
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-
Central
90
Mixed Obstructive
80
70 O 9~
60
V
50
40 t 0
,~
<20
20-30
50-40
40-50
>50
Apnea Duration (see) Fig. 2. Percentage of apnea associated with a heart rate fall to less than 100 beats/min, shown for apnea durations from less than 20 seconds to greater than 50 seconds by apnea type (central, mixed, and obstructive). Central apnea had a significantly greater association with a fall in heart rate to less than 100 beats/min, compared with mixed and obstructive events (p <0.000l).
event, there needed to be absence of the end-tidal signal with simultaneous evidence of desaturation or a fall in heart rate or both. Epochs associated with exaggerated impedance movement and sudden falls in saturation, especially of more than 30% for 5 to 15 seconds, were rejected as being probable movement artifact. All apnea episodes lasting 15 seconds or longer were stored and described as being central, mixed, or obstructive. A central event was defined as apnea in which no breaths were detected by chest movement and end-tidal CO2 recording. An obstructive event was defined as apnea during which the impedance recording of chest movement continued and was usually exaggerated, in association with the absence of detectable exhaled CO2 at the nares. A mixed event was defined as apnea in which there was evidence of both a central and an obstructive component; such events required at least 3 seconds of central apnea. Data on all epochs were then saved and reviewed. For each event, the computer file contained information regarding the mean value calculated for the 2 minutes before the event for heart rate and saturation, plus the entire apnea event. The falls in both heart rate and saturation were
I. Episodes of apnea of each type, in each duration category Table
Duration ($ec) <20 20-30 30-40 40-50 >50
Episodes of a p n e a (No.) Central
Mixed
Obstructive
213 455 115 27 22
152 537 180 80 83
62 103 30 16 7
Mean chronologicage = 4.32 days (range, 1 to 21 days).
characterized as the absolute fall, and the percentage fall was defined as the percentage of change from the previous mean. Apnea was analyzed by duration, the categories being less than 20 seconds, 20 to 30 seconds, 30 to 40 seconds, 40 to 50 seconds, and more than 50 seconds. In addition, the changes in heart rate and oxygen saturation were analyzed by treatment categories, including theophylline, doxapram, or no treatment.
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The Journal o f Pediatrics December 1992
70
60
Central Mixed Obstructive
~
50 o 40 09 o
30
20
10 0
<20
, , 20-30
~0-40
40-50
>50
Apnea Duration (see) Fig. 3. Percentage fall in heart rate (_+SD) plotted against apnea durations by apnea type (central, mixed, and obstructive). With increasing apnea duration, there was a lesser percentage fall in the heart rate for all types of apnea.
To further characterize the heart rate response to apnea, we visually reviewed 100 episodes of each type. We developed a classification for the pattern of the heart rate response, which included a step fall in heart rate or a more gradual fall either with or without interruption, an oscillating pattern during which the heart rate oscillated about the previous baseline, or an initial acceleration with or without a subsequent fall. We then reviewed all apnea episodes for which the original epoch had been saved in its entirety and determined the pattern of heart rate change. The statistical analysis included the use of a completely randomized one-way and three-way factorial analysis of variance and a Pearson correlation coefficient regression analysis. The Scheff6 procedure and the Fisher protected least significance difference were used for determining intergroup significant differences for one-way and three-way ANOVAs. A contingency table analysis was used for proportional data. In view of the multiple testing done by contingency table analysis, a p value of <0.001 was considered significant. The three-factor factorial ANOVA was used to reduce the number of analyses ~[serformed and to compare the effects of apnea type, apnea duration, and treatment on the percentage fall in heart rate during apnea. 8 For all analyses, a p value of <0.01 was considered significant in view of the multiple analyses performed. Results are presented as means • SD. All information analyzed in our
study was obtained from data on infants whose parents had consented to participation and analysis of results in the original trials. RESULTS Our study involved the analysis of 2082 episodes of apnea from 47 infants born at 27 to 34 weeks of gestation and weighing 920 to 2470 gm at birth. There was no significant difference in birth weight or gestational age between infants who received no therapy (1598 +__ 125 gm; 31.3 - .7 weeks) and those ~ho received arninophylline (1441 + 119 gm; 30.7 • 0.8 weeks) or doxapram (1303 _ 97 gin; 30.7 + 0.63 weeks). The infants were studied at a mean chronologic age of 41/2days (range, 1 to21 days). Of these episodes, 832 (39.9%) were central, i032 (49.6%)were mixed, and 218 (10.5%) Were obstructive (Table I). There were 585 episodes of apnea in infants who were not receiving pharmacologic therapy, 1204 in infants treated with aminophylline or theophylline (subsequently referred to as theophylline), 251 in infants treated with doxapram, and 42 in infants treated with both theophylline and doxapram. No further analysis of the last group was performed because of the small number. As apnea duration increased, the fall in oxygen saturation as recorded by pulse oximetry also increased (r = 0.26; p = 0.0001); this relationship was significant for all apnea
Volume t21 Number 6
Obstructive, mixed, a n d central apnea in the neonate
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Fig. 4. Examples representing 2 minutes of data acquisition. A, The 30-second central apnea episode demonstrates the most common pattern s e e n - - a gradual fall in heart rate interrupted by intermittent accelerations in 40% of central, 34.7% of mixed, and 24.0% of obstructive apnea events. Small arrows indicate onset and termination of apnea. Sao2, Oxygen saturation; ETcoe, end-tidal CO2. B, A 48-second mixed apnea episode with an acute fall in heart rate associated with subsequent accelerations. This second most common pattern was seen in 19.7% of central, 25.7% of mixed, and 6.8% of obstructive apnea events. Arrows indicate onset and termination of apnea. C, A 17-second obstructive event associated with an initial heart rate acceleration (seen in 26.4% of obstructive events). Arrows indicate onset and termination of apnea. t y p e s a n d did n o t differ s i g n i f i c a n t l y b e t w e e n a p n e a t y p e s or
p < 0 . 0 0 0 1 ) . H o w e v e r , t h e r e w a s a wide s c a t t e r to t h e d a t a .
