75
Polygraphy After Discharge in Preterm Infants with and without Apnea in the Nursery By T Hoppenbrouwers,]. E. Hodgman, K. Arakawa, M. Durand and L. A. Cabal
Abstract Nine of nineteen infants in this study exhibited two or more eentral apnea ~ 20 seeonds when they were older than one week and between 32-36 weeks posteoneeptional age (PCA). We foeused on the sequelae of these apneas. Apnea was separated from other morbidity assoeiated with immaturity by the seleetion of eonsistently healthy infants. Following diseharge, polygraphie traeings were obtained at 40, 44 and 52 weeks PCA in these non-apneie and previously apneie infants. Sleep states, minute by minute values for heart and respiratory rate, skin temperature and transeutaneous 02 (Ptc0 2) and CO2 (PtcC02), apnea and transient deereases in P tc02 were determined. Polygraphie measurements did not differentiate preterm infants with late apnea in the nursery from non-apneie ones. However, the apneie group exhibited a transient deerease in awakenings at 44 weeks PCA.
Keywords
most 1400 low-birthweight infants are born in our hospital yearly, but only 10-15 otherwise healthy infants exhibit these late apneie episodes. In the literature, infants with late apnea have not been distinguished from infants with apnea of prematurity beginning soon after birth. It seems reasonable to postulate that late apnea would be more likely to have physiologie eonsequenees than apnea resolving more promptly. This eonsideration led us to seleet this group for study during the age of highest risk for SIDS. We wished to separate apnea from other morbidity assoeiated with immaturity and therefore seleeted eonsistently healthy infants. The working hypothesis was that these apneie premature infants would be more likely to exhibit abnormal physiologie patterns during early infaney than eomparable non-apneie preterm infants. Systematie polygraphie studies after nursery diseharge of premature infants who have experieneed prolonged apnea beyond the first week of life have not been reported. It was the objeetive of the present study to eolleet polygraphie data for sleep state development, eardio-respiratory funetioning and transeutaneous gases in preterm infants after nursery diseharge and eompare the findings of infants with and without late apnea in the nursery.
Sleep states - Apnea of prematurity - SIDS - ALTE - Polygraphy
Method
1. Material and monitoring procedure Introduction The inereased risk for Sudden Infant Death Syndrome (SIDS) in premature infants is weIl established and appears to be inversely related to gestational age (2, 23). AIthough premature infants are perceived to be at greater risk for SIDS following neonatal apnea, whether or not prolonged apnea in the nursery indeed augments this risk has not been firmly established. At present, available evidenee suggests that preterm infants with apnea prior to 40 weeks post-eoneeptional age (PCA) are not at inereased risk eompared to preterms without apnea (6, 20, 30, 31). These findings are largely based on epidemiologieal rather than prospeetive studies. Apnea of prematurity, a frequent diagnosis in the high risk nursery, resolves in most infants during the first week of life (11). Apnea of prematurity after the first week is seen in a small number of otherwise healthy infants (29). AIReceived December 11, 1990; accepted January 10, 1991 Neuropediatrics 23 (1992) 75-81 © Hippokrates Verlag Stuttgart
The nursery was surveyed daily and the ehart of every newly admitted infant of < 35 weeks gestation was examined to identify potential eandidates for future study. Candidates had to be appropriate for gestational age and free from illness aeeording to the striet eriteria outlined in Table 1. Onee identified, their nursery progress was earefully monitored to ensure that they eontinued to qualify. To establish the presenee of apnea, preliminary eardio-respiratory monitoring was performed after the first week in the nursery when the infants were between 32 and 36 weeks PCA. Eight hour traeings obtained between 11 p.m. and 7 a.m. were visually analyzed for the presenee of eentral apnea ~ 20 seeonds (14). During a fourteen months period nine otherwise healthy, preterm infants were seleeted, who exhibited two or more eentral apnea ~ 20 seeonds after the first week of life. An effort was made to enroll all infants with these late apneas. Ten infants who did not exhibit apnea on the eardio-respiratory traeings nor had any history of apneie episodes served as a eomparison group. These healthy infants without apnea who fulfilled the study eriteria were aeeepted aeeording to availability of monitoring time in the sleep laboratory. There was a high ineidenee of maternal eomplieations and Cesarean seetion in both groups as would be expeeted
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Department of Pediatrics, University of Southern California School of Medicine and Los Angeles County, University of Southern California Medical Center, Los Angeles, California, USA
Neuropediatrics 23 (1992)
T Hoppenbrouwers et al
lable 1 Illness criteria in prematures. At any time during nursery course 1) Assisted ventilation for 24 hours or more except for management of apnea 2) Intracranial hemorrhage by CT scan or ultrasound (grades 1II and IV) 3) Culture proven sepsis 4) Oiagnosed medical conditions 5) Supplemental oxygen for more than 48 hours except for management of apnea.
Between 32-36 weeks postconceptional age 1) 2) 3) 4) 5)
Hypocalcemia « 7.5 mg/dl) Hypoglycemia « 30 mg/dl) or hyperglycemia (> 150 mg/dl) Hypothermia « 35.5 °c rectal) or hyperthermia (> 37.5 °c rectal) Hyponatremia « 130 meq/L) or hypernatremia (> 150 meq/L) Anemia - (HCT < 30 %)
for high risk infants but an absence of significant neonatal problems because of the selection criteria. A number of clinical characteristics are presented in Table 2. Our protocol was approved by the LAC/USC Medical Center Human Research Committee. The study design called for repetitive laboratory monitoring after discharge at 40, 44 and 52 weeks of PCA and informed consent was obtained prior to each session. Eighteen infants (8 apneic and 10 non-apneic) returned to the laboratory at 40 and seventeen (8 apneic and 9 non-apneic) at 44 weeks PCA. Only ten parents were willing to return the infants (6 apneic and 4 non-apneic) for laboratory monitoring at 52 weeks of age. An effort was made to contact all families at 9 months of age. Information was obtained for seven out of nine infants with apnea and five out of ten infants without apnea. Of the nine infants with apnea identified by cardio-respiratory monitoring six had clinical apnea severe enough to be treated in the nursery with aminophylline; at their first monitoring session in the sleep laboratory, however, infants had been off this drug for at least one month. In three infants the severity of the apnea warranted management with assisted ventilation and supplemental oxygen for 24-48 hours. One additional infant received supplemental oxygen alone. Each infant was admitted between 5:00 and 6:00 p.m. to the sleep laboratory for 2-4 hour recordings. The
session began with a short physical and neurological evaluation. The infants were fed during preparation for monitoring and application of electrodes whereafter a demand feeding schedule was followed. Arm restraints were applied before the initiation of recording. Monitoring was carried out in a darkened roorn adjacent to the room containing recording equipment. While room temperatures ranged between 19.4 and 24.5 degrees C, infants in both groups were exposed to comparable temperatures (21.6 + 0.24 vs 21.5 + 0.17 degrees C). The infants were placed in a supine or sidelying position and observed continuously with the help of a low-illumination television camera and monitor. Activities such as closing or opening of the eyes, startles, crying, and nursing interventions were charted on the polygraph paper (15).
