Chemoreceptor function and sleep state in apnea.

Resting ventilation and ventilatory responses to 100% oxygen and to 5% carbon dioxide in air were measured in REM and non-REM sleep in post-neonatal infants. Normal controls were compared to infants with prolonged apnea and to siblings of sudden infant death victims. No significant differences in ventilatory responses were found between the groups. We conclude that apnea may occur in infants whose central and peripheral chemoreceptor activity is normal while they are breathing.     

Central hypoventilation during quiet sleep in two infants.

Expired ventilation (VE), tidal volume (VT), frequency (f), and alveolar PCO2 (PACO2) were examined in six normal infants at 41 to 52 weeks post-conceptional age and in two infants who were apneic at birth. Their response to breathing 5% carbon dioxide in air and to 100% oxygen in quiet sleep were compared to those in rapid eye movement (REM) sleep. VE in normal infants was 259 ml/kg/min in REM and 200.2 ml/kg/min in quiet sleep with the difference being due to decreased carbon dioxide production and to decreased dead space. VE increased 34.4 ml/kg/min/mm Hg of PCO2 elevation with 5% carbon dioxide breathing during REM and was not significantly different during quiet sleep. During oxygen breathing VE fell by 32.7% at 30 seconds before increasing again. In the affected infants, VE and PACO2 during REM at 1 and 4 months were normal. At 1 month, during quiet sleep, each infant became apneic and PACO2 rose 9 and 8 mm Hg/min respectively. At this time mechanical ventilation was begun. At 4 months, during quiet sleep, VE was 0.064 and 0.063 ml/kg/min at PACO2 of 66 mm Hg in each infant. The change was due entirely to a decrease in VT to 2.3 and 2.5 ml/kg. At this time 5% carbon dioxide breathing given during normal ventilation in REM produced an abrupt fall in VT to 2.0 and 2.2 ml/kg with no change in frequency. Oxygen breathing during REM at one month had no effect but at 4 months produced apnea requiring mechanical ventilation after one minute. The findings suggest that the ventilatory response to carbon dioxide is (1) important in initiation of extrauterine ventilation and (2) in sustaining ventilation particularly in quiet sleep. It is not necessary in sustaining ventilation awake or in REM sleep and it represents a balance between the stimulatory and depressant effects of carbon dioxide on the central nervous system.     

Congenital central hypoventilation syndrome--loss of chemosensitivity in respiratory control

This report describes an infant with congenital central hypoventilation. There is no response to 4% CO2-breathing in sleep and in awake state. Hypoxia, behavioral and "behavioral like" inputs increase ventilation, but not to normal levels. Drugs such as theophylline, naloxone, acetazolamide, methylprogesterone, thyroxine and nicethamide have no effect on the respiratory control. Despite the insertion of a phrenic nerve pacemaker intermittent positive pressure ventilation must be provided in addition.     

Ventilatory control and carbon dioxide response in preterm infants with idiopathic apnea

Idiopathic apnea in preterm infants, more than 30 weeks of gestation, after the first week of life is uncommon and poorly understood. To study ventilatory control in these infants we measured minute ventilation, respiratory frequency, tidal volume, end-tidal oxygen pressure and carbon dioxide pressure, and transcutaneous oxygen pressure before and during the fifth minute of breathing 4% carbon dioxide in air. Nine healthy preterm infants and eight infants with three or more episodes of apnea (greater than or equal to 20 s) in 24 hours were studied during active sleep. We found that infants with apnea had a significantly increased alveolar carbon dioxide pressure while respiratory frequency, minute ventilation, and slope were significantly decreased. Alveolar-transcutaneous oxygen gradients were essentially unchanged. These preterm infants with apnea have a decreased carbon dioxide sensitivity. They have a decreased minute ventilation primarily as a result of decreased respiratory frequency and their alveolar-transcutaneous oxygen gradient is normal. Our findings suggest that the major deficit in these infants is a central disturbance in the regulation of breathing.     