b e t w e e n t r e a t m e n t g r o u p s ( F i g . 1), T h e fall in o x y g e n s a t -
There was a significant association between the preapnea
u r a t i o n w a s positively c o r r e l a t e d w i t h t h e m e a n p r e a p n e a
m e a n o x y g e n s a t u r a t i o n a n d a p n e a d u r a t i o n (r = - 0 . 1 4 ;
s a t u r a t i o n for all a p n e a t y p e s a n d d u r a t i o n s ( r - - - 0 . i 6 ;
p <0.0001).
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Finer et al.
The Journal of Pediatrics December 1992
T a b l e II. Percentage of apnea episodes associated with either a heart rate fall to less than 100 beats/min or a 20%fall in heart rate A p n e a episodes (%) Central No
Heart rate <100 beats/rain Fall in heart rate >20%
A
Mixecl
Obstructive
D
No
A
D
No
A
D
88.3*
66.2*
70.0*
70.4*
68.8*
45.6*
81.8"
59.7*
44.7*
94.1"
83.7",t
77.5*
92.9*
93.4",~f
61.4'
91.6"
68.7",t
44.7*
No, No treatment;A, treatmentwith aminophyllineor theophylline;D, treatmentwith doxapram. *Within-groupdifferenceby contingencytable:p <0.0007 for all groups. tBetween-groupsdifferenceby contingencytable:p <0.0001 (aminophylline,heart rate fall >20%).
All apnea: heart rate. The mean resting heart rate before apnea was not significantly different for the various apnea types (central, 146.7 + 15.7; mixed, 147.4 +__ 16.3; obstructive, 145.9 +_ 18.41). The mean resting heart rate before apnea was 142.8 + 16.59 beats/min in untreated infants, 149.7 +_ 15.4 beats/min in infants receiving theophylline, and 137.8 _+ 10.5 beats/min in infants receiving doxapram; these differences were significant (ANOVA, p <0.001; Scheff6, p <0.001). Heart rate less than 100 beats/rain. Central apnea was more frequently associated with a fall to less than 100 beats/min (83.5%) than was mixed (66.7%) or obstructive apnea (60.5%) (chi-square statistic = 87.5; p <0.0001); when therapy was considered, this remained true only for untreated infants (p = <0.0001) (Fig. 2). For all apnea types and durations, therapy with theophylline or doxapram significantly reduced the proportion of apnea episodes with a heart rate fall to <100 beats/rain (Table II). There was no significant difference in mean preapnea saturation for any of the apnea types with and without a fall in heart rate to less than 100 beats/rain. Percentage fall in heart rate. Because the absolute fall in heart rate and the percentage fall in heart rate were closely related and not significantly different, we performed analyses comparing the percentage fall in heart rate versus apnea duration by apnea type (Fig. 3). As apnea duration increased, the percentage fall in heart rate decreased, this trend being significantly greater for central and obstructive apnea than for mixed events (ANOVA, p = 0.001; Scheff6, p = <0.01). Doxapram therapy was associated with a significantly lesser fall in heart rate during apnea than was theophylline or no treatment (p <0.001; Table II). Mixed apnea was associated with a greater percentage fall in heart rate than was central or obstructive apnea. As the duration of central apnea became longer, untreated infants had a significantly lesser fall in heart rate; apnea between 40 and 50 seconds
in duration was associated with a mean fall in heart rate of 38%, compared with 51% during apnea lasting 20 to 30 seconds (p = <0.0001). We calculated the number of apnea episodes associated with falls in heart rate of 20% or more below the previous mean heart rate and compared this to the number of episodes with a heart rate of less than 100 beats/min. The occurrence of a fall in heart rate to less than 100 beats/rain or a greater than 20% fall in heart rate was more frequent with central apnea and with apnea in infants not receiving pharmacologic therapy (contingency table, p <0.0001). A heart rate fall of 20% or greater from the baseline occurred significantlymore frequently than a fall in heart rate to less than 100 beats/rain for all apnea (82.3% vs 64.2%), for each apnea type and for apnea in infants receiving no therapy and in infants receiving pharmacotherapy (all, p <0.0001) (Table lI). Heart rate: pattern. The most common heart rate pattern was a gradual fall interrupted by accelerations (Fig. 4, A), this pattern being seen in 40% of central apnea, 34.7% of mixed apnea, and 24% of obstructive apnea, followed by an acute heart rate fall with interruptions (Fig. 4, B) (19.7% of central, 25.7% of mixed, 6.8% of obstructive apnea). For obstructive apnea, however, the most common pattern overall was an initial acceleration of heart rate, seen in 26.4% of obstructive events (Fig. 4, C). DISCUSSION We have consistently observed that approximately 50% Of episodes of apnea included in our studies have had an obstructive component, the majority of which represent mixed apnea.1, 7, 9 Our results are similar to those of Dransfield et al., 6 who evaluated apnea lasting 20 seconds or longer. Other studies have demonstrated a lower incidence of mixed and obstructive events, but this may reflect their methods and the fact that such studies have included apnea of shorter duration. As apnea duration increases, the proportion of
Volume 121 Number 6
Obstructive, mixed, and central apnea in the neonate