2. Physiological recording methods For each infant, the sleep variables included two EEG derivations (approximating C1-C5 and C2-C6, according to the International 10-20 system), a chin electromyogram and eye movements. Thoraeie and abdominal excursions were monitored with strain gauges. In addition, a Beckman PC0 2 monitor sampled expired gas through a miniature cannula taped under the infant's nostrils. The ECG was recorded with two disposable electrodes placed symmetrically beneath the clavicles. AdditionaIly, a skin temperature probe was applied to the abdomen below the right costal margin. Electrodes on the mattress surface under the crib sheet registered the infant's gross body movements (15). P tc0 2 and P tcC0 2 were measured with a Novametrix monitor. The electrodes were applied to either side of the upper ehest. An 02 electrode temperature of 43.5 °C was selected while the CO2 electrode was unheated. Both electrodes were calibrated at the onset and termination of each recording with gases of known 02 and CO 2 concentration (0 and 92 mrn Hg for 02; 38 and 76 mm Hg for CO2). Humidity of the roorn air was sampled on an hourly basis during the monitoring and was comparable in both study groups. The data were recorded on a 16 channel Grass Model 76 polygraph at 6 mmlsec paper speed, an eight channel Brush recorder at 1 cmlmin paper speed, and stored simultaneously, together with a time code on a 14 channel HoneyweIl analog tape recorder (Figure 1).
labte 2 Clinical characteristics. Premature infants with apnea (n = 9)
without apnea (n = 10)
1660 (362) 1210-2215
1577 (285) 1340-2250
31.3 (1.9) 28-34
32.9 (1.3) 31-35
Birth weight (gms) Mean (SO) Range
Gestational age (wks) Mean (SO) Range
Race Hispanic Black White
7 1 1
9 1
SexM/F Apgar (Mean)
8/1
6/4
1 min 5 min
5.3 7.4
7.1 8.5
Age at 40 wks (in days)
64
53
3. Data analysis The polygraphie tracings were coded by trained observers into minutes of active sleep (AS), quiet sleep (QS), awake (AW) and indeterminate (IN), according to generally accepted criteria described elsewhere (16). Every 50th minute of the tracing was independently recorded by a second observer to ensure an agreement between coders of at least 80 percent. Central apnea equal to or longer than 12 seconds during sleep as weIl as transient decreases in P tc0 2 in excess of 15 mm Hg were identified. In addition, we recorded the presence of shorter apnea when accompanied by either a transient episode of bradycardia (TEB), defined as a heart rate drop to below 90 beats/minute or a P tc0 2 decrease, as defined above. Data on the analog tapes were digitized by a preprocessing micro-computer with eight channels of analog to
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76
Neuropediatrics 23 (1992)
Polygraphy After Late Apnea in the Nursery Fig. 1 Segment of a recording in a 40 week PCA preterm infant at 1 cm/min paper speed. Ptc 0 2 calibration 20, 60 and 92 mmHg, Ptc C0 2 calibration 60 and 76 mmHg. Note the Ptc 0 2 decrease following an apnea and a movement. This pattern was seldom seen in these infants. The temperature (temp) control tracing reflects 02 electrode heating and an estimate of vasodilation and constriction under the electrode. BPM = beats/minute; BRPM = breaths/ minute.
77
PAEMATURE 40 WKS CARDIAC RATE
~jM,"r·~'V"J~,,"'"Tf'·r~~'1~,/.'ir ""'ft",'I't :::
BPM
11 ·~1
~C02
~ I~l
L-.-..~a,' ~~'1l--
MOVEMENTS
- - - - - - - - - - - - - - - - - - - ~~----78 -80 - 9 2 MMHG
-------~~
~-----
'/
8U
-20
TEMP CONTROL
RESP (C02)
RESP RATE
digital interface. It consisted of a Zilog Z80 microprocessor, eight timers, 1024 bytes of memory (ROM), 1024 bytes of random access memory for data, a 16line parallel inpuVoutput interface and a RS-232C serial interface. The sampling rate was l/second for P tc0 2 , P tcC0 2, room and skin temperature. The expired CO 2 signal from which breath to breath intervals were derived was digitized at a rate of 8/second. The ECG R-R interval was measured separately with specially designed hardware. The digitized data was stored for 30 seconds in memory before it was transmitted to the main microprocessor, a Radioshack TRS 80 Model 2 with two megabytes of 8 inch floppy disk storage. A peak to peak breath detection program using the expired CO 2 signal determined respiratory rates (25). The data listed in Table 3 were generated for each minute on an on-line basis and displayed simultaneously on the screen. Several steps were taken to reduce contamination of the data by artefact: First, each minute of the computer output was scanned for abnormal values with the polygraphie recording used as an ultimate reference. Second, in the case of transcutaneous gases, the magnitude of the electrode drift was measured by comparing initial and end calibrations. If the drift between the onset and end of the recording equalled or exceeded 5 mm Hg, the minute by minute values were adjusted by the formula m(adj) = m-(a+bm)t (see Appendix 1). This formula assurnes that the drift is linear, an assumption which did not bias the data in favor of any of the study groups. The P tcC02 values were further adjusted by the formula: P tcC0 2 = 1.14 PaC02 + 4.88, to better reflect arterial values (4).
ACTIVE SLEEP
1 MINUTE
CALIBRATION
Sleep state classifications were then integrated with the computer data and together plotted on aminute by minute basis (Fig. 2). The means of all the valid minute to minute data were obtained for each infant and compared as a function of study group, age and sleep state, with the aid of an analysis of variance (BMD P4V) or a Student t-test (7).
Results
1. Clinical jindings The mean gestational age of the apneic prematures was slightly lower than that of the non-apneic infants but this difference was not significant (Table 2). Approximately half of each group was readmitted to the hospital after nursery discharge but for different reasons (Table 4). Two preterms with apnea in the nursery had an apparent life threatening event (ALTE) associated with seizures. Growth was essentially normal and comparable in the two groups with one infant in each showing head circumference below the fifth percentile. There were no major neurologie abnormalities in either group. In 7 of 9 apneic infants neurologie examination after nursery discharge revealed minor findings such as increased tone in the lower extremities, decreased tone in the upper extremities, irritability and tremors. Most of these findings were transient but one infant still had suspect neurologie signs when last seen at four Table 4
Hospital readmissions premature infants.
With apnea 5/9
I
Without apnea
,,4/10
Table 3 Variables and statistical measures collected on aminute by minute basis. Variable
Ptc 0 2
Respiratory rate Heart rate Skin temperature
IStatistics Pertussis followed by ALTE with seizures in hospital (41 wks)
Staphylococcal sepsis (36 wks)
Vomiting (42 wks)
Croup (55 wks)
Failure to thrive (85 wks)
Viral meningitis (47 wks)
Bronchiolitis (52 wks) * ALTE = apparent life threatening event **PCA on readmission
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QUiET SLEEP
Neuropediatrics 23 (1992)
T. Hoppenbrouwers et al
PRETERM INFANT WITH APNEA IN THE NURSERY
Tabla 5
44wks
40wks
Age (weeks)
~~~~STATE
brpm
I:l~~ o
i
•
lU~1 i
•
,
,
%AW % QS* %AS* %IN
15.3 35.7 39.7 9.2
* % of total recording time; ** p < 0.05 AW: awake, QS: quiet sleep, AS: active sleep, IN: indeterminate sleep
i
RESP. RATE (C02)
brpm
~. ~l~ l~ ~l~ ~~I~
--..-----.-
IQR
bpm
HEARTRATE
bpm
IQR
100
torr
~
,J\~
-----,.---,------.----r-Ptc02
gl~
torr
L~ i
i
•
4Oj~~
:L TEMP.l
l·~
~
Sleep behavior at 40 weeks PCA was eomparable in the infants with and without apnea. The pereentages of AS, QS, AW and IN did not differ among the two groups at that age (Table 5). At 44 weeks, however, the infants without apnea in the neonatal period exhibited more interrupted sleep than the group with apnea. This was refleeted in a signifieant reduetion in AS (p < 0.05) and a doubling in the number of awakenings (5 versus 10; p < 0.05, Fig. 3). There was no differenee in QS. At 52 weeks PCA laboratory sleep was again similar in the two groups.
3. Transcutaneous gases
--r--r--
degree C
2. Sleep and waking
i
L----r----r--·~
PtcC02
years of age. Minor neurologie findings were less eommon in the non-apneie preterms. Only two of 10 exhibited transient inereased tone with irritability. When last seen one apneie infant showed a developmental delay. The remainder exhibited normal progress as did all the non-apneie infants.
