Arousal from sleep in infants is impaired following an infection

Early Human Development 66 (2002) 89 – 100 www.elsevier.com/locate/earlhumdev

Arousal from sleep in infants is impaired following an infection Rosemary S.C. Horne a,b,*, Andrew Osborne a, Jessica Vitkovic a,b, Brendan Lacey a, Sarah Andrew a, Bonnie Chau a, Susan M. Cranage a,b, T. Michael Adamson a,b b

a Department of Paediatrics, Monash University, Wellington Road, Clayton, Victoria, Australia Ritchie Centre for Baby Health Research, Monash University, Wellington Road, Clayton, Victoria, Australia

Received 4 May 2001; received in revised form 8 August 2001; accepted 15 September 2001

Abstract Numerous studies have postulated a link between recent infection and Sudden Infant Death Syndrome (SIDS). In this study we contrasted arousal responses from sleep in infants on the day of discharge from hospital following an infection with those when fully recovered and also with well age-matched control infants. Thirteen term infants comprised the infection group and nine well infants acted as age-matched controls. All infants were studied using daytime polysomnography and multiple measurements of arousal threshold (cm H2O) in response to air-jet stimulation applied alternately to the nares were made in both active sleep (AS) and quiet sleep (QS). All infants were studied on two occasions: firstly, immediately before discharge from the Paediatric ward, and secondly, 10 – 15 days later when they were completely well in the case of the infection group. Arousal thresholds in QS in the infection group were significantly elevated on the day of discharge (262 ± 48 cm H2O) compared with 10 – 15 days later (205 ± 31 cm H2O, p < 0.05). Thresholds in the control group were not different between studies. This study provides evidence that arousability from QS is impaired following an infection and we postulate that this may explain the increased risk for SIDS following infection observed in previous studies. D 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Arousal; Infection; Sudden Infant Death Syndrome; Sleep

* Corresponding author. Department of Paediatrics, Monash Medical Centre, Monash University, 246 Clayton Road, Clayton, Victoria 3168, Australia. Tel.: +61-3-9594-4504; fax: +61-3-9594-6259. E-mail address: [email protected] (R.S.C. Horne).

0378-3782/02/$ - see front matter D 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 3 7 8 - 3 7 8 2 ( 0 1 ) 0 0 2 3 7 - 7

90

R.S.C. Horne et al. / Early Human Development 66 (2002) 89–100

1. Introduction Although the underlying pathophysiological processes involved in Sudden Infant Death Syndrome (SIDS) are still unexplained, significant progress in the understanding of a number of risk factors associated with SIDS has been made through extensive epidemiological studies. Many of the developmental and environmental risk factors associated with SIDS are also associated with susceptibility of infants to infection, particularly that of upper respiratory tract infection. The number of SIDS cases is greater during winter [1], coinciding with the seasonal increase in respiratory viral infections [2]. The peak period for vulnerability to SIDS, between 2 and 4 months of age, is also the period when infants are particularly vulnerable to infection as stores of maternal antibodies are decreased before the infant’s immune system has fully matured [3,4]. In addition, infants have been demonstrated to be particularly vulnerable to heat stress during this period [5]. SIDS occurs more frequently in the lower socio-economic classes in developed countries in which infectious diseases are also more common [6]. Infection can also been linked with the major risk factors for SIDS. The prone sleeping position, identified as the major risk factor for SIDS in numerous studies, [1,7 – 12] has been found to be an even greater risk when associated with a recent illness [9]. In addition, bacterial counts from nasal swabs were elevated when infants slept prone [13]. Many studies have found that maternal smoking is associated with an increased incidence of SIDS [10,11,14] and infants and children with parents who smoke have increased levels of respiratory tract infections [15]. Cigarette smoke may also alter the pathophysiology following viral infections [16]. Approximately half of the SIDS victims in some studies had slight respiratory infection prior to death [4]. Infection also changes both the amount and nature of sleep in both humans and animals, quiet sleep (QS) being increased in both depth and duration [17,18]. The close temporal association between SIDS and sleep has led to the hypothesis that SIDS may result from a failure to arouse from sleep [19]. In previous studies our group have demonstrated that arousal thresholds in QS are elevated compared to active sleep (AS), and that QS thresholds increase with the length of time the infant has been asleep in both term and preterm infants [20,21]. In addition. infection is often associated with sleep fragmentation, which is known to impair arousal responses in both animals and humans [22,23]. In the current study we investigated the effects of a recent infection on arousability from sleep.