central episodes appears to decrease and that of mixed apnea episodes to increase. 10These events evade diagnosis because of difficulties with impedance-type respiration monitorsZ-5; moreover, nurses will miss up to 40% of all types of neonatal apnea. 1, 1l, lZ Some of the difficulty with the recognition of apnea relates to the fact that impedance monitors record chest movement, which occurs during an airway obstruction.4 Nurses are more likely to underdiagnose events with an obstructive component.l, 7 In view of the unreliability of impedance monitoring for the detection of mixed or obstructive apnea, a knowledge of the heart rate pattern associated with such apnea may allow for improved detection. Bradycardia has usually been defined as a heart rate of less than 100 beats/min, 5, 13, 14and this is the level commonly used to set alarms for neonatal monitoring. However, not all apnea is associated with a fall of heart rate to less than 100 beats/rain. 1316 Because apnea in our study was at least 15 seconds in duration and required the occurrence of bradycardia or hypoxemia or both, it is not surprising that we found a consistently higher percentage of events associated with a heart rate fall to less than 100 beats/min than was found in previous studies. However, even in our study, many episodes of apnea were not associated with a heart rate less than 100 beats/min, especially apnea with an obstructive component in infants who received doxapram. The mechanism of the lesser fall in heart rate with doxapram is unclear. Doxapram therapy was associated with a lower resting heart rate, which may reflect its potential to increase blood pressure, 17 the lower resting heart rate reflecting the possible influence of the baroreceptor reflex. 18 A similar effect was noted in intact fetal lambs after doxapram infusion,19 whereas in the cat, intravenous injection of doxapram caused an increase in the arterial blood pressure, but there was no change in heart rate. z~ In addition, doxapram is a sympathetic stimulant, and the decreased fall in heart rate may reflect this effect. 21 One could postulate that a given level of bradycardia was required to allow recognition and subsequent termination of an event by the caretaker; thus apnea associated with a lesser fall in heart rate may not be recognized until the detection of desaturation. This could explain the lesser heart rate fall with longer episodes of apnea. Hoppenbrouwers et al. 22 described heart rate patterns seen during short episodes of apnea in normal infants and those thought to be at risk for sudden infant distress syndrome. The most common pattern observed in their infants born at term was an initial fall followed by a rise; this pattern appears to be similar to our interrupted falls. During obstructive events, an accelerating or oscillating heart rate pattern was common in our subjects. It is possible that during obstructive apnea, lung afferents are stimulated and
949
activate the lung inflation reflex, leading to heart rate acceleration,z3,24 During tracheal occlusion, pulmonary stretch receptors remain active but increase their frequency of discharge by only 6%. 25The oscillating heart rate pattern that we observed during obstructive apnea has been noted by others. 1~ The failure to recognize apnea with an obstructive component is a result not only of inadequate clinical monitoring of respiration but also, in part, of an alarm threshold set so low that heart rate seldom falls below the threshold, which is the case in most nurseries. In addition, therapy with drugs such as doxapram reduces the likelihood that the heart rate will fall below such preset limits. After we completed these analyses, we observed very prolonged mixed apnea episodes lasting up to 21~ minutes in association with minimal falls in heart rate in two infants receiving doxapram. These observations suggest that doxapram should be used with caution for neonatal apnea; it is no more effective than theophylline7 and may impede the recognition of mixed and obstructive events. Monitoring to detect a percentage fall in heart rate may be more effective than using an arbitrarily assigned heart rate limit. Pulse oximetry is useful for detecting hypoxemia but will not discriminate among apnea types and is prone to movement artifact in active babies.26 However, we evaluated falls in heart rate and skin oxygen saturation only in association with significant apnea. Our observations with multiple CO2 sensors have demonstrated infrequent, spontaneous oral breathing during which COz excretion was always detected at the nares, similar to the results of Miller et al., 27 who demonstrated that spontaneous oral breathing was infrequent in the preterm infant and that spontaneous oral breathing never occurred in the absence of nasal breathing. 2s Thus it is unlikely that our obstructive events represented spontaneous oral breathing. Although the ultimate significance of apnea for the longterm neurodevelopment of infants remains uncertain, apnea lasting 15 seconds or more in association with falls in oxygen saturation must be considered an adverse event in view of the necessary decline in tissue oxygen delivery. Others have argued that even shorter durations of apnea in association with bradycardia and desaturation is harmful. 29 That a majority of the apnea recorded in this study occurred in infants already receiving therapy reemphasizes the finding that current therapy does not eradicate apnea, 7 especially when an obstructive component is present. We performed this study to determine whether apnea with an obstructive component is associated with consistent and reproducible patterns of heart rate response that would allow the recognition of these events with current monitoring techniques. Our results demonstrated that there are
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Finer et al.
different h e a r t rate responses to apnea, and t h a t episodes with an obstructive component are associated with lesser falls in h e a r t rate. T h e use of a percentage fall in h e a r t r a t e m a y allow detection of a greater n u m b e r of events, but furt h e r studies are required to evaluate this m e t h o d with specific reference to sensitivity and specificity. Theophylline therapy and d o x a p r a m therapy reduce the fall in h e a r t r a t e seen with apnea. T h e specific detection of n e o n a t a l a p n e a will continue to require both some form of air flow monitoring and continuous pulse oximetry, despite its limitations, in c o m b i n a t i o n with h e a r t rate monitoring. F u r t h e r refinem e n t s are required to improve our ability to recognize t h e occurrence of apnea in the p r e m a t u r e infant, and different strategies are required if we are to eradicate such events.