1llME(hrs)
Fig. 2 Minute by minute computer plots of two recordings in the same apneic preterm infant at 40 and 44 weeks PCA. Sieep and waking modulation of both respiratory and heart rate is apparent. No dramatic changes mark the transition between 40 and 44 weeks but respiratory and temperature variability decreased. Abbreviations: aw: awake, as: active sleep, qs: quiet sleep, in: indeterminate, brpm: breaths/minute, bpm: beats/minute, IQR: interquartile range, RESP: respiration, TEMP: temperature.
Computer analyses revealed that mean P tc0 2 and P tcC0 2 levels in apneie and non-apneie infants did not differ in any of the ages nor the sleep states studied (Table 6). Dips in P tc0 2 in exeess of two standard deviations of the mean oeeurred throughout the reeording in eaeh infant. As many as nine or ten per minute were seen with no systematie distribution aeeording to sleep states or ages. The typical range for number of dips was 0-3, and overall there was an average of 1.1 per minute. Low P tcC0 2 values with the mean as referenee were also seen an average of 1.1 per minute with similar ranges in both groups. Elevated P tcC0 2 values followed an identieal pattern. Finally, mean adjusted P tcC0 2 values in exeess of 50 mmHg were seen in 35 % of infants at 40 weeks, 29 % at 44 weeks and 9 % at 52 weeks. These hypereapnie values were more likely to oeeur during QS, espeeially in the youngest non-apneie infants (56 %).
1 MONTH OLD INFANTS
~~--r-----. Sl.EEP STATE
non-apneic
preterm
apneic preter m
Fig. 3 State plots from three non-apneic and apneic preterms; these selected tracings best represent the findings for the two groups. Note the paucity in R, elsewhere referred to as active sleep and the frequent brief awakenings in the non-apneic infants. A: awake, Q: quiet sleep, T: transitional or indeterminate.
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78
Neuropediatrics 23 (1992)
Table 6 Autonomie variables in preterm infants as a funetion of age and sleep state.
Age (weeks) Apneic preterms Median HR HRIQ Median RR RRIQ Mean Ptc 0 2
I~~
44
52
1
I~g
44
1
52
I~~
1
1
44 1
153.3 8.8 47.0 15.9 62.0 1.6 45.5 0.5
144.5 10.9 44.8 12.6 69.7 1.8 46.7 0.3
133.7 9.8 38.2 12.3 82.3 1.6 42.2 0.6
150.5 3.8 41.4 6.8 64.0 1.0 44.8 0.3
142.9 7.5 38.0 5.1 69.4 0.9 48.2 0.3
131.5 6.3 32.5 5.5 81.8 0.9 42.9 0.5
181.1 12.9 56.0 31.3 70.3 2.5 42.8 0.6
178.4 13.0 57.9 31.6 75.3 2.5 44.7 0.5
Non-apneic preterms Median HR 152.8 9.2 HRIQ Median RR 52.8 14.1 RRIQ Mean Ptc 0 2 68.0 SO 1.6 47.8 Mean PtcC02 SO 0.4
143.6 13.8 46.9 13.4 75.8 1.6 42.2 0.5
129.8 7.1 35.5 12.3 77.4 1.2 44.3 0.4
150.8 3.7 43.7 6.4 68.3 0.8 49.5 0.3
139.1 5.9 39.7 5.9 73.0 0.9 44.1 0.4
126.0 6.4 29.5 5.8 77.0 0.7 45.4 0.3
183.0 12.8 57.3 29.1 74.4 2.5 47.1 0.6
183.6 17.6 57.4 30.6 78.8 2.5 41.7 0.7
SO
Mean PtcC02
SO
During sleep absolute decreases in P tc 0 2 equal to or greater than 15 mmHg were rare in both study groups. Seventyand 67 percent of preterms without apnea and 88.5 and 75 percent of preterms with apnea exhibited no absolute decreases of this magnitude at 40, 44 weeks respectively. At 52 weeks PCA none of the infants had any such P tc0 2 decreases. One previously apneic infant had 16 decreases at 40 weeks. At the same age this infant had seven apnea > 12 seconds, four accompanied by TEB's and three by a decrease in P tc0 2 • The most apnea > 12 seconds in any other infant at that age was two and the highest number of Ptc02 decreases was 4. Thus, only one infant exhibited a relatively high count of apnea together with TEB's and P tc0 2 decreases at 40 weeks. This infant's findings at 44 weeks were within the normal range.
4. Autonomie variables Neither the median respiratory rate nor the interquartile range, an estimate of variability, were different in the apneic and non-apneic infants (Table 6). Values were indistinguishable between the groups in every state at every age. The median heart rate in AS, QS and AW was similar in both groups at every age. The variability as measured by the interquartile range was also indistinguishable (Table 6). The mean skin temperature of the apneic infants was 34.8 degrees C, compared to 36.0 in non-apneic infants (NS).
79
~ 161.8 12.7 47.2 28.8 83.5 1.8 39.3 0.6
169.4 14.2 50.0 33.3 77.8 1.6 44.3 0.5
Discussion The number of infants with prolonged apnea in the nursery is smaller in our study than reported in previous studies. For example, Henderson-Smart in a survey of 25,000 infants found an ineidence of seven percent between 34-35 weeks (10). We wished to study the sequelae of late apnea of prematurity and wanted to separate apnea from other morbidity associated with immaturity and therefore selected consistently healthy infants. Our mueh lower figure of approximately one percent is due to our striet exclusion eriteria. Sequential polygraphie reeordings in preterm infants are diffieult to obtain because parents of these infants are reluctant to return their ehildren for research studies. Compared to previous studies in term babies, we experieneed problems convincing parents to eontinue with the program. Consequently, the number of previously apneic infants in the present study was relatively smalI. We believe these data are nonetheless valuable beeause the infants were selected aeeording to weIl defined eriteria and eonstituted a rather homogeneous group for whom results from systematie polygraphie studies are not typieally reported.
Beeause of differences in ease selection and methodology our follow-up polygraphie data in infants who were apneic in the nursery are difficult to compare with published reports. Our comparison group, however, resembles samThe number of infants with polygraphieally repIes studied by others (1, 3). Respiratory data show maturationcorded apnea after nursery discharge deereased over time. In al trends as deseribed by other investigators such as a relative preterms without apnea in the nursery we found no apnea > 12 paueity of long apnea (> 12 seeonds), a deerease in both ineiseeonds in 70, 89 and 100 percent at 40, 44 and 52 weeks redenee and duration with age and an absence of a eleareut sleep speetively. The eomparable figures in the apneie group were 50, state eorrelation (1, 3, 24). In many respeets these and other 88 and 83 percent. The maximum number of infants who exmaturational trends are similar to those found in term infants hibited apnea at any time was 4 with a median value of 2 apnea (9,16). Briefer apnea in term infants, however, are typieally nu> 12 seeonds and a range of 1-7. There were no differenees be- merous and state related in frequeney (17). Our heart and respitween study groups. Briefer apnea aeeompanied by either a ratory rate data resemble those of Katona and Egbert (21) TEB or a P tc0 2 decrease were also not eommon. With one exmeasured during QS, although these authors ealeulated their ceplioll l,ll~:Y~ "'~.Te!'~ nhserved in two infants in eaeh study group at data on the basis of chronologie age rather than PCA. every age with a range of 1-6 and a meriiau ü~ 2. T~~ pxr.eption i~~ ~!,~~prm infants with apnea in the neonatal oceurred at one month of age when a median of two apneas was period exhibited a transient deerease in awakenings at 44 weeks observed in three previously non-apneie infants.