2. Methods 2.1. Subjects Approval for this project was granted by the Monash Medical Centre Human Ethics Committee and infants were studied after informed parental consent was obtained. Subjects were recruited from the Paediatric ward at Monash Medical Centre, Melbourne. The patient admissions book was examined daily for infants born at term (38 – 42 weeks of gestation), aged between 1 and 4 months with a diagnosis of either a respiratory infection or nonrespiratory infection. A paediatrician (TMA) confirmed the diagnosis.

R.S.C. Horne et al. / Early Human Development 66 (2002) 89–100

91

Fourteen (nine males and five females) infants with an infection participated in this study. All infants were born at term, mean length of gestation was 40 ± 0.3 weeks (mean ± SEM) (range 38 –41 weeks). Birth weights were between 3100 and 4791 g (mean 3507 ± 130 g) and median Apgar scores were 9 (range 8 –10) at 1 min and 9 (range 9– 10) at 5 min. The mean age at Study 1 was 96 ± 9 days (range 31– 136d) and infants were studied 10– 15 days apart. Of the 13 infants 10 had been hospitalised with bronchiolitis, 3 with an urinary tract infection (UTI), and one infant with right lower lobe pneumonia (RLLP). All bronchiolitis infants had Respiratory Syncitial Virus (RSV) isolated from naso-pharyngeal aspirates and had spent 2 – 8 days (median 4) in hospital with 0– 6 (median 1.5) days on supplemental oxygen and 0 –5 days (median 0) on intravenous fluids. Five infants had temperature above 37.5 °C for 1 –4 days. All UTI infants had E. coli cultured from a urine sample. These infants spent 3 – 4 days in hospital (median 4). One infant had a temperature above 37.5 °C for 3 days. The infant with RLLP was hospitalised for 7 days with IV fluids and antibiotics for 5 days. None of the infants had been admitted to the Paediatric intensive care unit. Control infants for this study were nine (six males, three females) infants recruited from local Maternal and Child Health Centres. Control infants were also born at term, mean length of gestation was 40 ± 0.3 weeks (range 38 –41 weeks). Birth weights were between 3100 and 3995 g (mean 3567 ± 97 g) and median Apgar scores were 9 (range 5 – 10) at 1 min and 9 (range 9 – 10) at 5 min. The mean age at Study 1 was 89 ± 12 days (range 32– 161 days). All infants were well and exhibited no clinical signs of infection at the time of both studies. 2.2. Recording methods Infants participating in this study underwent daytime, polysomnographic studies at the Melbourne Children’s Sleep Unit within the Department of Paediatrics between 09:30 and 17:00. In the case of the infection group, infants were studied on two occasions: firstly, immediately before discharge from the Paediatric ward, and secondly, 10 –15 days later when they were completely well. Control infants were studied 10 –15 days apart and were well at the time of both studies. All infants were studied in the supine position, in both AS and QS. On arrival, the electrodes for the physiological variables were attached to the baby while the infant fed and when drowsy the infant was placed in a bassinet under dim lighting and constant room temperature (22 – 23 °C). The study did not begin until the infant was in a stable sleep state. Recordings were made on a Grass Polygraph Model 78A 16-channel recorder (Grass Instrument, Quincey, MA) of electroencephalogram (EEG), electroocculogram (EOG), chin electromyogram (EMG) and electrocardiogram (ECG), instantaneous heart rate, thoracic and abdominal breathing movements (Resp-ez Piezo-electric sensor, EPM Systems, Midlothian, VA), expired CO2 (CO2/O2 Analyser, Engstrom Eliza MC, Bromma, Sweden), blood oxygen saturation (SaO2) (Biox 3700e Pulse Oximeter, Ohmeda, Louisville, CO) and abdominal skin and rectal temperature (YSI 400 series thermistor (NTC) probes). Sleep state was assessed as either quiet sleep (QS), active sleep (AS) or indeterminant sleep using EEG, behavioural, heart rate and breathing pattern criteria according to the manual by Anders et al. [24].