REFERENCES 1. Muttitt SC, Finer NN, Tierney A J, Rossmann J. Neonatal apnea: diagnosis by nurse versus computer. Pediatrics 1988; 82:713-20. 2. Southall DP, Richards JM, Lau KC, et al. An explanation for failure of impedance apnea alarm systems. Arch Dis Child 1980;55:63-5. 3. Southall DP, Levitt GA, Richards JM, et al. Undetected episodes of prolonged apnea and severe bradycardia in preterm infants. 1983;72:541-51. 4. Warburton D, Stark AR, Taeusch HW. Apnea monitor failure in infants with upper airway obstruction. Pediatrics 1977; 60:742-4. 5. MacFadyen UM, Borthwick G, Simpson H, McKay M, Neilson J. Monitoring for central apnoea in infancy: limitations of single channel recordings. Arch Dis Child 1988;63:282-7. 6. Dransfield DA, Spitzer AR, Fox WW. Episodic airway obstruction in premature infants. Am J Dis Child 1983;137: 441-3. 7. Peliowski A, Finer NN. A blinded randomized placebocontrolled trial to compare theophylline and doxapram for the treatment of apnea of prematurity. J PEDIATR 1990;116:64853. 8. Snedecor GW, Cochran WG. Statistical methods. 7th ed. Ames, Iowa: State University Press, 1980. 9. Barrington K J, Finer NN, Torok-Both GA, Jamali F, Coutts RT. Dose-response relationship of doxapram in the therapy for refractory idiopathic apnea of prematurity. Pediatrics 1987; 80:22-7. 10. Butcher-Puech MC, Henderson-Smart DJ, Holley D, Lacey JL, Edwards DA. Relation between apnoea duration and type and neurological status of preterm infants. Arch Dis Child 1985;60:953-8. 11. Stein IM, Shannon DC. The pediatric pneumogram: a new method for detecting and quantitating apnea in infants. Pediatrics 1975;55:599-603.
The Journal o f Pediatrics December 1992
12. Peabody JL, Gregory GA, Wills MM, et al. Failure of conventional respiratory monitoring to detect hypoxemia [Abstract]. Pediatr Res 1977;11:539A. 13. Gabriel M, Albani M, Schulte FJ. Apneic spells and sleep states in preterm infants. Pediatrics 1976;57:142-7. 14. Krauss AN, Soloman GE, Auld PAM. Sleep state, apnea and bradycardia in preterm infants. Dev Med Child Neurol 1977;19:160-8. 15. Girling DJ. Changes in heart rate, blood pressure, and pulse pressure during apnoeic attacks in newborn babies. Arch Dis Child 1972;47:405-10. 16. Vyas H, Milner D, Hopkin IE. Relationship between apnoea and bradycardia in preterm infants. Acta Paediatr Scand 1981;70:785-90. 17. Barrington KL, Finer NN, Peters KL, Barton J. Physiologic effects of doxapram in idiopathic apnea of prematurity. J PEBIATR 1986;108:125-9. 18. Cowley AW, Liard JF, Buyton AC. Role of the barorecept0r reflex in daily control of arterial blood pressure and other variables in dogs. Circ Res 1973;32:564-78. 19. Bamford OS, Dawes GS, Hanson MA, Ward RA. The effects of doxapram on breathing, heart rate and blood pressure in fetal lambs. Respir Physiol 1986;66:387-96. 20. Mitchell RA, Herbert DA. Potencies of doxapram and hypoxia in stimulating carotid-body chemoreceptors and ventilation in anesthetized cats. Anesthesiology 1975;42:559-66. 2l. Gay GR, Kirkman JH, Alexander GA, Rappolt RT. Modification of cardiopressor and respirogenic effects of doxapram by propranolol. Clin Toxicol 1978;13:487-504. 22. Hoppenbrouwers J, Hodgman JE, Arakawa K, et al. Sleep apnea as part of a sequence of events: a comparison of threemonth-old infants at low and increased risk for sudden infant death syndrome (SIDS). Neuropediatrics 1978;9:320-37. 23. Lin YC, Shida KK, Hong SK. Effects of hypercapnia, hypoxia, and rebreathing on heart rate response during apnea. J Appl Physiol 1983;54:166-71. 24. Angell James JE, DeBurgh Daly M. Cardiovascular responses in apnoeic asphyxia: role of arterial chemoreceptors and the modification of their effects by a pulmonary vagal inflation reflex. J Physiol 1969;201:87-104. 25. Richardson PS, Santambrogio G, Mortola J, Bianconi R. The activity of lung afferent nerves during tracheal occlusion. Respir Physiol 1973;18:273-83. 26. Barrington K J, Finer NN, Ryan CA. Evaluation of pulse oximetry as a.,eontinuous monitoring technique in the neonatal intensive care unit. Crit Care Med 1988;16:1147-53. 27. Miller M J, Carlo WA, Strohl KP, Fanaroff AA, Martin RJ. Effect of maturation on oral breathing in sleeping premature infants. J PEDIATR 1986;109:515-9. 28. Miller M J, Martin R J, Carlo WA, Fouke JM, Strohl KP, Fanaroff AA. Oral breathing in newborn infants. J PEDIATR 1985;107:465-9. 29. Upton C J, Milner AD, Stokes GM. Apnoea, bradycardia, and oxygen saturation in preterm infants. Arch Dis Child 1991; 66:381-5.