Congenital central hypoventilation syndrome: not just another rare disorder

Congenital central hypoventilation syndrome (CCHS) is a rare syndrome, present from birth, and is defined as the failure of automatic control of breathing. Patients have absent or negligible ventilatory sensitivity to hypercapnia and hypoxaemia during sleep and wakefulness. Therefore, especially while asleep, children with CCHS experience progressive hypercapnia and hypoxaemia. They lack arousal responses and sensations of dyspnoea to the endogenous challenges of isolated hypercapnia and hypoxaemia and to the combined stimulus of hypercapnia and hypoxaemia. Patients with CCHS do not exhibit signs of respiratory distress when challenged with hypercarbia or hypoxia. The diagnosis is one of exclusion, ruling out any primary pulmonary, cardiac, metabolic or neurologic cause for central hypoventilation. CCHS is associated with other manifestations of autonomic nervous system dysfunction, including Hirschsprung's disease. All patients with CCHS require lifelong ventilatory support during sleep but some will be able to maintain adequate ventilation without assistance while awake once past infancy. However, some CCHS patients require ventilatory support for 24h/day. Modalities of home mechanical-assisted ventilation include positive pressure ventilation via tracheostomy, non-invasive positive pressure ventilation (bi-level ventilation), negative pressure ventilation and diaphragmatic pacers. Supplemental oxygen alone is inadequate treatment. With early diagnosis and adequate ventilatory support, these children can have good outcomes and lead productive lives.     

Ventilation and sleep states in newborn infants.

Recent studies have shown that ventilation in the newborn period is affected by sleep state. We investigated various measures affecting ventilation using the single breath airway occlusion technique in ten healthy, full-term newborn infants. There was a significant increase in respiratory rate and in minute ventilation in rapid eye movement sleep compared to non-REM sleep, and there was no significant change in tidal volume between the two sleep states. The variability of ventilation was increased in REM sleep, and inspiratory pressure at one-tenth of a second following airway occlusion was significantly increased in REM sleep. Effective elastance was similar in both sleep states. Measures that reflect activity of the Hering-Breuer reflex were significantly increased in non-REM sleep as compared with REM sleep. These results document the interdependence of sleep state and respiratory control mechanisms in full-term infants.     

Respiratory aid using a diaphragmatic pacemaker in high paraplegia

Spastic tetraplegia due to cervical medullary injury above the origin of the phrenic nerve neurons means complete respiratory paralysis. In this case a phrenic pacemaker can be considered as an alternative to long term mechanical ventilation. An implantable 8-channel stimulation device has been developed for functional electrical stimulation of the phrenic nerves. The "Karussellstimulation" provides fatigue free stimulation for 24 hours a day. We report the case of a 12 year old girl with complete ventilatory insufficiency who underwent implantation of a phrenic pacemaker. 18 month after implantation she is independent of a conventional respirator and limits rehabilitation could be achieved. Electrophrenic respiration is of value in the rehabilitation management of tetraplegic patients with ventilatory insufficiency.     

Effects of theophylline on ventilatory response to hypoxic challenge.

The respiratory and arousal responses to mild hypoxia during quiet sleep were studied using inductive plethysmography and transcutaneous gas electrodes in 11 apnoeic infants before and after the administration of oral theophylline (3 mg/kg). Theophylline changed the ventilatory response to a more biphasic pattern--that is, ventilation decreased after an initial increase. The relative ventilatory slope (defined as the decrease in transcutaneous carbon dioxide tension (PCO2) in relation to the fall in transcutaneous oxygen tension (PO2)) decreased significantly after theophylline. Four infants were roused during hypoxia before theophylline administration compared with none after treatment. Theophylline abolished the periodic breathing induced by hypoxia in one of six infants. These findings suggest that methylxanthines may not, as previously thought, enhance the respiratory drive during hypoxia.     