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Polygraphy After Late Apnea in the Nursery
Neuropediatrics 23 (1992)
T Hoppenbrouwers et al
but had no abnormal polygraphie eardio-respiratory findings eompared to preterms without apnea. The fewer sleep interruptions at 44 weeks PCA were eomparable to the number found in term infants at a similar age (18). A pattern of fewer awakenings as seen in the apneie babies at 44 weeks PCA has also been observed in subsequent siblings of SIDS (10, 19). Three additional groups of investigators have reported similar findings in infants following an ALTE (5, 8, 27). Infants with neonatal apnea had an exeess of mild neurologie findings that persisted into early infaney but tended to disappear before their first birthday. Two of these infants suffered from ALTE after nursery discharge eompared to none of the non-apneie infants. These results are of interest in light of the report by Korobkin and Guilleminault doeumenting shoulder hypotonia in infants following an ALTE (22). Prolonged apneas are almost always eentral in origin (12, 24). In order to guard against overlooking significant obstruetive episodes, we examined brief apneas assoeiated with either a drop in heart rate or oxygen level. These episodes were not different in the two groups on follow-up. The remaining eardio-respiratory findings from the two groups were also indistinguishable. This failure to diseriminate infants on the basis of polygraphie traeings is akin to our inability to prediet from polygraphie traeings in subsequent siblings or infants following an ALTE whieh infants will subsequently die of SIDS (13, 20, 26, 28, 30). We earefully seleeted apparently healthy infants with late apnea, and distinguished apnea due to neonatal morbidity from apnea of prematurity and apnea oeeurring early in the neonatal course whieh is eommon, from persistent or late apnea, whieh is relatively rare. As a result our apneie group was fairly homogenous and perhaps at inereased risk for SIDS. Compared to infants who had not experieneed late apnea, we eould not deteet eardio-respiratory abnormalities in the polygraphie traeings from these infants. The relatively small number of eases mitigates against arriving at definitive eonelusions. However, polygraphie data from a larger group of such infants might weIl eonfirm these findings. Also the interesting differenees in sleep, museIe tone and subsequent ALTE, whieh may be related to risk for SIDS, warrant further investigation. Appendix 1
Let m(t) = measurement at time t, ealibration low value at t = 0 LB ealibration high value at t = 0 HB ealibration low value at t = T LE HE = ealibration high value at t = T. Then the drift is LE HE'
~
at m (T)
=
L E and HE - H B at m (T)
=
If it is assumed that the drift is proportional to t and linearly related to m so that the drift at time t is given by (a + bm) t, then the adjusted measurement m adj at time t is madj = m - (a + bm) 1. Sinee (a + b . HE) T = HE - H B and (a + b . LE) T = LE - LB , we ean determine a and b as
(HE - H B )
- (LE (HE-LE) T
b
~)
Acknowledgment
This Research was supported by NICHD Grant # 13689, the Orange County Chapter of the Guild for Infant
Survival, The Los Angeles Chapter of The National SIDS Foundation and the Arthur Zimtbaum Foundation of New York. We thank Ms. Lori ]udson, MS, RN, Ms. Maria Elena Ruiz RN, Ms. Nance Alba, Ms.]ane Peckham, Ms. Kristin Moore and Mr. Alan Keys for their eontribution to the data eolleetion and analysis.
References Albani, M., K. H. P. Bentele, C. Budde, F.]. Schulte: Infant sleep apnea profile: Preterm vs. term infants. Eur. J. Pediatr. 143 (1985) 261-268 2 Black, L., R.]. David, R. T. Brouilette: Hunt CE effects of birth weight and ethnicity on incidence of sudden infant death syndrome. J. Pediatr. 108 (1986) 209-214 3 Booth, C. L., V. N. Morin, S. Waite, E. B. Thoman: Periodic and nonperiodic sleep apnea in premature and fullterm infants. Dev. Med. Child Neurol. 25 (1983) 283-296 4 Cabal, L., H. Cruz, C. Plajstek, S. Yeh, B. Siassi,]. E. Hodgman: Factors affecting heated transcutaneous P0 2 and unheated transcutaneous PC0 2 in preterm infants. Crit. Care Med. 9 (1981) 298-304 5 Challamel, M.]., G. Debilly, C. Leszcynski: Sleep state development in near-miss sudden death infants. In: R. M. Harper, H.]. Hoffinan (Eds.), Sudden Infant Death Syndrome, Risk Factors and Basic Mechanisms. New York, PMA Publishing Co (1989) 423-434 6 Damus, K., ]. Pakter, E. Krongrad: Postnatal medical and epidemiological risk factors for the sudden infant death syndrome. In: R. M. Harper, H.]. Hoffinan (Eds.), Sudden Infant Death Syndrome, Risk Factors and Basic Mechanisms. New York, PMA Publishing Co (1989) 187-202 7 Dixon, W. ].: BMD Biomedical Computer Programs. Los Angeles, University of California Press (1973) 8 Guilleminault, C., S. Coons: Sleep states and maturation of sleep: A comparative study between full term normal controls and near miss SIDS infants. In:]. T. Tildon, L. M. Roeder, A. Steinschneider (Eds.): Sudden Infant Death Syndrome. New York, Academic Press (1983) 401-412 9 Harper, R. M., T. Hoppenbrouwers, M. B. Sterman, D.]. McGinty,]. E. Hodgman: Polygraphie studies of normal infants during the first six months of life. I. Heart rate and variability as a function of state. Pediatr. Res. 10(1976)945-951 10 Harper, R. M., B. Leake, H. Hoffinan, D. O. Walter, T. Hoppenbrouwers, ]. E. Hodgman, M. B. Sterman: Periodicity of sleep states is altered in infants at risk for the Sudden Infant Death Syndrome. Science 213 (1981) 1030-1032 11 Henderson-Smart, D.].: The effect of gestational age on the ineidence and duration of recurrent apnoea in newborn babies. Aust. Paediatr. J. 17 (1981) 273-276 12 Henderson-Smart, D. ]., G. Cohen: Apnoea in the newborn infant Aust. Paediatr. J. Suppl. (1986) 63-66 13 Hodgman,]. E., T. Hoppenbrouwers: Cardiorespiratory behavior in infants at increased epidemiological risk for SIDS. In:]. T. Tildon, L. M. Roeder, A. Steinschneider (Eds.): Sudden Infant Death Syndrome. New York, Academic Press (1983) 401-412 14 Hodgman,]. E., F. Gonzales, T. Hoppenbrouwers, L. A. Cabal: Apnea, transient episodes of bradycardia and periodic breathing in preterms. Am. J. Dis. Child. 144 (1990) 54-57 15 Hofmann, E., B. Havens, S. Geidel, T. Hoppenbrouwers: Long-term continuous monitoring of multiple physiological parameters in newborn and 1
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16
17
18
19
20
21
22
23
24
25 26
27
28 29
30
31
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Neuropediatrics 23 (1992)
young infants. Procedural manual. Acta Paediatr. Scand. Suppl. 266 (1977) Hoppenbrouwers, T, R. M. Harper,]' E. Hodgman, M. B. Sterman, D.]. McGinty: Polygraphic studies of normal infants during the first six months of life. 11. Respiratory rate and variability as a function of state. Pediatr. Res. 12 (1978) 120-125 Hoppenbrouwers, T,]. E. Hodgman, K. Arakawa, R. M. Harper, M. B. Sterman: Respiration during the first six months of life in normal infants. 111. Computer identification of breathing pauses. Pediatr. Res. 14 (1980) 1230-1233 Hoppenbrouwers, T,]. E. Hodgman, K. Arakawa, N. Alba, M. Durand, L. A. Cabal: Are sleep states influenced by apnea and prematurity? Pediatr. Res. 18 (1984) 139A Hoppenbrouwers, T,]. E. Hodgman, K. Arakawa, S. A. Geidel, M. B. Sterman: Sleep and waking states in infancy: Normative studies sleep 11 (1988) 387-401 Infantile Apnea and Horne Monitoring. A Consensus Report. U.S. Department of Health and Human Services, NIH Publication 87-2905 (1987) 1-23 Katona, P. G.,]. R. Egbert: Heart rate and respiratory rate differences between preterm and full-term infants during quiet sleep: Possible implications for sudden infant death syndrome. Pediatrics 62 (1978) 91-95 Korobkin, R., C. Guilleminault: Neurologie abnormalities in near miss for sudden infant death syndrome infants. Pediatrics 64 (1979) 309-312 Kulkarni, P., R. T Hall, P. G. Rhodes, M. B. Sheehan: Post-neonatal infant mortality in infants admitted to a neonatal intensive care unit. Pediatrics 62 (1978) 178-183 Lee, D., R. Caces, K. Kwiatkowski, D. Cates, H. Rigatto: A developmental study on types and frequency distribution of short apneas (3-15 seconds) in term and preterm infants. Pediatr. Res. 22 (1987) 344-349 Mason,]., R. M. Harper, R. Pacheco: Analysis ofrespiratory data during sleep and waking. Proc. Dig. Equip. Comput. Users Soc 567 (1974) Monod, N., P. Plouin, B. Sternberg, P. Peirano, N. Pajot: Apnea and periodic breathing: A risk factor for SIDS? 8th Annual Conf. of the Engineering in Med. and Biol. Society (1986) 1192-1194 Navelet, Y., O. Benoit,]. Lacombe: Respiration et sommeil de nuit chez des enfants "a risques" pour mort subite du nourrisson. Rev. EEG Neurophysiol. 