Obstructive, mixed, and central apnea in the neonate' Physiologic correlates Nell N. Finer, MD, Keith J. Barrington, MD, Barbara J. Hayes, RN, a n d Aston Hugh, BSc From the Department of Newborn Medicine, Royal Alexandra Hospital, and the Department of Pediatrics, Universityof Alberta, Edmonton, Alberta, Canada In an attempt to determine physiologic responses to neonatal apnea, we evaluated changes in heart rate and o x y g e n saturation as measured by pulse oximetry during 2082 episodes of a p n e a lasting 15 seconds or more in 47 infants less than 34 weeks of gestational a g e with i d i o p a t h i c apnea of prematurity. Of these episodes, 832 (39.9%) were central, 1032 (49.6%) were mixed, and 218 (10.5%) w e r e obstructive. Oxygen saturation d e c r e a s e d with increasing duration of apnea regardless of type or treatment, and the decrease in saturation was correlated with preapnea saturation. The baseline heart rate was similar for all a p n e a types. Infants receiving d o x a p r a m had a l o w e r b a s e l i n e h e a r t r a t e ( 1 3 7 . 8 _ 10.5 beats/min) than did infants receiving no therapy (142.8 _ 16.6 b e a t s / m i n ) and infants receiving theophylline (149.7 _+ 15.0 beats/min) (p = <0.001). A heart rate fall to less than 100 b e a t s / m i n was seen more frequently with central a p n e a than with mixed or obstructive events, and in infants who were not receiving therapy. Falls in heart rate were significantly less in infants receiving d o x a p r a m ( 2 7 . 8 % ___18.0%) than in infants receiving theophylline (44.5% _+ 19.0%) or no therapy (48.4% _+ 18.3%) (p = <0.001). The most common heart rate pattern o v e r a l l was a gradual decrease interrupted by accelerations, whereas an initial heart rate a c c e l e r a t i o n was the most c o m m o n pattern in obstructive apnea. We c o n c l u d e that heart rate response to neonatal a p n e a is c o m p l e x and is dependent on therapy and on type and duration of apnea. (J PEDIATR1992;121:943-50)
Idiopathic apnea of prematurity is common in low birth weight neonates. Central apnea is usually readily diagnosed by using current monitoring systems and nursing surveillance, but mixed and obstructive events are more difficult to diagnose because the monitoring of chest wall movement is unreliable.1-5 In our experience, 50% of significant idiopathic apnea of prematurity has an obstructive component; approximately 40% of all episodes are mixed events, and 10% are obstructive. I The most commonly employed methods of detecting obstructive apnea have involved the measurement of air flow at the nose with thermistors or the measurement of exhaled
Submitted for publication Nov. 14, 1992; accepted July 17, 1992. Reprint requests: Nell N. Finer, MD, Royal Alexandra Hospital, 10240 Kingsway, Edmonton, Alberta T5H 3V9, Canada. 9/23/41044
carbon dioxide by using end-tidal CO2 devices. 6 None of these devices, however, is currently available for routine monitoring of the low birth weight infant with apnea. Because all of our studies evaluating apnea of prematurity have involved the use of end-tidal CO2 along with measurement of heart rate, impedance pneumography, and pulse oximetry, we thought that it would be useful to evaluate the ANOVA
Analysis of variance
physiologic response of the neonate to the different apnea types. We questioned whether there may be some pattern of abnormalities in the currently monitored measurements that might facilitate the recognition of these events without the use of more cumbersome monitoring. In addition, we wished to evaluate the effects of pharmacologic therapy on the physiologic response to neonatal apnea.
943
944
Finer et al.
The Journal of Pediatrics December 1992
5O 45
~-~
Central Mixed ObsLruetive
40 r.~
35 o . ,-q
bO 25 oO
2O 15
r_)
10 5 0 0
<20
:0-30
Apnea
50-40
40-50
Duration
(sec)
>50
Fig. I. Falls in oxygen saturation plotted against durations of apnea from less than 20 seconds to more than 50 seconds by apnea type (central, mixed, and obstructive). Increasing apnea length was associated with greater desaturation (r = 0.26; p = 0.0001).
METHODS
We reviewed and analyzed apnea epochs that had been recorded during two previous prospective trials using identical methods to evaluate idiopathic apnea of prematurity. !, v The first trial involved infants receiving theophylline or no therapy, and the second was a randomized, placebocontrolled evaluation of doxapram and theophylline. In both studies, infants were treated if they had more than 0.3 episode of apnea per hour, lasting 15 seconds or more, with either a 5% or greater desaturation or a 20% decrease in heart rate, or both. All infants had normal findings on clinical examination, no evidence of intracranial abnormality by ultrasound examination, no evidence of sepsis or of electrolyte or metabolic disorder, and no evidence of pulmonary parenchymal disorders. Oxygen was administered only to infants whose baseline oxygen saturation was less than 90% to 92%. The infant's sleep state during the recording was not determined. The methods have been described previously. A computerized data acquisition system inolttded a personal computer (Compaq 286 or Compaq 386; Compaq Computer Corp., Houston, Tex.) with an analog to digital conversion device (DT2801, Data Translation Inc., Marlborough, Mass.). The computer was interfaced to the neonates' mon-
itors by using the outputs available from the monitor (model 78833B or 78801A; Hewlett Packard, Federal Republic of Germany) to record heart rate, impedance respiration, and the outputs available from the pulse oximeter (model N-100 or N-200; NeUcor Inc., Hayward, Calif.) and an end-tidal CO2 monitor (Traverse Capnometer, model 2200; Trudell Medical, Saline, Mich.). An acquisition program was written with proprietary software (Asyst, Macmillan Software Co., New York, N.Y.) for the data acquisition and subsequent analysis. After each 12 hot/rs of data acquisition, the computer identified epochs in which there had been a fall to baseline ( + 5%) of the end-tidal CO2 signal, which was associated with either a fall in heart rate of 20% from the previous mean (which was continuously calculated) or a fall in pulse oximetry-measured oxygen saturation of more than 5%. Any event that was thought to be secondary to artifact, either move~nent by the infant or dislodgment of the end-tidal CO2 catheter from the tip of the nares, or secondary to artifactual change in the other measurements was not further considered. Only epochs in which there was evidence of an appropriate end-tidal CO2 signal, both before and after the event, were analyzed to avoid long periods of potential mouth breathing. In addition, to qualify as a significant
Volume 121 Number 6
Obstructive, mixed, and central apnea in the neonate
100
945
-
Central
90
Mixed Obstructive
80
70 O 9~
60
V
50
40 t 0
,~
<20
20-30
50-40
40-50
>50
Apnea Duration (see) Fig. 2. Percentage of apnea associated with a heart rate fall to less than 100 beats/min, shown for apnea durations from less than 20 seconds to greater than 50 seconds by apnea type (central, mixed, and obstructive). Central apnea had a significantly greater association with a fall in heart rate to less than 100 beats/min, compared with mixed and obstructive events (p <0.000l).