92

R.S.C. Horne et al. / Early Human Development 66 (2002) 89–100

2.3. Sleep diaries and sleep profiles Parents were asked to complete a sleep diary covering the 48-h period prior to each sleep study. Analysis of daytime sleeping patterns and sleep duration over the period of the study was made to see if the arousal studies affected the usual sleeping pattern or sleep duration. 2.4. Stimulus and arousal criteria A pulsatile air-jet (frequency 3 Hz for 5 s) delivered to the nostrils of the infant was used to induce arousal in both AS and QS, and arousal thresholds were calculated in a similar manner to that described previously [21,22]. Briefly, this method was based on the Double Staircase Method of Cornsweet [25]. The stimulus was presented alternately to the left and right nostrils; if the infant failed to arouse the air-jet pressure was increased and the stimulus again presented to that nostril. Whenever an arousal response occurred the pressure was then decreased. The changes in pressure between stimuli were in the range of ± 25 to ± 100 cm H2O, but were usually ± 100 cm H2O. Arousal threshold was calculated as the mean pressure between each arousal and nonarousal response. In determining whether a presentation elicited an arousal response, the four criteria described in Horne et al. [21] were used: change in ventilatory pattern of more than two breaths, an observed behavioural response such as a small movement away from the stimulus, a heart-rate acceleration of greater than 10% above baseline, and an increase in EMG activity. All these changes needed to occur within 7 s of the stimulus onset, allowing for the time delay to reach peak HR acceleration. The 10 s of recording immediately preceding the stimulus presentation were the baseline level used to assess the change in each variable. A change in at least three out of the four criteria was required to designate an arousal response. Calculated arousal thresholds were removed from analysis if they fulfilled three criteria: there was an absence or significant decrease in the magnitude of the expired CO2 trace, notation of nostril blockage had been made during the study by the investigator, and the arousal thresholds on this nostril were significantly higher than those on the other. 2.5. Data analysis For each infant AS and QS epochs were numbered in sequence, and the time of presentation of each stimulation from the onset of each sleep epoch was recorded. The site of presentation (left or right nostril), stimulus driving pressure (cm H2O), and the researcher’s designation of the response was noted on the chart recording at the time each stimulation was given. The probability of a spontaneous arousal, using the same arousal criteria, was determined by identifying the number of arousals coinciding with calibration of the stimulus prior to each stimulus presentation, expressed as a percentage of the total number of calibrations. Data were first tested using the Kolmogorov – Smirnov normality test and the Levene Median test for equal variance. Arousal thresholds for left and right nostrils were compared using a one-way analysis of variance (ANOVA, SigmaStat v2, SPSS). There

R.S.C. Horne et al. / Early Human Development 66 (2002) 89–100

93

was no significant difference between arousal thresholds calculated for the left or right nostrils (left nostril 185 ± 34 cm H2O, right nostril 174 ± 34 cm H2O), therefore, for subsequent analysis data from both nostrils were pooled. Mean arousal thresholds for AS and QS, sleep epoch length and sleep cycle length were calculated for each infant and compared within individual studies and between studies using a two-way ANOVA for repeated measures. Comparisons of arousal thresholds between control and infection groups were made with two-way ANOVA. Comparisons of the spontaneous and test arousal probabilites were made using Chi Square analysis. Sleep durations recorded by parents in the sleep diaries were compared with those obtained during the sleep studies with paired Student’s t test. All values are expressed as mean ± SEM and a p value of < 0.05 was considered significant.

3. Results 3.1. Demographics of the study groups There was no difference between the mean gestational age at birth or birth weight of the infection and control groups of infants, nor was there a difference between the mean ages at which the two groups were studied. 3.2. Arousal threshold In the infection group of infants (N = 13) arousal thresholds in QS were significantly elevated on the day of discharge at Study 1 (262 ± 48 cm H2O) compared with Study 2 (205 ± 31 cm H2O) when infants were fully recovered ( p < 0.05). There was no significant difference between the mean arousal thresholds in AS between Study 1(92 ± 12 cm H2O) and Study 2 (90 ± 22 cm H2O). Individual data for all 14 infants are presented in Fig. 1(A) and (B). Mean arousal thresholds in QS were significantly higher than those in AS at both Study 1 ( p < 0.001) and Study 2 ( p < 0.01). In control infants there was no difference in arousal thresholds between the two studies in either sleep state (QS Study 1: 291 ± 59 cm H2O, Study 2: 364 ± 76 cm H2O; AS Study 1: 95 ± 23 cm H2O, Study 2: 94 ± 17 cm H2O). Individual data for the control infants are presented in Fig. 1(C) and (D). There was no significant difference in arousal thresholds between the infection and control groups in either sleep state at either of the two studies. However, it can be seen from Fig. 1(A) that arousal threshold in QS decreased or remained unchanged between the two studies in the infection group in contrast to the control group in Fig. 1(C) where arousal thresholds in 4/8 infants tended to increase. Arousal thresholds for the control group were also significantly higher in QS than AS in both Study 1 ( p < 0.008) and Study 2 ( p < 0.005). 3.3. Case studies One infant with RSV was omitted from the data analysis as she had an elevated rectal temperature of > 38.5 °C for the duration of her second study. Her data are represented by the dashed line in Fig. 1(A) and (B) and are discussed separately. One of the infants (Infant