9 (1979) 258-265 Oren,]., D. H. Kelly, D. C. Shannon: Pneumogram recordings in infants resuscitated for apnea of infancy. Pediatrics 83 (1989) 364-368 Sims, M. E., G. Yau, S. Rambhatla, L. Cabal, P. Y. K. Wu: Limitations of theophylline in the treatment of apnea of prematurity. Am. J. Dis. Child. 139 (1985) 567-570 Southall, D. P.,]. M. Richards, K.]. Rhoden, ]. R. Alexander, E. A. Shinebourne, W. A. Arrowsmith,]. E. Cree, P.]. Fleming, A. Goncalves, R. L. Orme: Prolonged apnea and cardiac arrhythmias in infants discharged from neonatal intensive care units: Failure to predict an increased risk for sudden infant death syndrome. Pediatrics 70 (1982) 844851 Wielenga, H.: Cot death in preterm and small for gestational age infants in the Netherlands. Doctoral Dissertation (1988)
, Hippokrates Mikrobiologische Diagnostik und antimikrobielle Chemotherapie Von W. OPFERKUCH, Bochum 1989. 92 Seiten, 10 X 19 cm, kartoniert DM 16,ISBN 3-7773-0958-3
Aus dem Inhalt: Untersuchungsmethoden und Hinweise zur Probenentnahme für lnikrobiologische Untersuchungen: A. Bakteriologische Untersuchungen. B. Virologische Untersuchungen. C. Parasitologische Untersuchungen. D. Mykologische Untersuchungen. E. Immunologische Untersuchungen. - Hinweise zur antimikrobiellen Chemotherapie: Antibiotika (Wirkspektrum, Applikation, Dosierung). - Anhang: J. Normenbereich für serologische und immunologische Untersuchungen. 11. Hinweise zu klinisch-chemischen Untersuchungen. Ich bestelle aus dem Hippokrates Verlag Stuttgart durch die Buchhandlung: ................ Expl. OPFERKUCH, Mikrobiol. Diagnostik u. antimikrob. Chemotherap. DM 16,ISBN 3-7773-0958-3
Toke Hoppenbrouwers, Ph. D.
Director, Sudden Infant Death Syndrome Research Project Room 9L19, Women's Hospital LAC/USC Medical Center 1240 North Mission Rd Los Angeles, CA 90033, USA
Unterschrift Name (möglichst Stempel)
Straße
Ort
Datum
(Preisänderung vorbehalten)
Hippokrates Verlag Stuttgart Postfach 102263
7000 Stuttgart 10
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Polygraphy After Late Apnea in the Nursery
Polygraphy After Discharge in Preterm Infants with and without Apnea in the Nursery By T Hoppenbrouwers,]. E. Hodgman, K. Arakawa, M. Durand and L. A. Cabal
Abstract Nine of nineteen infants in this study exhibited two or more eentral apnea ~ 20 seeonds when they were older than one week and between 32-36 weeks posteoneeptional age (PCA). We foeused on the sequelae of these apneas. Apnea was separated from other morbidity assoeiated with immaturity by the seleetion of eonsistently healthy infants. Following diseharge, polygraphie traeings were obtained at 40, 44 and 52 weeks PCA in these non-apneie and previously apneie infants. Sleep states, minute by minute values for heart and respiratory rate, skin temperature and transeutaneous 02 (Ptc0 2) and CO2 (PtcC02), apnea and transient deereases in P tc02 were determined. Polygraphie measurements did not differentiate preterm infants with late apnea in the nursery from non-apneie ones. However, the apneie group exhibited a transient deerease in awakenings at 44 weeks PCA.
Keywords
most 1400 low-birthweight infants are born in our hospital yearly, but only 10-15 otherwise healthy infants exhibit these late apneie episodes. In the literature, infants with late apnea have not been distinguished from infants with apnea of prematurity beginning soon after birth. It seems reasonable to postulate that late apnea would be more likely to have physiologie eonsequenees than apnea resolving more promptly. This eonsideration led us to seleet this group for study during the age of highest risk for SIDS. We wished to separate apnea from other morbidity assoeiated with immaturity and therefore seleeted eonsistently healthy infants. The working hypothesis was that these apneie premature infants would be more likely to exhibit abnormal physiologie patterns during early infaney than eomparable non-apneie preterm infants. Systematie polygraphie studies after nursery diseharge of premature infants who have experieneed prolonged apnea beyond the first week of life have not been reported. It was the objeetive of the present study to eolleet polygraphie data for sleep state development, eardio-respiratory funetioning and transeutaneous gases in preterm infants after nursery diseharge and eompare the findings of infants with and without late apnea in the nursery.
Sleep states - Apnea of prematurity - SIDS - ALTE - Polygraphy
Method
1. Material and monitoring procedure Introduction The inereased risk for Sudden Infant Death Syndrome (SIDS) in premature infants is weIl established and appears to be inversely related to gestational age (2, 23). AIthough premature infants are perceived to be at greater risk for SIDS following neonatal apnea, whether or not prolonged apnea in the nursery indeed augments this risk has not been firmly established. At present, available evidenee suggests that preterm infants with apnea prior to 40 weeks post-eoneeptional age (PCA) are not at inereased risk eompared to preterms without apnea (6, 20, 30, 31). These findings are largely based on epidemiologieal rather than prospeetive studies. Apnea of prematurity, a frequent diagnosis in the high risk nursery, resolves in most infants during the first week of life (11). Apnea of prematurity after the first week is seen in a small number of otherwise healthy infants (29). AIReceived December 11, 1990; accepted January 10, 1991 Neuropediatrics 23 (1992) 75-81 © Hippokrates Verlag Stuttgart
The nursery was surveyed daily and the ehart of every newly admitted infant of < 35 weeks gestation was examined to identify potential eandidates for future study. Candidates had to be appropriate for gestational age and free from illness aeeording to the striet eriteria outlined in Table 1. Onee identified, their nursery progress was earefully monitored to ensure that they eontinued to qualify. To establish the presenee of apnea, preliminary eardio-respiratory monitoring was performed after the first week in the nursery when the infants were between 32 and 36 weeks PCA. Eight hour traeings obtained between 11 p.m. and 7 a.m. were visually analyzed for the presenee of eentral apnea ~ 20 seeonds (14). During a fourteen months period nine otherwise healthy, preterm infants were seleeted, who exhibited two or more eentral apnea ~ 20 seeonds after the first week of life. An effort was made to enroll all infants with these late apneas. Ten infants who did not exhibit apnea on the eardio-respiratory traeings nor had any history of apneie episodes served as a eomparison group. These healthy infants without apnea who fulfilled the study eriteria were aeeepted aeeording to availability of monitoring time in the sleep laboratory. There was a high ineidenee of maternal eomplieations and Cesarean seetion in both groups as would be expeeted
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Department of Pediatrics, University of Southern California School of Medicine and Los Angeles County, University of Southern California Medical Center, Los Angeles, California, USA
Neuropediatrics 23 (1992)
T Hoppenbrouwers et al
lable 1 Illness criteria in prematures. At any time during nursery course 1) Assisted ventilation for 24 hours or more except for management of apnea 2) Intracranial hemorrhage by CT scan or ultrasound (grades 1II and IV) 3) Culture proven sepsis 4) Oiagnosed medical conditions 5) Supplemental oxygen for more than 48 hours except for management of apnea.