event, there needed to be absence of the end-tidal signal with simultaneous evidence of desaturation or a fall in heart rate or both. Epochs associated with exaggerated impedance movement and sudden falls in saturation, especially of more than 30% for 5 to 15 seconds, were rejected as being probable movement artifact. All apnea episodes lasting 15 seconds or longer were stored and described as being central, mixed, or obstructive. A central event was defined as apnea in which no breaths were detected by chest movement and end-tidal CO2 recording. An obstructive event was defined as apnea during which the impedance recording of chest movement continued and was usually exaggerated, in association with the absence of detectable exhaled CO2 at the nares. A mixed event was defined as apnea in which there was evidence of both a central and an obstructive component; such events required at least 3 seconds of central apnea. Data on all epochs were then saved and reviewed. For each event, the computer file contained information regarding the mean value calculated for the 2 minutes before the event for heart rate and saturation, plus the entire apnea event. The falls in both heart rate and saturation were
I. Episodes of apnea of each type, in each duration category Table
Duration ($ec) <20 20-30 30-40 40-50 >50
Episodes of a p n e a (No.) Central
Mixed
Obstructive
213 455 115 27 22
152 537 180 80 83
62 103 30 16 7
Mean chronologicage = 4.32 days (range, 1 to 21 days).
characterized as the absolute fall, and the percentage fall was defined as the percentage of change from the previous mean. Apnea was analyzed by duration, the categories being less than 20 seconds, 20 to 30 seconds, 30 to 40 seconds, 40 to 50 seconds, and more than 50 seconds. In addition, the changes in heart rate and oxygen saturation were analyzed by treatment categories, including theophylline, doxapram, or no treatment.
946
Finer et al.
The Journal o f Pediatrics December 1992
70
60
Central Mixed Obstructive
~
50 o 40 09 o
30
20
10 0
<20
, , 20-30
~0-40
40-50
>50
Apnea Duration (see) Fig. 3. Percentage fall in heart rate (_+SD) plotted against apnea durations by apnea type (central, mixed, and obstructive). With increasing apnea duration, there was a lesser percentage fall in the heart rate for all types of apnea.
To further characterize the heart rate response to apnea, we visually reviewed 100 episodes of each type. We developed a classification for the pattern of the heart rate response, which included a step fall in heart rate or a more gradual fall either with or without interruption, an oscillating pattern during which the heart rate oscillated about the previous baseline, or an initial acceleration with or without a subsequent fall. We then reviewed all apnea episodes for which the original epoch had been saved in its entirety and determined the pattern of heart rate change. The statistical analysis included the use of a completely randomized one-way and three-way factorial analysis of variance and a Pearson correlation coefficient regression analysis. The Scheff6 procedure and the Fisher protected least significance difference were used for determining intergroup significant differences for one-way and three-way ANOVAs. A contingency table analysis was used for proportional data. In view of the multiple testing done by contingency table analysis, a p value of <0.001 was considered significant. The three-factor factorial ANOVA was used to reduce the number of analyses ~[serformed and to compare the effects of apnea type, apnea duration, and treatment on the percentage fall in heart rate during apnea. 8 For all analyses, a p value of <0.01 was considered significant in view of the multiple analyses performed. Results are presented as means • SD. All information analyzed in our
study was obtained from data on infants whose parents had consented to participation and analysis of results in the original trials. RESULTS Our study involved the analysis of 2082 episodes of apnea from 47 infants born at 27 to 34 weeks of gestation and weighing 920 to 2470 gm at birth. There was no significant difference in birth weight or gestational age between infants who received no therapy (1598 +__ 125 gm; 31.3 - .7 weeks) and those ~ho received arninophylline (1441 + 119 gm; 30.7 • 0.8 weeks) or doxapram (1303 _ 97 gin; 30.7 + 0.63 weeks). The infants were studied at a mean chronologic age of 41/2days (range, 1 to21 days). Of these episodes, 832 (39.9%) were central, i032 (49.6%)were mixed, and 218 (10.5%) Were obstructive (Table I). There were 585 episodes of apnea in infants who were not receiving pharmacologic therapy, 1204 in infants treated with aminophylline or theophylline (subsequently referred to as theophylline), 251 in infants treated with doxapram, and 42 in infants treated with both theophylline and doxapram. No further analysis of the last group was performed because of the small number. As apnea duration increased, the fall in oxygen saturation as recorded by pulse oximetry also increased (r = 0.26; p = 0.0001); this relationship was significant for all apnea
Volume t21 Number 6
Obstructive, mixed, a n d central apnea in the neonate
947
CENTRAL 208
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Fig. 4. Examples representing 2 minutes of data acquisition. A, The 30-second central apnea episode demonstrates the most common pattern s e e n - - a gradual fall in heart rate interrupted by intermittent accelerations in 40% of central, 34.7% of mixed, and 24.0% of obstructive apnea events. Small arrows indicate onset and termination of apnea. Sao2, Oxygen saturation; ETcoe, end-tidal CO2. B, A 48-second mixed apnea episode with an acute fall in heart rate associated with subsequent accelerations. This second most common pattern was seen in 19.7% of central, 25.7% of mixed, and 6.8% of obstructive apnea events. Arrows indicate onset and termination of apnea. C, A 17-second obstructive event associated with an initial heart rate acceleration (seen in 26.4% of obstructive events). Arrows indicate onset and termination of apnea. t y p e s a n d did n o t differ s i g n i f i c a n t l y b e t w e e n a p n e a t y p e s or
p < 0 . 0 0 0 1 ) . H o w e v e r , t h e r e w a s a wide s c a t t e r to t h e d a t a .
