Defective reflex responses to impeded breathing during quiet sleep or anesthesia in thiamine-deficient kittens and puppies

Abstract

Our interest in the regulation of breathing during sleep, and its relation to neuropathology and thiamine deficiency, has developed from our studies of normal infants (Henderson-Smart and Read, 1978) and adult patients with sleep apnea syndromes (Hensley and Read, 1976; Coverdale et al., 1980). Our early work on normal breathing mechanisms suggested that infants might be more vulnerable to the development of asphyxia during active sleep. In active sleep, intercostal muscle activity is inhibited, with the following results: (1) the rib cage moves paradoxically, by deflating during the period of inspiration (Henderson-Smart and Read, 1976); (2) the lung volume and the O2 stores also decreased during periods of active sleep, thus predisposing to earlier and more severe hypoxia during any breathing disturbance (Henderson-Smart and Read, 1979); and (3) reflex augmentation of intercostal muscle activity no longer occurs when inspiration is obstructed (Henderson-Smart and Read, 1976). Animal studies supoort the concept of vulnerability in active sleep. Arousal responses to hypercapnia and hypoxia are depressed during rapid eye movement sleep (Phillipson et al., 1977, 1978), and the ventilatory response to hypercapnia is diminished. While in the adult dog the ventilatory response to hypoxia is sustained (Phillipson et al., 1978), both arousal and ventilatory responses to hypoxia may be depressed in young animals (Jeffery and Read, 1980). Our early work led naturally to an interest in the sudden infant death syndrome (SIDS), since these deaths seemed to be linked to sleep. Histological evidence at autopsy was consistent not only with an asphyxial mode of death, but also with preceding episodes of asphyxia (Naeye, 1973, 1974). Our interest in deranged thiamine neurochemistry and breathing defect arose by chance. When a child with severe sleep apnea presented as a result of an inherited disorder of thiamine neurochemistry, a literature review was undertaken (Read, 1978). This revealed similar case reports (Lonsdale and Mercer, 1972), and many remarkable epidemiological and clinical similarities between modern SIDS and historical accounts of sudden death syndromes: in 1908 sudden death of apparently thriving infants became a major problem in the Pacific island of Nauru when nutritional deficiency of thiamine developed in association with high intakes of carbohydrate (Bray, 1928); similar reports exist from Hong Kong (Fehily, 1944). The present studies were undertaken in animals to evaluate the effects of thiamine deficiency during early life on the neural control of breathing during sleep. Since it was known that thiamine deficiency in older subjects results in damage to long nerves, particularly those with high levels of neural activity (Novak and Victor, 1974; Victor, 1975), the study was designed to detect damage to vagally mediated respiratory reflexes. Vagal afferents from mechanoreceptors in the lungs play important roles not only in the generation of respiratory rhythm by brain-stem centers, but also in the reflex augmentation of respiratory muscle activity during impeded breathing (Callanan and Read, 1974).