Between 32-36 weeks postconceptional age 1) 2) 3) 4) 5)
Hypocalcemia « 7.5 mg/dl) Hypoglycemia « 30 mg/dl) or hyperglycemia (> 150 mg/dl) Hypothermia « 35.5 °c rectal) or hyperthermia (> 37.5 °c rectal) Hyponatremia « 130 meq/L) or hypernatremia (> 150 meq/L) Anemia - (HCT < 30 %)
for high risk infants but an absence of significant neonatal problems because of the selection criteria. A number of clinical characteristics are presented in Table 2. Our protocol was approved by the LAC/USC Medical Center Human Research Committee. The study design called for repetitive laboratory monitoring after discharge at 40, 44 and 52 weeks of PCA and informed consent was obtained prior to each session. Eighteen infants (8 apneic and 10 non-apneic) returned to the laboratory at 40 and seventeen (8 apneic and 9 non-apneic) at 44 weeks PCA. Only ten parents were willing to return the infants (6 apneic and 4 non-apneic) for laboratory monitoring at 52 weeks of age. An effort was made to contact all families at 9 months of age. Information was obtained for seven out of nine infants with apnea and five out of ten infants without apnea. Of the nine infants with apnea identified by cardio-respiratory monitoring six had clinical apnea severe enough to be treated in the nursery with aminophylline; at their first monitoring session in the sleep laboratory, however, infants had been off this drug for at least one month. In three infants the severity of the apnea warranted management with assisted ventilation and supplemental oxygen for 24-48 hours. One additional infant received supplemental oxygen alone. Each infant was admitted between 5:00 and 6:00 p.m. to the sleep laboratory for 2-4 hour recordings. The
session began with a short physical and neurological evaluation. The infants were fed during preparation for monitoring and application of electrodes whereafter a demand feeding schedule was followed. Arm restraints were applied before the initiation of recording. Monitoring was carried out in a darkened roorn adjacent to the room containing recording equipment. While room temperatures ranged between 19.4 and 24.5 degrees C, infants in both groups were exposed to comparable temperatures (21.6 + 0.24 vs 21.5 + 0.17 degrees C). The infants were placed in a supine or sidelying position and observed continuously with the help of a low-illumination television camera and monitor. Activities such as closing or opening of the eyes, startles, crying, and nursing interventions were charted on the polygraph paper (15).
2. Physiological recording methods For each infant, the sleep variables included two EEG derivations (approximating C1-C5 and C2-C6, according to the International 10-20 system), a chin electromyogram and eye movements. Thoraeie and abdominal excursions were monitored with strain gauges. In addition, a Beckman PC0 2 monitor sampled expired gas through a miniature cannula taped under the infant's nostrils. The ECG was recorded with two disposable electrodes placed symmetrically beneath the clavicles. AdditionaIly, a skin temperature probe was applied to the abdomen below the right costal margin. Electrodes on the mattress surface under the crib sheet registered the infant's gross body movements (15). P tc0 2 and P tcC0 2 were measured with a Novametrix monitor. The electrodes were applied to either side of the upper ehest. An 02 electrode temperature of 43.5 °C was selected while the CO2 electrode was unheated. Both electrodes were calibrated at the onset and termination of each recording with gases of known 02 and CO 2 concentration (0 and 92 mrn Hg for 02; 38 and 76 mm Hg for CO2). Humidity of the roorn air was sampled on an hourly basis during the monitoring and was comparable in both study groups. The data were recorded on a 16 channel Grass Model 76 polygraph at 6 mmlsec paper speed, an eight channel Brush recorder at 1 cmlmin paper speed, and stored simultaneously, together with a time code on a 14 channel HoneyweIl analog tape recorder (Figure 1).
labte 2 Clinical characteristics. Premature infants with apnea (n = 9)
without apnea (n = 10)
1660 (362) 1210-2215
1577 (285) 1340-2250
31.3 (1.9) 28-34
32.9 (1.3) 31-35
Birth weight (gms) Mean (SO) Range
Gestational age (wks) Mean (SO) Range
Race Hispanic Black White
7 1 1
9 1
SexM/F Apgar (Mean)
8/1
6/4
1 min 5 min
5.3 7.4
7.1 8.5
Age at 40 wks (in days)
64
53
3. Data analysis The polygraphie tracings were coded by trained observers into minutes of active sleep (AS), quiet sleep (QS), awake (AW) and indeterminate (IN), according to generally accepted criteria described elsewhere (16). Every 50th minute of the tracing was independently recorded by a second observer to ensure an agreement between coders of at least 80 percent. Central apnea equal to or longer than 12 seconds during sleep as weIl as transient decreases in P tc0 2 in excess of 15 mm Hg were identified. In addition, we recorded the presence of shorter apnea when accompanied by either a transient episode of bradycardia (TEB), defined as a heart rate drop to below 90 beats/minute or a P tc0 2 decrease, as defined above. Data on the analog tapes were digitized by a preprocessing micro-computer with eight channels of analog to
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76
Neuropediatrics 23 (1992)
Polygraphy After Late Apnea in the Nursery Fig. 1 Segment of a recording in a 40 week PCA preterm infant at 1 cm/min paper speed. Ptc 0 2 calibration 20, 60 and 92 mmHg, Ptc C0 2 calibration 60 and 76 mmHg. Note the Ptc 0 2 decrease following an apnea and a movement. This pattern was seldom seen in these infants. The temperature (temp) control tracing reflects 02 electrode heating and an estimate of vasodilation and constriction under the electrode. BPM = beats/minute; BRPM = breaths/ minute.