b e t w e e n t r e a t m e n t g r o u p s ( F i g . 1), T h e fall in o x y g e n s a t -
There was a significant association between the preapnea
u r a t i o n w a s positively c o r r e l a t e d w i t h t h e m e a n p r e a p n e a
m e a n o x y g e n s a t u r a t i o n a n d a p n e a d u r a t i o n (r = - 0 . 1 4 ;
s a t u r a t i o n for all a p n e a t y p e s a n d d u r a t i o n s ( r - - - 0 . i 6 ;
p <0.0001).
948
Finer et al.
The Journal of Pediatrics December 1992
T a b l e II. Percentage of apnea episodes associated with either a heart rate fall to less than 100 beats/min or a 20%fall in heart rate A p n e a episodes (%) Central No
Heart rate <100 beats/rain Fall in heart rate >20%
A
Mixecl
Obstructive
D
No
A
D
No
A
D
88.3*
66.2*
70.0*
70.4*
68.8*
45.6*
81.8"
59.7*
44.7*
94.1"
83.7",t
77.5*
92.9*
93.4",~f
61.4'
91.6"
68.7",t
44.7*
No, No treatment;A, treatmentwith aminophyllineor theophylline;D, treatmentwith doxapram. *Within-groupdifferenceby contingencytable:p <0.0007 for all groups. tBetween-groupsdifferenceby contingencytable:p <0.0001 (aminophylline,heart rate fall >20%).
All apnea: heart rate. The mean resting heart rate before apnea was not significantly different for the various apnea types (central, 146.7 + 15.7; mixed, 147.4 +__ 16.3; obstructive, 145.9 +_ 18.41). The mean resting heart rate before apnea was 142.8 + 16.59 beats/min in untreated infants, 149.7 +_ 15.4 beats/min in infants receiving theophylline, and 137.8 _+ 10.5 beats/min in infants receiving doxapram; these differences were significant (ANOVA, p <0.001; Scheff6, p <0.001). Heart rate less than 100 beats/rain. Central apnea was more frequently associated with a fall to less than 100 beats/min (83.5%) than was mixed (66.7%) or obstructive apnea (60.5%) (chi-square statistic = 87.5; p <0.0001); when therapy was considered, this remained true only for untreated infants (p = <0.0001) (Fig. 2). For all apnea types and durations, therapy with theophylline or doxapram significantly reduced the proportion of apnea episodes with a heart rate fall to <100 beats/rain (Table II). There was no significant difference in mean preapnea saturation for any of the apnea types with and without a fall in heart rate to less than 100 beats/rain. Percentage fall in heart rate. Because the absolute fall in heart rate and the percentage fall in heart rate were closely related and not significantly different, we performed analyses comparing the percentage fall in heart rate versus apnea duration by apnea type (Fig. 3). As apnea duration increased, the percentage fall in heart rate decreased, this trend being significantly greater for central and obstructive apnea than for mixed events (ANOVA, p = 0.001; Scheff6, p = <0.01). Doxapram therapy was associated with a significantly lesser fall in heart rate during apnea than was theophylline or no treatment (p <0.001; Table II). Mixed apnea was associated with a greater percentage fall in heart rate than was central or obstructive apnea. As the duration of central apnea became longer, untreated infants had a significantly lesser fall in heart rate; apnea between 40 and 50 seconds
in duration was associated with a mean fall in heart rate of 38%, compared with 51% during apnea lasting 20 to 30 seconds (p = <0.0001). We calculated the number of apnea episodes associated with falls in heart rate of 20% or more below the previous mean heart rate and compared this to the number of episodes with a heart rate of less than 100 beats/min. The occurrence of a fall in heart rate to less than 100 beats/rain or a greater than 20% fall in heart rate was more frequent with central apnea and with apnea in infants not receiving pharmacologic therapy (contingency table, p <0.0001). A heart rate fall of 20% or greater from the baseline occurred significantlymore frequently than a fall in heart rate to less than 100 beats/rain for all apnea (82.3% vs 64.2%), for each apnea type and for apnea in infants receiving no therapy and in infants receiving pharmacotherapy (all, p <0.0001) (Table lI). Heart rate: pattern. The most common heart rate pattern was a gradual fall interrupted by accelerations (Fig. 4, A), this pattern being seen in 40% of central apnea, 34.7% of mixed apnea, and 24% of obstructive apnea, followed by an acute heart rate fall with interruptions (Fig. 4, B) (19.7% of central, 25.7% of mixed, 6.8% of obstructive apnea). For obstructive apnea, however, the most common pattern overall was an initial acceleration of heart rate, seen in 26.4% of obstructive events (Fig. 4, C). DISCUSSION We have consistently observed that approximately 50% Of episodes of apnea included in our studies have had an obstructive component, the majority of which represent mixed apnea.1, 7, 9 Our results are similar to those of Dransfield et al., 6 who evaluated apnea lasting 20 seconds or longer. Other studies have demonstrated a lower incidence of mixed and obstructive events, but this may reflect their methods and the fact that such studies have included apnea of shorter duration. As apnea duration increases, the proportion of
Volume 121 Number 6
Obstructive, mixed, and central apnea in the neonate