94

R.S.C. Horne et al. / Early Human Development 66 (2002) 89–100

Fig. 1. Comparison of mean individual arousal thresholds (cm H2O) in infection group of infants (n = 13) in QS (A) and AS (B) between Study 1 on the day of discharge from hospital and Study 2 10 – 14 days later when infants were well. Data for infant excluded from group data analysis is represented by the dashed line. Data for the control group (n = 9) are presented for QS (C) and AS (D) at the two studies 10 – 14 days apart.

13) had been studied 2 days prior to being admitted to hospital with RSV as part of another study with an identical protocol. Results from this infant are shown in Fig. 2. Mean arousal thresholds in AS fell slightly across the three studies from 154 ± 13 cm H2O in the prone – supine (P/S) study to 146 ± 18 cm H2O on the day of discharge, then to 94 ± 9 cm H2O 14 days later. However, his QS mean arousal thresholds were elevated on the day of discharge in comparison with values before admission: values being 730 ± 93 and 417 ± 85 cm H2O, respectively; 14 days later his mean QS arousal threshold had fallen to a value near that of the prone –supine study, 444 ± 123 cm H2O. 3.4. Spontaneous arousal In order to eliminate the possibility that an arousal response to our stimulus was not due to spontaneous arousal, the number of spontaneous arousals coinciding with the calibration of the stimulus prior to each presentation was recorded using the same arousal criteria. In both the infection group and control group of infants at both Study 1 and Study 2, in both sleep states arousal in response to our stimulus was significantly more likely to occur than spontaneous arousal ( p < 0.001) (Table 1).

R.S.C. Horne et al. / Early Human Development 66 (2002) 89–100

95

Fig. 2. Comparison of mean arousal thresholds (cm H2O) in case study infant 13, in AS (solid bars) and QS (open bars). Infant 13 was studied prior to being hospitalised with RSV on 18/8, on the day of discharge from hospital Study 1 on 24/8 and Study 2 14 days later when he was completely well on 7/9. Number of arousal threshold determinations, N, is indicated above each mean value.

In the infection group spontaneous arousal was more likely to occur in AS than QS in both studies ( p < 0.001; p < 0.01, respectively). Similarly, in the control group spontaneous arousal occurred more frequently in AS than QS in both studies ( p < 0.05; p < 0.001, respectively) (Table 1). There was no difference between the numbers of spontaneous arousals occurring in either sleep state between the two studies in the infection group. However, the number of spontaneous arousals in AS in Study 2 in the control group was elevated compared to Study 1 ( p < 0.01). 3.5. Physiological parameters To assess the possible effect of temperature on arousal, abdominal skin and rectal temperatures were recorded prior to each stimulus presentation. There was no difference between either mean rectal or abdominal skin temperatures between the two studies in either sleep state in either the infection or control group of infants (Table 2). Mean

Table 1 Summary of stimulus presentations and responses in infection and control infants Study

Infection group

Sleep State Number of stimulus presentations % Stimulus arousal responses % Spontaneous arousal

AS 238 51 7

Study 1

Control group Study 2

QS 448 32 1

AS 200 43 4

Study 1 QS 463 35 1

AS 207 38 5

Study 2 QS 200 30 2

AS 163 44 11

QS 208 30 1

96

R.S.C. Horne et al. / Early Human Development 66 (2002) 89–100

Table 2 Sleep cycle and physiological variables in each sleep state for infection and control groups of infants Study