77
PAEMATURE 40 WKS CARDIAC RATE
~jM,"r·~'V"J~,,"'"Tf'·r~~'1~,/.'ir ""'ft",'I't :::
BPM
11 ·~1
~C02
~ I~l
L-.-..~a,' ~~'1l--
MOVEMENTS
- - - - - - - - - - - - - - - - - - - ~~----78 -80 - 9 2 MMHG
-------~~
~-----
'/
8U
-20
TEMP CONTROL
RESP (C02)
RESP RATE
digital interface. It consisted of a Zilog Z80 microprocessor, eight timers, 1024 bytes of memory (ROM), 1024 bytes of random access memory for data, a 16line parallel inpuVoutput interface and a RS-232C serial interface. The sampling rate was l/second for P tc0 2 , P tcC0 2, room and skin temperature. The expired CO 2 signal from which breath to breath intervals were derived was digitized at a rate of 8/second. The ECG R-R interval was measured separately with specially designed hardware. The digitized data was stored for 30 seconds in memory before it was transmitted to the main microprocessor, a Radioshack TRS 80 Model 2 with two megabytes of 8 inch floppy disk storage. A peak to peak breath detection program using the expired CO 2 signal determined respiratory rates (25). The data listed in Table 3 were generated for each minute on an on-line basis and displayed simultaneously on the screen. Several steps were taken to reduce contamination of the data by artefact: First, each minute of the computer output was scanned for abnormal values with the polygraphie recording used as an ultimate reference. Second, in the case of transcutaneous gases, the magnitude of the electrode drift was measured by comparing initial and end calibrations. If the drift between the onset and end of the recording equalled or exceeded 5 mm Hg, the minute by minute values were adjusted by the formula m(adj) = m-(a+bm)t (see Appendix 1). This formula assurnes that the drift is linear, an assumption which did not bias the data in favor of any of the study groups. The P tcC02 values were further adjusted by the formula: P tcC0 2 = 1.14 PaC02 + 4.88, to better reflect arterial values (4).
ACTIVE SLEEP
1 MINUTE
CALIBRATION
Sleep state classifications were then integrated with the computer data and together plotted on aminute by minute basis (Fig. 2). The means of all the valid minute to minute data were obtained for each infant and compared as a function of study group, age and sleep state, with the aid of an analysis of variance (BMD P4V) or a Student t-test (7).
Results
1. Clinical jindings The mean gestational age of the apneic prematures was slightly lower than that of the non-apneic infants but this difference was not significant (Table 2). Approximately half of each group was readmitted to the hospital after nursery discharge but for different reasons (Table 4). Two preterms with apnea in the nursery had an apparent life threatening event (ALTE) associated with seizures. Growth was essentially normal and comparable in the two groups with one infant in each showing head circumference below the fifth percentile. There were no major neurologie abnormalities in either group. In 7 of 9 apneic infants neurologie examination after nursery discharge revealed minor findings such as increased tone in the lower extremities, decreased tone in the upper extremities, irritability and tremors. Most of these findings were transient but one infant still had suspect neurologie signs when last seen at four Table 4
Hospital readmissions premature infants.
With apnea 5/9
I
Without apnea
,,4/10
Table 3 Variables and statistical measures collected on aminute by minute basis. Variable
Ptc 0 2
Respiratory rate Heart rate Skin temperature
IStatistics Pertussis followed by ALTE with seizures in hospital (41 wks)
Staphylococcal sepsis (36 wks)
Vomiting (42 wks)
Croup (55 wks)
Failure to thrive (85 wks)
Viral meningitis (47 wks)
Bronchiolitis (52 wks) * ALTE = apparent life threatening event **PCA on readmission
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QUiET SLEEP
Neuropediatrics 23 (1992)
T. Hoppenbrouwers et al
PRETERM INFANT WITH APNEA IN THE NURSERY
Tabla 5
44wks
40wks
Age (weeks)
~~~~STATE
brpm
I:l~~ o
i
•
lU~1 i
•
,
,
%AW % QS* %AS* %IN
15.3 35.7 39.7 9.2
* % of total recording time; ** p < 0.05 AW: awake, QS: quiet sleep, AS: active sleep, IN: indeterminate sleep
i
RESP. RATE (C02)
brpm
~. ~l~ l~ ~l~ ~~I~
--..-----.-
IQR
bpm
HEARTRATE
bpm
IQR
100
torr
~
,J\~
-----,.---,------.----r-Ptc02
gl~
torr
L~ i
i
•
4Oj~~
:L TEMP.l
l·~
~
Sleep behavior at 40 weeks PCA was eomparable in the infants with and without apnea. The pereentages of AS, QS, AW and IN did not differ among the two groups at that age (Table 5). At 44 weeks, however, the infants without apnea in the neonatal period exhibited more interrupted sleep than the group with apnea. This was refleeted in a signifieant reduetion in AS (p < 0.05) and a doubling in the number of awakenings (5 versus 10; p < 0.05, Fig. 3). There was no differenee in QS. At 52 weeks PCA laboratory sleep was again similar in the two groups.
3. Transcutaneous gases
--r--r--
degree C
2. Sleep and waking
i
L----r----r--·~
PtcC02
years of age. Minor neurologie findings were less eommon in the non-apneie preterms. Only two of 10 exhibited transient inereased tone with irritability. When last seen one apneie infant showed a developmental delay. The remainder exhibited normal progress as did all the non-apneie infants.
1llME(hrs)
Fig. 2 Minute by minute computer plots of two recordings in the same apneic preterm infant at 40 and 44 weeks PCA. Sieep and waking modulation of both respiratory and heart rate is apparent. No dramatic changes mark the transition between 40 and 44 weeks but respiratory and temperature variability decreased. Abbreviations: aw: awake, as: active sleep, qs: quiet sleep, in: indeterminate, brpm: breaths/minute, bpm: beats/minute, IQR: interquartile range, RESP: respiration, TEMP: temperature.
Computer analyses revealed that mean P tc0 2 and P tcC0 2 levels in apneie and non-apneie infants did not differ in any of the ages nor the sleep states studied (Table 6). Dips in P tc0 2 in exeess of two standard deviations of the mean oeeurred throughout the reeording in eaeh infant. As many as nine or ten per minute were seen with no systematie distribution aeeording to sleep states or ages. The typical range for number of dips was 0-3, and overall there was an average of 1.1 per minute. Low P tcC0 2 values with the mean as referenee were also seen an average of 1.1 per minute with similar ranges in both groups. Elevated P tcC0 2 values followed an identieal pattern. Finally, mean adjusted P tcC0 2 values in exeess of 50 mmHg were seen in 35 % of infants at 40 weeks, 29 % at 44 weeks and 9 % at 52 weeks. These hypereapnie values were more likely to oeeur during QS, espeeially in the youngest non-apneie infants (56 %).
1 MONTH OLD INFANTS
~~--r-----. Sl.EEP STATE
non-apneic
preterm
apneic preter m
Fig. 3 State plots from three non-apneic and apneic preterms; these selected tracings best represent the findings for the two groups. Note the paucity in R, elsewhere referred to as active sleep and the frequent brief awakenings in the non-apneic infants. A: awake, Q: quiet sleep, T: transitional or indeterminate.
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78
Neuropediatrics 23 (1992)
Table 6 Autonomie variables in preterm infants as a funetion of age and sleep state.
Age (weeks) Apneic preterms Median HR HRIQ Median RR RRIQ Mean Ptc 0 2
I~~
44
52
1
I~g
44
1
52
I~~
1
1
44 1
153.3 8.8 47.0 15.9 62.0 1.6 45.5 0.5
144.5 10.9 44.8 12.6 69.7 1.8 46.7 0.3
133.7 9.8 38.2 12.3 82.3 1.6 42.2 0.6
150.5 3.8 41.4 6.8 64.0 1.0 44.8 0.3
142.9 7.5 38.0 5.1 69.4 0.9 48.2 0.3
131.5 6.3 32.5 5.5 81.8 0.9 42.9 0.5
181.1 12.9 56.0 31.3 70.3 2.5 42.8 0.6
178.4 13.0 57.9 31.6 75.3 2.5 44.7 0.5
Non-apneic preterms Median HR 152.8 9.2 HRIQ Median RR 52.8 14.1 RRIQ Mean Ptc 0 2 68.0 SO 1.6 47.8 Mean PtcC02 SO 0.4
143.6 13.8 46.9 13.4 75.8 1.6 42.2 0.5
129.8 7.1 35.5 12.3 77.4 1.2 44.3 0.4
150.8 3.7 43.7 6.4 68.3 0.8 49.5 0.3
139.1 5.9 39.7 5.9 73.0 0.9 44.1 0.4
126.0 6.4 29.5 5.8 77.0 0.7 45.4 0.3
183.0 12.8 57.3 29.1 74.4 2.5 47.1 0.6
183.6 17.6 57.4 30.6 78.8 2.5 41.7 0.7
SO
Mean PtcC02
SO
During sleep absolute decreases in P tc 0 2 equal to or greater than 15 mmHg were rare in both study groups. Seventyand 67 percent of preterms without apnea and 88.5 and 75 percent of preterms with apnea exhibited no absolute decreases of this magnitude at 40, 44 weeks respectively. At 52 weeks PCA none of the infants had any such P tc0 2 decreases. One previously apneic infant had 16 decreases at 40 weeks. At the same age this infant had seven apnea > 12 seconds, four accompanied by TEB's and three by a decrease in P tc0 2 • The most apnea > 12 seconds in any other infant at that age was two and the highest number of Ptc02 decreases was 4. Thus, only one infant exhibited a relatively high count of apnea together with TEB's and P tc0 2 decreases at 40 weeks. This infant's findings at 44 weeks were within the normal range.