REM sleep prevents sudden infant death syndrome

Near-miss events were observed to occur in indeterminate sleep in a preterm infant reaching term at 6 weeks after birth. Moreover, prolonged sleep apnea and periodic respiration were frequently encountered in non-REM sleep. In view of the observation that pathologic sleep apnea occurs in non-REM sleep and the apparently contradictory findings of respiratory depression and more frequent apneas during REM sleep, apneic episodes during REM sleep were analysed in relation to phasic REM events. The frequent occurrence of respiratory pauses in REM burst-free periods of REM sleep suggests that tonic REM mechanisms inhibit respiratory neurons, while phasic REM mechanisms are facilitatory and protect an infant from prolonged sleep apnea.     

Sleep-related abdominal muscle behavior during partial or complete obstructed breathing in prepubertal children

We have evaluated the influence of nonrapid eye movement (NREM), REM sleep, and arousal on abdominal muscle contractions during snoring and/or obstructive apnea in 10 prepubertal children. All children were known habitual snorers and eight had a sleep apnea index above 10. During stage 3-4 non-REM sleep, non-apneic breathing with snoring was always associated with the presence of expiratory abdominal muscle electromyogram (EMG) discharges. During non-REM sleep apneas, abdominal muscle EMG discharges increased from the beginning to the end of each apnea. Termination of non-REM sleep apnea was marked by an "EEG arousal" in 12% of the apneic events and by a "movement arousal" in the other 88%. The highest abdominal muscle EMG discharge was always observed during the arousal response. During "phasic" REM sleep, abdominal muscle EMG discharges were absent during both nonapneic breathing (with or without snoring) and obstructive apneas. All REM sleep apneas ended with a "movement arousal," during which abdominal muscle EMG discharges were observed. Thus, abdominal muscle EMG discharges associated with "arousal" were seen independent of the immediately preceding sleep state.     

The divergent ventilatory and heart rate response to moderate hypercapnia in infants with apnoea of infancy

BACKGROUND: Inspired CO2 is a potent ventilatory stimulant exhibiting a paradoxical inhibitory effect on breathing at high concentrations. Severe respiratory depression as a result of CO2 rebreathing during sleep has been implicated as a possible trigger factor in sudden infant death syndrome (SIDS). OBJECTIVE: To investigate the ventilatory and heart rate (HR) responses to inhaled CO2 in infants with apnoea of infancy, a group believed to be at increased risk of SIDS. STUDY DESIGN: Thirty one infants with severe sleep related apnoea, 31 infants with mild recurrent apnoea, and 31 age and sex matched controls for the infants with severe sleep related apnoea were studied. HR was computed from digitised RR intervals, "ventilation" was recorded by inductance plethysmography, and PCO2 and PO2 were monitored by transcutaneous electrodes. The ventilatory and HR responses to CO2 were expressed as percentage increase in ventilation and change in HR/unit change in transcutaneous PCO2. RESULTS: The mean increase in transcutaneous PCO2 during CO2 challenge (0.45 kPa = 3.4 mm Hg) resulted in a mean increase in ventilation of 291%/1 kPa (7.3 mm Hg) increase in transcutaneous PCO2, with no difference between the groups. A significant difference between infants with severe sleep related apnoea and mild recurrent apnoea versus controls (p < 0.02, p < 0.01, respectively) was found in their HR response to CO2 challenge: HR decreased in 12 severe sleep related apnoea infants and 10 infants with mild recurrent apnoea, but only in two controls. CONCLUSION: Infants with apnoea of infancy frequently show a paradoxical decrease in HR during CO2 challenge, possibly because of an insufficient ability to mobilise cardiovascular defence mechanisms when challenged with hypercapnia.     

Behaviour and physiological responses during prone and supine sleep in early infancy

AIMS: To study the effect of prone and supine sleep on infant behaviour, peripheral skin temperature, and cardiorespiratory parameters to aid understanding of why prone sleeping is associated with an increased risk of sudden infant death syndrome. METHODS: Of 33 enrolled infants, 32 were studied at 2.5 and 28 at 5 months of age. A computer aided multichannel system was used for polysomnographic recordings. Behaviour was charted separately. RESULTS: Prone REM (active) sleep was associated with lower frequencies of short arousals, body movements and sighs, and a shorter duration of apnoeas than supine REM sleep at both ages. At 2.5 months there were less frequent episodes of periodic breathing during prone sleep in non-REM (quiet) and REM sleep. Heart rate and peripheral skin temperature were higher in the prone position during both sleep states at both ages. CONCLUSIONS: The observation of decreased variation in behaviour and respiratory pattern, increased heart rate, and increased peripheral skin temperature during prone compared with supine sleep may indicate that young infants are less able to maintain adequate respiratory and metabolic homoeostasis during prone sleep.     