Infection group

Sleep state Mean epoch length (min) Mean cycle length (min) Heart rate (bpm) Respiratory rate (breaths/min) Rectal temperature (°C) Skin temperature (°C) Oxygen saturation (%)

AS 15 ± 3

Study 1

Control group Study 2

QS 21 ± 1

38 ± 4

AS 12 ± 1

Study 1 QS 20 ± 2

31 ± 3

AS 15 ± 3

Study 2 QS 16 ± 2

29 ± 4

AS 16 ± 3

QS 17 ± 2

40 ± 4

133 ± 4 38 ± 2

132 ± 3y 41 ± 3

131 ± 4 35 ± 2

37.1 ± 0.1

37.1 ± 0.1

36.6 ± 0.1 36.9 ± 0.1 36.6 ± 0.2 36.6 ± 0.2 36.9 ± 0.1 36.8 ± 0.1

35.7 ± 0.2

36.0 ± 0.2

35.8 ± 0.2 35.9 ± 0.2 35.9 ± 0.2 35.8 ± 0.2 35.6 ± 0.3 35.7 ± 0.4

126 ± 4 35 ± 2

126 ± 3 43 ± 3

121 ± 4 39 ± 3

126 ± 2 40 ± 2

124 ± 3 39 ± 3

92.7 ± 0.5 * 92.6 ± 0.6 * 94.9 ± 0.3 94.8 ± 0.6 94.9 ± 0.3 94.8 ± 0.4 94.9 ± 0.4 95.1 ± 0.5

y

p < 0.05, infection vs. control. * p < 0.05, Study 1 vs. Study 2.

respiratory rates were calculated over 3 min at the start of the first AS and first QS period for each study during a time when there were no stimulus presentations. Again, there was no difference in respiratory rates between studies in either sleep state in either infection or control group of infants (Table 2). Heart rate was averaged over the 10 s prior to each stimulus. There was no difference in heart rate between studies in either the infection or the control group, however, heart rate was significantly elevated in QS study 1 in the infection group compared with the control group ( p < 0.05). Oxygen saturation was recorded prior to each stimulus presentation. Mean oxygen saturation was significantly lower in the infection group ( p < 0.05) at study 1 for both AS and QS (92 ± 1%) than at study 2 (95 ± 1%). There was no significant difference in oxygen saturation between states at either study. 3.6. Sleep characteristics The parental sleep diary data for the 48-h period prior to the second study were analysed to see if the study environment affected normal sleep patterns. Diaries were not collected prior to the first study as infection babies were hospitalised and therefore not in their usual routine. Mean sleep duration during the period of the study was 80 ± 8 min; this was not different to that recorded in the babies own homes over the same period averaged over the 2 days prior to the study (110 ± 15 min). Similarly, in control infants, sleep duration at home (53 ± 7 min) was not different to that recorded during the study (69 ± 6 min). Sleep epoch durations during the study were also analysed. For this analysis only complete sleep periods were measured, those in which the onset or offset times were not certain (usually due to the infant falling asleep before recording had started) were not included. The effect of infection on sleep was analysed by examining three different

R.S.C. Horne et al. / Early Human Development 66 (2002) 89–100

97

measurements: sleep cycle times, the percentage of time spent in AS and QS and the mean length of individual AS and QS periods. There was no difference between any of the three measures between the two studies in either the infection group or the control group of infants (Table 2).