4. Autonomie variables Neither the median respiratory rate nor the interquartile range, an estimate of variability, were different in the apneic and non-apneic infants (Table 6). Values were indistinguishable between the groups in every state at every age. The median heart rate in AS, QS and AW was similar in both groups at every age. The variability as measured by the interquartile range was also indistinguishable (Table 6). The mean skin temperature of the apneic infants was 34.8 degrees C, compared to 36.0 in non-apneic infants (NS).
79
~ 161.8 12.7 47.2 28.8 83.5 1.8 39.3 0.6
169.4 14.2 50.0 33.3 77.8 1.6 44.3 0.5
Discussion The number of infants with prolonged apnea in the nursery is smaller in our study than reported in previous studies. For example, Henderson-Smart in a survey of 25,000 infants found an ineidence of seven percent between 34-35 weeks (10). We wished to study the sequelae of late apnea of prematurity and wanted to separate apnea from other morbidity associated with immaturity and therefore selected consistently healthy infants. Our mueh lower figure of approximately one percent is due to our striet exclusion eriteria. Sequential polygraphie reeordings in preterm infants are diffieult to obtain because parents of these infants are reluctant to return their ehildren for research studies. Compared to previous studies in term babies, we experieneed problems convincing parents to eontinue with the program. Consequently, the number of previously apneic infants in the present study was relatively smalI. We believe these data are nonetheless valuable beeause the infants were selected aeeording to weIl defined eriteria and eonstituted a rather homogeneous group for whom results from systematie polygraphie studies are not typieally reported.
Beeause of differences in ease selection and methodology our follow-up polygraphie data in infants who were apneic in the nursery are difficult to compare with published reports. Our comparison group, however, resembles samThe number of infants with polygraphieally repIes studied by others (1, 3). Respiratory data show maturationcorded apnea after nursery discharge deereased over time. In al trends as deseribed by other investigators such as a relative preterms without apnea in the nursery we found no apnea > 12 paueity of long apnea (> 12 seeonds), a deerease in both ineiseeonds in 70, 89 and 100 percent at 40, 44 and 52 weeks redenee and duration with age and an absence of a eleareut sleep speetively. The eomparable figures in the apneie group were 50, state eorrelation (1, 3, 24). In many respeets these and other 88 and 83 percent. The maximum number of infants who exmaturational trends are similar to those found in term infants hibited apnea at any time was 4 with a median value of 2 apnea (9,16). Briefer apnea in term infants, however, are typieally nu> 12 seeonds and a range of 1-7. There were no differenees be- merous and state related in frequeney (17). Our heart and respitween study groups. Briefer apnea aeeompanied by either a ratory rate data resemble those of Katona and Egbert (21) TEB or a P tc0 2 decrease were also not eommon. With one exmeasured during QS, although these authors ealeulated their ceplioll l,ll~:Y~ "'~.Te!'~ nhserved in two infants in eaeh study group at data on the basis of chronologie age rather than PCA. every age with a range of 1-6 and a meriiau ü~ 2. T~~ pxr.eption i~~ ~!,~~prm infants with apnea in the neonatal oceurred at one month of age when a median of two apneas was period exhibited a transient deerease in awakenings at 44 weeks observed in three previously non-apneie infants.
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Polygraphy After Late Apnea in the Nursery
Neuropediatrics 23 (1992)
T Hoppenbrouwers et al
but had no abnormal polygraphie eardio-respiratory findings eompared to preterms without apnea. The fewer sleep interruptions at 44 weeks PCA were eomparable to the number found in term infants at a similar age (18). A pattern of fewer awakenings as seen in the apneie babies at 44 weeks PCA has also been observed in subsequent siblings of SIDS (10, 19). Three additional groups of investigators have reported similar findings in infants following an ALTE (5, 8, 27). Infants with neonatal apnea had an exeess of mild neurologie findings that persisted into early infaney but tended to disappear before their first birthday. Two of these infants suffered from ALTE after nursery discharge eompared to none of the non-apneie infants. These results are of interest in light of the report by Korobkin and Guilleminault doeumenting shoulder hypotonia in infants following an ALTE (22). Prolonged apneas are almost always eentral in origin (12, 24). In order to guard against overlooking significant obstruetive episodes, we examined brief apneas assoeiated with either a drop in heart rate or oxygen level. These episodes were not different in the two groups on follow-up. The remaining eardio-respiratory findings from the two groups were also indistinguishable. This failure to diseriminate infants on the basis of polygraphie traeings is akin to our inability to prediet from polygraphie traeings in subsequent siblings or infants following an ALTE whieh infants will subsequently die of SIDS (13, 20, 26, 28, 30). We earefully seleeted apparently healthy infants with late apnea, and distinguished apnea due to neonatal morbidity from apnea of prematurity and apnea oeeurring early in the neonatal course whieh is eommon, from persistent or late apnea, whieh is relatively rare. As a result our apneie group was fairly homogenous and perhaps at inereased risk for SIDS. Compared to infants who had not experieneed late apnea, we eould not deteet eardio-respiratory abnormalities in the polygraphie traeings from these infants. The relatively small number of eases mitigates against arriving at definitive eonelusions. However, polygraphie data from a larger group of such infants might weIl eonfirm these findings. Also the interesting differenees in sleep, museIe tone and subsequent ALTE, whieh may be related to risk for SIDS, warrant further investigation. Appendix 1
Let m(t) = measurement at time t, ealibration low value at t = 0 LB ealibration high value at t = 0 HB ealibration low value at t = T LE HE = ealibration high value at t = T. Then the drift is LE HE'
~
at m (T)
=
L E and HE - H B at m (T)
=
If it is assumed that the drift is proportional to t and linearly related to m so that the drift at time t is given by (a + bm) t, then the adjusted measurement m adj at time t is madj = m - (a + bm) 1. Sinee (a + b . HE) T = HE - H B and (a + b . LE) T = LE - LB , we ean determine a and b as
(HE - H B )
- (LE (HE-LE) T
b
~)
Acknowledgment
This Research was supported by NICHD Grant # 13689, the Orange County Chapter of the Guild for Infant
Survival, The Los Angeles Chapter of The National SIDS Foundation and the Arthur Zimtbaum Foundation of New York. We thank Ms. Lori ]udson, MS, RN, Ms. Maria Elena Ruiz RN, Ms. Nance Alba, Ms.]ane Peckham, Ms. Kristin Moore and Mr. Alan Keys for their eontribution to the data eolleetion and analysis.
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, Hippokrates Mikrobiologische Diagnostik und antimikrobielle Chemotherapie Von W. OPFERKUCH, Bochum 1989. 92 Seiten, 10 X 19 cm, kartoniert DM 16,ISBN 3-7773-0958-3
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Polygraphy After Late Apnea in the Nursery