The divergent ventilatory and heart rate response to moderate hypercapnia in infants with apnoea of infancy

BACKGROUND—Inspired CO₂ is a potent ventilatory stimulant exhibiting a paradoxical inhibitory effect on breathing at high concentrations. Severe respiratory depression as a result of CO₂ rebreathing during sleep has been implicated as a possible trigger factor in sudden infant death syndrome (SIDS).OBJECTIVE—To investigate the ventilatory and heart rate (HR) responses to inhaled CO₂ in infants with apnoea of infancy, a group believed to be at increased risk of SIDS.STUDY DESIGN—Thirty one infants with severe sleep related apnoea, 31 infants with mild recurrent apnoea, and 31 age and sex matched controls for the infants with severe sleep related apnoea were studied. HR was computed from digitised RR intervals, "ventilation" was recorded by inductance plethysmography, and PCO₂ and PO₂ were monitored by transcutaneous electrodes. The ventilatory and HR responses to CO₂ were expressed as percentage increase in ventilation and change in HR/unit change in transcutaneous PCO₂.RESULTS—The mean increase in transcutaneous PCO₂ during CO₂ challenge (0.45 kPa = 3.4 mm Hg) resulted in a mean increase in ventilation of 291%/1 kPa (7.3 mm Hg) increase in transcutaneous PCO₂, with no difference between the groups. A significant difference between infants with severe sleep related apnoea and mild recurrent apnoea versus controls (p < 0.02, p < 0.01, respectively) was found in their HR response to CO₂ challenge: HR decreased in 12 severe sleep related apnoea infants and 10 infants with mild recurrent apnoea, but only in two controls.CONCLUSION—Infants with apnoea of infancy frequently show a paradoxical decrease in HR during CO₂ challenge, possibly because of an insufficient ability to mobilise cardiovascular defence mechanisms when challenged with hypercapnia.     

肥胖儿童阻塞性睡眠呼吸暂停的临床特征

目的 研究肥胖儿童合并阻塞性睡眠呼吸暂停（obstructive sleep apnea，OSA）的临床特征。 方法 对在深圳市儿童医院呼吸科行多导睡眠监测的肥胖并诊断为OSA的33例7~15岁儿童的临床资料进行回顾性分析，并选取50例体重正常的、性别及年龄相匹配的OSA患儿作为对照组。 结果 33例合并肥胖的OSA儿童中，常见的日间症状前3位为：注意力不集中30例（91%），嗜睡22例（67%），晨起疲劳21例（64%）；夜间症状前3位为：打鼾27例（82%），张口呼吸20例（61%），出汗16例（48%）。与正常儿童参考值相比，肥胖OSA组和对照组两组患儿浅睡眠延长，深睡眠缩短，快速动眼期明显缩短，但两组之间这些指标的比较差异无统计学意义（P>0.05）。与对照组比较，肥胖OSA组呼吸暂停低通气指数和阻塞性呼吸暂停低通气指数均显著增加（P<0.05）；快速动眼期及非快速动眼期氧减指数均显著增加（P<0.05）；肥胖OSA组睡眠期间最低血氧饱和度显著低于对照组（P<0.05）。 结论 肥胖合并OSA儿童临床日间症状以注意力不集中、嗜睡、晨起疲劳为主，夜间症状以打鼾、张口呼吸、出汗为主。与体重正常OSA患儿相比，肥胖合并OSA儿童的睡眠结构无明显差别，但呼吸事件及血氧饱和度下降更严重。 引用格式:     

Ventilatory response to 100% and 15% O2 during wakefulness and sleep in preterm infants