4. Discussion Arousal from sleep is an important response that may protect an infant from a lifethreatening event and impairment in arousability has been postulated as a likely mechanism to explain SIDS [19]. Moreover, it has been postulated that the increased risk for SIDS associated with infection may result from elevated body temperatures during infection [26]. This study has provided evidence that arousal from QS is impaired in infants following a recent infection. Arousal thresholds determined for the infection group on the day of discharge from hospital were significantly elevated in QS compared with those determined 10– 15 days later when infants were fully recovered. These findings cannot be explained by maturational changes occurring between the two studies, as arousal thresholds in age matched control infants who were healthy at both studies showed no such change. Previous studies by our group support these data that arousal thresholds in both AS and QS do not change significantly in infants studied at 2 –3 weeks and 2 –3 months post-term [20]. Additional evidence for the idea that arousal thresholds are elevated in QS by infection is provided by the case studies. Infant 13, who was studied prior to hospital admission, exhibited arousal thresholds in QS that were similar both before infection and 14 days after discharge from hospital, while thresholds measured on the day of discharge were elevated. Additionally, the infant excluded from group analysis, exhibited an elevated arousal threshold at the second study when she had a temperature of >38.5 °C. It has been postulated that the increased risk for SIDS associated with infection may result from elevated body temperatures during infection, as the peak incidence of SIDS coincides with a time in infant development of thermoregulation that may render it more vulnerable to heat stress [26]. Support for this hypothesis has been provided by the finding that hyperthermia alters ventilatory responses to both hypoxia and hypercapnia [27]. However, in this study there was no difference in either rectal temperature or abdominal skin temperature at the time of the study that could explain the observed difference in arousability in QS between the two studies. The finding of an elevated arousal threshold to the air-jet stimulus in QS compared with AS is consistent with our previous studies using the same stimulus in both term [20,28] and preterm infants [21]. It is also consistent with findings using other external sensory stimuli [29 – 32]. It has been postulated that the elevated arousal threshold observed in QS may render an infant more vulnerable to an external stress in this sleep state [20], and any further elevation in arousal threshold may be of significance. Although mean arousal thresholds in QS were higher in control infants than in the infection group in both studies this did not reach statistical significance, nor did they exhibit a difference between studies as did the infection group. Previous studies by our group [20,21] have demonstrated that arousal thresholds in QS have a wider variability both within the same infant and between

98

R.S.C. Horne et al. / Early Human Development 66 (2002) 89–100

infants than arousal thresholds in AS. This individual variability may explain these observed differences. Ten of the 14 infants studied were recovering from RSV. The persisting effects of RSV infection may have been associated with the elevated respiratory rates (although this was not statistically significant) and decreased oxygen saturation observed at the first study. However, when respiratory and oxygen saturation data were analysed for the respiratory infection infants only, no difference in the results was observed. In support of our findings studies in lambs have demonstrated that animals infected with RSV had impaired arousal responses to laryngeal chemostimulation [33]. These findings were however most marked in AS rather than QS. However, it is important to note that arousal responses in lamb studies differ from those in human studies with arousability to a variety of stimuli being impaired in AS compared to QS [34 –38]. Infection is known to alter sleep patterns in both animal and human studies. It has been demonstrated that infection enhances slow wave sleep in rabbits [17]. This sleep enhancement is mediated via a variety of substances released by the immune system, including interlukin-1 [17]. In previous studies we have demonstrated that arousal thresholds in QS increase with time spent asleep in infants at 2– 3 months of age [20]. This study did not however demonstrate any differences in QS epoch lengths between the two studies and hence this cannot serve as an explanation for the observed differences in arousal threshold between the two studies. The effects of infection on sleep patterns are however a balance between sleep-enhancing and sleep-reducing factors during the different phases of the illness, with a switch from active enhancement to active reduction of sleep duration and intensity during the course of an illness [18]. Additionally, it has been demonstrated that different strains of organism have differing effects on the immune response and conceivably therefore on arousal responses [3]. A major factor associated with infection and hospitalisation is disruption to normal sleep patterns. All infants in this study were hospitalised for varying stays in the Paediatric ward where the unfamiliar environment and routine medical interventions would disrupt sleep routines. Sleep fragmentation has been demonstrated to impair arousal responses to laryngeal stimulation in adult dogs [22] and also to normal apnoeic events in adult humans [23]. We postulate that the sleep fragmentation experienced by the infection group of infants prior to study 1 may have been a contributing factor to the elevated arousal thresholds observed in this study. In previous arousal studies using the air-jet stimulus in healthy term and preterm infants [20,21], stimulus-induced arousal and spontaneous arousal were well correlated, suggesting that the pathways involved in naturally occurring arousal are similar to those produced by our external stimulus. In this study, we also found that spontaneous and stimulusinduced arousability were well correlated with more frequent spontaneous arousal in AS corresponding to lower arousal thresholds in this state. Infection had no effect on spontaneous arousal from QS, however, this is not an unexpected finding as probability of spontaneous arousal from QS is normally low, occurring in conjunction with only 1 – 2% of sham stimuli presentations. In conclusion, our studies have provided evidence that arousability from QS is depressed following a recent illness and we postulate that this alteration may be a contributing factor in the increased incidence of SIDS following an infection.