central episodes appears to decrease and that of mixed apnea episodes to increase. 10These events evade diagnosis because of difficulties with impedance-type respiration monitorsZ-5; moreover, nurses will miss up to 40% of all types of neonatal apnea. 1, 1l, lZ Some of the difficulty with the recognition of apnea relates to the fact that impedance monitors record chest movement, which occurs during an airway obstruction.4 Nurses are more likely to underdiagnose events with an obstructive component.l, 7 In view of the unreliability of impedance monitoring for the detection of mixed or obstructive apnea, a knowledge of the heart rate pattern associated with such apnea may allow for improved detection. Bradycardia has usually been defined as a heart rate of less than 100 beats/min, 5, 13, 14and this is the level commonly used to set alarms for neonatal monitoring. However, not all apnea is associated with a fall of heart rate to less than 100 beats/rain. 1316 Because apnea in our study was at least 15 seconds in duration and required the occurrence of bradycardia or hypoxemia or both, it is not surprising that we found a consistently higher percentage of events associated with a heart rate fall to less than 100 beats/min than was found in previous studies. However, even in our study, many episodes of apnea were not associated with a heart rate less than 100 beats/min, especially apnea with an obstructive component in infants who received doxapram. The mechanism of the lesser fall in heart rate with doxapram is unclear. Doxapram therapy was associated with a lower resting heart rate, which may reflect its potential to increase blood pressure, 17 the lower resting heart rate reflecting the possible influence of the baroreceptor reflex. 18 A similar effect was noted in intact fetal lambs after doxapram infusion,19 whereas in the cat, intravenous injection of doxapram caused an increase in the arterial blood pressure, but there was no change in heart rate. z~ In addition, doxapram is a sympathetic stimulant, and the decreased fall in heart rate may reflect this effect. 21 One could postulate that a given level of bradycardia was required to allow recognition and subsequent termination of an event by the caretaker; thus apnea associated with a lesser fall in heart rate may not be recognized until the detection of desaturation. This could explain the lesser heart rate fall with longer episodes of apnea. Hoppenbrouwers et al. 22 described heart rate patterns seen during short episodes of apnea in normal infants and those thought to be at risk for sudden infant distress syndrome. The most common pattern observed in their infants born at term was an initial fall followed by a rise; this pattern appears to be similar to our interrupted falls. During obstructive events, an accelerating or oscillating heart rate pattern was common in our subjects. It is possible that during obstructive apnea, lung afferents are stimulated and
949
activate the lung inflation reflex, leading to heart rate acceleration,z3,24 During tracheal occlusion, pulmonary stretch receptors remain active but increase their frequency of discharge by only 6%. 25The oscillating heart rate pattern that we observed during obstructive apnea has been noted by others. 1~ The failure to recognize apnea with an obstructive component is a result not only of inadequate clinical monitoring of respiration but also, in part, of an alarm threshold set so low that heart rate seldom falls below the threshold, which is the case in most nurseries. In addition, therapy with drugs such as doxapram reduces the likelihood that the heart rate will fall below such preset limits. After we completed these analyses, we observed very prolonged mixed apnea episodes lasting up to 21~ minutes in association with minimal falls in heart rate in two infants receiving doxapram. These observations suggest that doxapram should be used with caution for neonatal apnea; it is no more effective than theophylline7 and may impede the recognition of mixed and obstructive events. Monitoring to detect a percentage fall in heart rate may be more effective than using an arbitrarily assigned heart rate limit. Pulse oximetry is useful for detecting hypoxemia but will not discriminate among apnea types and is prone to movement artifact in active babies.26 However, we evaluated falls in heart rate and skin oxygen saturation only in association with significant apnea. Our observations with multiple CO2 sensors have demonstrated infrequent, spontaneous oral breathing during which COz excretion was always detected at the nares, similar to the results of Miller et al., 27 who demonstrated that spontaneous oral breathing was infrequent in the preterm infant and that spontaneous oral breathing never occurred in the absence of nasal breathing. 2s Thus it is unlikely that our obstructive events represented spontaneous oral breathing. Although the ultimate significance of apnea for the longterm neurodevelopment of infants remains uncertain, apnea lasting 15 seconds or more in association with falls in oxygen saturation must be considered an adverse event in view of the necessary decline in tissue oxygen delivery. Others have argued that even shorter durations of apnea in association with bradycardia and desaturation is harmful. 29 That a majority of the apnea recorded in this study occurred in infants already receiving therapy reemphasizes the finding that current therapy does not eradicate apnea, 7 especially when an obstructive component is present. We performed this study to determine whether apnea with an obstructive component is associated with consistent and reproducible patterns of heart rate response that would allow the recognition of these events with current monitoring techniques. Our results demonstrated that there are
950
Finer et al.
different h e a r t rate responses to apnea, and t h a t episodes with an obstructive component are associated with lesser falls in h e a r t rate. T h e use of a percentage fall in h e a r t r a t e m a y allow detection of a greater n u m b e r of events, but furt h e r studies are required to evaluate this m e t h o d with specific reference to sensitivity and specificity. Theophylline therapy and d o x a p r a m therapy reduce the fall in h e a r t r a t e seen with apnea. T h e specific detection of n e o n a t a l a p n e a will continue to require both some form of air flow monitoring and continuous pulse oximetry, despite its limitations, in c o m b i n a t i o n with h e a r t rate monitoring. F u r t h e r refinem e n t s are required to improve our ability to recognize t h e occurrence of apnea in the p r e m a t u r e infant, and different strategies are required if we are to eradicate such events.
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