To examine the ventilatory response to 100% and 15% O₂during wakefulness and sleep, we studied eleven preterm infants birthweight 1770 ± 102 g; gestational age 32 ±1 weeks; postnatal age 31 ±5 days) on two occasions each. Wakefulness (W) was present around feeding time and was defined by open eyes for more than 2 min plus presence of purposeful movements. Rapid eye movement (REM) and non-rapid eye movement (N-REM) sleep were defined using electroencephalogram (EEG), electrooculogram (EOG), electrocardiogram (ECG), and body movements. During 100% O₂ breathing, immediate (30 s) decreases of 28, 39 and 37% followed by late (5 min) increases in ventilation (_E) of 42, 49 and 27% were observed during W, REM and N-REM sleep (P > 0.05 between states). PaCO₂decreased significantly towards the end of 5 min of breathing 100% 0₂in W, REM and N-REM sleep (P>0.05). Average duration of apnea following sudden administration of 100% O₂was 8.5, 11.1 and 8.8 s during W, REM and N-REM sleep (P > 0.05 between states). During inhalation of 15% O₂, there was a late decrease in ventilation of 19 and 23% during wakefulness and REM sleep, and a sustained increase in V_E of 17% during N-REM sleep (P < 0.05). PaCO₂ at the end of hypoxia (5 min) was significantly decreased in N-REM sleep only (P < 0.05). We suggest that (i) peripheral chemoreceptor activity is qualitatively intact during W and sleep, as reflected by (a) the immediate changes in V_E during inhalation of high and low O₂, and (b) apnea following administration of 100% O₂: (ii) The late decrease in ventilation with hypoxia is absent in N-REM sleep.     

Alveolar hypoventilation treated with medroxyprogesterone.

Two children aged 1 and 20 months developed alveolar hypoventilation syndrome. They suffered severe apnoeic episodes and periodically required assisted ventilation. Their ventilatory response to carbon dioxide was lower than that of normal children and the transcutaneous oxygen tension during sleep was well below the normal range. Treatment with medroxyprogesterone acetate resulted in an improved response to carbon dioxide, and assisted ventilation was no longer needed. Oxygen and carbon dioxide tensions improved but were still slightly abnormal during sleep. There were no clinical side effects of treatment but one infant had slight pituitary suppression.     

Triosephosphate isomerase deficiency with elevated sweat chloride test: report of a case

A 15-month-old girl with severe hemolytic anemia and progressive respiratory failure is presented. She was well until the age of six months when she developed a pulmonary infection. During the next six months, she had frequent respiratory infections and her paleness became evident. At the age of 12 months, she was observed to have easy fatigability and muscle weakness, and she received her first blood transfusion. She was referred to our hospital at the age of 15 months. The physical examination revealed a malnourished girl with hypotonia, nystagmus, generalized muscle weakness and severe breathing difficulty requiring ventilatory support The hemoglobin (Hb) was 9.7 g/dl; hematocrit (Hct) 29%, mean corpuscular volume (MCV) 101 fl and reticulocyte count 15%. Peripheral blood smear revealed macrocytosis and stomatocytosis (30% of the red cells) and polychromasia. Sweat chloride test was 90 and 94 mEq/L on two separate occasions. The serum vitamin E level was 0.26 mg/dl (N: 0.44-0.68). She was found to be heterozygous for factor V Leiden mutation. Although malnutrition, low serum vitamin E and elevated sweat chloride test were suggestive of cystic fibrosis, this diagnosis failed to account for all the findings in the patient. A search for a red cell enzyme deficiency revealed that the red cell triosephosphate isomerase (TPI) activity was low. DNA analysis showed the 315 G-C (105 Glu-Asp) TPI mutation, thus confirming the diagnosis of TPI deficiency.     