R.S.C. Horne et al. / Early Human Development 66 (2002) 89–100

99

Acknowledgements This project was supported by the Sudden Infant Death Research Foundation of South Australia. The authors thank the staff of the Paediatrics Ward at the Monash Medical Centre, and the parents and infants who participated in this study. We also wish to thank Professor Adrian Walker for his comments on drafts of this manuscript. References [1] Gibson A. Current epidemiology of SIDS. J Clinical Pathology 1992;45:7 – 10 (Suppl.). [2] Fitzgerald K. The role of risk factors: how SIDS organizations and the community cope. In: Rognum TO, editor. Sudden infant death syndrome: new trends in the nineties. Olso: Scandinavian University Press; 1995. p. 119 – 23. [3] Blackwell CC, Weir DM, Busuttil A, Saadi AT, Essery SD, Raza MW, et al. Infection, inflammation, and the developmental stage of infants: a new hypothesis for the aetiology of SIDS. In: Rognum TO, editor. Sudden infant death syndrome: new trends in the nineties. Olso: Scandinavian University Press; 1995. p. 189 – 98. [4] Stoltenberg L, Vege A, Opdal SH, Saugstad OD, Rognum TO. Does immunostimulation play a role in SIDS. In: Rognum TO, editor. Sudden infant death syndrome: new trends in the nineties. Olso: Scandinavian University Press; 1995. p. 177 – 81. [5] Fleming KA. Viral respiratory infection and SIDS. J Clinical Pathology 1992;45:29 – 32 (Suppl.). [6] Blackwell CC, Weir DM, Busuttil A, Saadi AT, Essery SD, Raza MW, et al. The role of infectious agents in sudden infant death syndrome. FEMS Immunol Med Microbiol 1994;9:91 – 100. [7] Taylor BJ. A review of epidemiological studies of sudden infant death syndrome in Southern New Zealand. J Paediatr Child Health 1991;27:344 – 8. [8] Mitchell EA, Taylor BJ, Ford RPK, Steward AW, Becroft DMO, Thompson JMD, et al. Four modifiable and other major risk factors for cot death: the New Zealand study. J Paediatr Child Health 1992;28(Suppl. 1):3 – 8. [9] Ponsonby A, Dwyer T, Gibbons L, Cochrane J, Wang Y. Factors potentiating the risk of sudden infant death syndrome associated with the prone position. N Engl J Med 1993;329(6):377 – 81. [10] Stewart AJ, Williams S, Mitchell E, Taylor B, Allen E, Group NZCDS. Antenatal and intrapartum factors associated with sudden infant death syndrome in the New Zealand cot death study. J Paediatr Child Health 1995;31:473 – 8. [11] Fleming P, Blair P, Bacon C, Bensley D, Smith I, Taylor E, et al. Environment of infants during sleep and risk of the sudden infant death syndrome: results of 1993 – 1995 case-control study for confidential inquiry into stillbirths and deaths in infants. BMJ 1996;313:191 – 5. [12] Oyen N, Markestad T, Skjaeven R, Irgens L, Helweg-Larsen K, Alm B, et al. Combined effects of sleeping position and prenatal risk factors in sudden infant death syndrome: the Nordic Epidemiological SIDS Study. Pediatrics 1997;100(4):613 – 21. [13] Bell S, Crawley BA, Oppenheim BA, Drucker DB, Morris JA. Sleeping position and upper airways bacterial flora: relevance to cot death. J Clin Pathol 1996;49:170 – 2. [14] Hoffman H, Hillman L. Epidemiology of the sudden infant death syndrome: maternal, neonatal, and postneonatal risk factors. Clin Perinatol 1992;19(4):717 – 37. [15] Harlap S, Davies A. Infant admission to hospital and material smoking. Lancet 1974;30:529 – 32. March. [16] Raza MW, Essery SD, Elton RA, Weir DM, Busuttil A, Blackwell C. Exposure to cigarette smoke, a major risk factor for sudden infant death syndrome: effects of cigarette smoke on inflammatory responses to viral infection and bacterial toxins. FEMS Immunol Med Microbiol 1999;25(1 – 2):145 – 54. [17] Toth L, Kruger J. Effects of microbial challenge on sleep in rabbits. FASEB 1989;3:2062 – 6. [18] Toth L. Sleep, sleep deprivation and infectious disease: studies in animals. Adv Neuroimmunol 1995;5: 79 – 92. [19] Hunt C. The cardiorespiratory control hypothesis for sudden infant death syndrome. Clin Perinatol 1992;19(4):757 – 71. [20] Read PA, Horne RSC, Cranage SM, Walker AW, Walker DW, Adamson TM. Dynamic changes in arousal thresholds during sleep in the human infant. Pediatr Res 1998;43(5):697 – 703.

100

R.S.C. Horne et al. / Early Human Development 66 (2002) 89–100

[21] Horne RSC, Sly DJ, Cranage SM, Chau B, Adamson TM. Effects of prematurity on arousal from sleep in the newborn infant. Pediatr Res 2000;47(4):468 – 74. [22] Bowes G, Woolf GM, Sullivan CE, Phillipson EA. Effect of sleep fragmentation on ventilatory and arousal responses of sleeping dogs to respiratory stimuli. Am Rev Respir Dis 1980;122:899 – 907. [23] Guilleminault C, Rosekind M. The arousal threshold: sleep deprivation, sleep fragmentation, and obstructive sleep apnea syndrome. Bull Eur Physiopathol Respir 1981;17:341 – 9. [24] Anders T, Emde R, Parmelee A. A manual of standardized terminology, techniques and criteria for scoring of states of sleep and wakefulness in newborn infants. Los Angeles, CA: UCLA Brain Information Service/ BRI; 1971. [25] Cornsweet T. The staircase method in psychophysics. Am J Psychol 1962;62:485 – 91. [26] Fleming PJ, Levine MR, Azaz Y, Wigfield R, Stewart AJ. Interactions between thermoregulation and the control of respiration in infants: possible relationship to sudden infant death. Acta Paediatr 1993(Suppl. 389):57 – 9. [27] Maskrey M. Body temperature effects on hypoxic and hypercapnic responses in awake rats. Am J Physiol 1990;259:R492 – 8. [28] Loy C, Horne R, Read P, Cranage S, Chau B, Adamson T. Immunisation has no effect on arousal from sleep in the newborn infant. J Paediatr Child Health 1998;34:349 – 54. [29] Newman N, Frost J, Bury L, Jordan K, Phillips K. Responses to partial nasal obstruction in sleeping infants. Aust Paediatr J 1986;22:111 – 6. [30] Newman N, Trinder J, Phillips K, Jordan K, Cruickshank J. Arousal deficit: mechanism of the sudden infant death syndrome? Aust Paediatr J 1989;25:196 – 201. [31] Trinder J, Newman N, Kay A, Whitworth F, LeGrande M, Jordan K. Arousal from sleep and the sudden infant death syndrome. In: Bond N, Siddle D, editors. Psychobiology: issues and applications. North Holland: Elsevier; 1989. p. 325 – 35. [32] Trinder J, Newman NM, LeGrande M, Whitworth F, Kay A, Pirkis J, et al. Behavioural and EEG responses to auditory stimuli during sleep in newborn infants and in infants aged 3 months. Biol Psychol 1990;31:213 – 27. [33] Lindgren C, Lin J, Graham B, Gray M, Parker R, Sundell H. Respiratory syncytial virus infection enhances the response to laryngeal chemostimulation and inhibits arousal from sleep in young lambs. Acta Paediatr 1996;85:789 – 97. [34] Marchal F, Crance JP, Arnould P. Ventilatory and waking response to laryngeal stimulation in sleeping mature lambs. Respir Physiol 1986;63:31 – 41. [35] Horne RSC, Berger PJ, Bowes G, Walker AM. Effect of sino-aortic denervation on arousal responses to hypotension in newborn lambs. Am J Physiol 1989;256(2):H434 – 40. [36] Fewell JE, Baker SB. Arousal from sleep during rapidly developing hypoxemia in lambs. Pediatr Res 1987;22(4):471 – 7. [37] Horne RSC, De Preu ND, Berger PJ, Walker AM. Arousal responses to hypertension in lambs: effect of sinoaortic denervation. Am J Physiol 1991;260(4):H1283 – 9. [38] Walker AM, Johnston RV, Grant DA, Wilkinson MH. Repetitive hypoxia abolishes arousal from sleep in newborn lambs. In: Rognum TO, editor. Sudden infant death syndrome: new trends in the nineties. Olso: Scandinavian University Press; 1995. p. 238 – 41.