Aminophylline reduces hypoxic ventilatory depression: possible role of adenosine

Newborn infants and animals typically exhibit a paradoxical ventilatory response to hypoxia. The depressive phase of the response has not been adequately explained. It has been suggested that hypoxia may cause the release of inhibitory neuromodulators which depress ventilation. We have postulated that the nucleoside, adenosine, may be involved because 1) it is rapidly released during hypoxia, 2) it depresses ventilation, and 3) theophylline, a competitive inhibitor, has successfully been used to treat apnea of prematurity. Herein we describe the effects of aminophylline on ventilation during hypoxia in the spontaneously breathing newborn piglet administered both rapidly after ventilatory depression has occurred (bolus) and before the onset of hypoxia (pretreatment). Ten percent oxygen breathing produced a typical biphasic ventilatory response. The decrease in minute ventilation was caused by a decrease in both tidal volume and respiratory frequency. The bolus administration of aminophylline reversed the depression in minute ventilation (p less than 0.001) by increasing tidal volume (p less than 0.002). Pretreatment with aminophylline decreased the amount of ventilatory depression (p less than 0.05) by preventing a decrease in respiratory frequency. We conclude that aminophylline, an adenosine antagonist, reduces the decrease in ventilation which occurs during hypoxia in the newborn. We speculate that adenosine may play a role in hypoxic ventilatory depression and respiratory control in the newborn.     

Hypercapnic and hypoxic ventilatory and cardiac responses in school-aged siblings of sudden infant death syndrome victims.

Siblings of sudden infant death syndrome (SIDS) victims have been shown to have abnormal ventilatory patterns and altered responses to respiratory stimuli during infancy. To evaluate whether these abnormalities persist, we studied ventilatory responses in 20 older SIDS siblings (9.8 +/- 0.9 (mean +/- SEM) years of age) and 20 control subjects (10.2 +/- 0.9 years of age). To evaluate hypercapnic ventilatory responses, we had subjects rebreathe 5% carbon dioxide and 95% oxygen until end-tidal carbon dioxide tension reached 65 mm Hg. Instantaneous minute ventilation, mean inspiratory flow, and respiratory rate were calculated breath by breath. Hypercapnic responses did not differ between SIDS siblings (2.08 +/- 0.14 L/min per mm Hg) and control subjects (1.90 +/- 0.10 L/min per mm Hg; not significant). To assess hypoxic ventilatory responses, we asked subjects to rebreathe 13% oxygen and 7% carbon dioxide, with the balance nitrogen, at mixed-venous end-tidal carbon dioxide tension, until arterial oxygen saturation by pulse oximetry fell to 75%. No differences in hypoxic ventilatory responses were found between the SIDS siblings (-1.39 +/- 0.15 L/min/% saturation) and the control subjects (-1.22 +/- 0.17 L/min/% saturation; not significant). The mean inspiratory flow, tidal volume, respiratory rate, and heart rate responses to hypercapnia and hypoxia were also similar in the two groups. We conclude that there is no difference in hypercapnic and hypoxic ventilatory and cardiac responses, as assessed by rebreathing techniques, between school-aged SIDS siblings and control subjects. We speculate that in SIDS siblings the control of breathing is immature during infancy and that they achieve maturity of control and resolution of breathing abnormalities with time.     

Behaviour and physiological responses during prone and supine sleep in early infancy

Accepted 23 December 1996
AIMS—To study the effect of prone and supine sleep on infant behaviour, peripheral skin temperature, and cardiorespiratory parameters to aid understanding of why prone sleeping is associated with an increased risk of sudden infant death syndrome.
METHODS—Of 33 enrolled infants, 32 were studied at 2.5 and 28 at 5 months of age. A computer aided multichannel system was used for polysomnographic recordings. Behaviour was charted separately.
RESULTS—Prone REM (active) sleep was associated with lower frequencies of short arousals, body movements and sighs, and a shorter duration of apnoeas than supine REM sleep at both ages. At 2.5months there were less frequent episodes of periodic breathing during prone sleep in non-REM (quiet) and REM sleep. Heart rate and peripheral skin temperature were higher in the prone position during both sleep states at both ages.
CONCLUSIONS—The observation of decreased variation in behaviour and respiratory pattern, increased heart rate, and increased peripheral skin temperature during prone compared with supine sleep may indicate that young infants are less able to maintain adequate respiratory and metabolic homoeostasis during prone sleep.